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NAGANO China
University Hospital / Pediatrics
Assistant Professor

Researcher basic information

■ Research news
  • 03 Jul. 2020, Discovery of new disease-susceptibility gene for steroid-sensitive nephrotic syndrome
    Link to Kobe Univ. HP
■ Research Areas
  • Other / Other

Research activity information

■ Award
  • Feb. 2021 第55回日本小児腎臓病学会学術集会, 優秀演題奨励賞 臨床研究部門

  • Jun. 2019 Japanese Society of Nephrology, Excellent Presentation Award
    NAGANO China

  • Jun. 2018 Japanese Society for Pediatric Nephrology, Excellent Presentation Award
    NAGANO China

■ Paper
  • Yoshitaka Asagai, Yu Tanaka, Hiroaki Hanafusa, China Nagano, Tomoko Horinouchi, Shingo Ishimori, Hiroshi Kaito, Kazumoto Iijima, Kandai Nozu, Naoya Morisada
    BACKGROUND: The Spalt-like transcription factor 1 (SALL1) gene is essential for kidney development. Pathogenic SALL1 variants cause Townes-Brocks syndrome 1 (TBS1), which typically presents with imperforate anus, dysplastic ears, and digital anomalies. However, clinical features vary widely. Some patients present only with dysplastic ears and hearing loss (HL) or with congenital anomalies of the kidney and urinary tract (CAKUT), resembling branchio-oto-renal syndrome (BORS), a presentation referred to as Townes-Brocks branchio-oto-renal-like (TBS BOR-like) syndrome. In this study, we aimed to describe the clinical characteristics of patients with SALL1-related disorders in the Japanese population. METHODS: We analyzed phenotypes of a nationwide cohort comprising 1108 families with chronic kidney disease (CKD) or mild urinary anomalies, using genetic testing conducted from 2010 to 2024. RESULTS: We identified SALL1 variants in 14 families (20 individuals): seven frameshift, four nonsense, one missense, one exon 2 deletion, and one whole-gene deletion. Ten variants were novel. The median age at diagnosis was 16 years (male:female = 13:7). Dysplastic ears were observed in 45%, HL in 40%, digital anomalies in 40%, and anorectal malformations in 25%. Based on clinical features, eight individuals were diagnosed with TBS1, four with TBS BOR-like syndrome, and seven with non-syndromic CAKUT. One case lacked detailed clinical data. Most variants were truncating and located in exon 2. CONCLUSIONS: SALL1-related disorders exhibit broad phenotypic variability. Some cases present with atypical features overlapping with TBS BOR-like syndrome or isolated CAKUT, rather than with typical TBS1. These findings enhance the understanding and diagnosis of SALL1-related disorders.
    Nov. 2025, Pediatric nephrology (Berlin, Germany), 40(11) (11), 3407 - 3414, English, International magazine
    Scientific journal

  • China Nagano, Masafumi Matuso, Yuta Inoki, Yu Tanaka, Yuta Ichikawa, Chika Ueda, Hideaki Kitakado, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Kandai Nozu
    INTRODUCTION: WT1-related disorders are associated with WT1 gene variants. Recent advances in genetic medicine have led to a better understanding of the genotype-phenotype correlation in WT1-related diseases, particularly missense variants in exons 8 or 9 that lead to a wide range of severities. Exonic variants can lead to splicing abnormalities in rare diseases. No reports have investigated exonic variants in WT1 that cause aberrant splicing. We examined whether exonic variants in WT1 exon 8 or 9 cause splicing abnormalities and affect disease severity. METHODS: We selected nine rare missense variants in exon 8 or 9 in WT1 outside the DNA binding domain and C2H2 sites from the Human Gene Variant Database Professional that unexpectedly present severe phenotypes. We conducted functional splicing assays using hybrid minigenes for the nine variants containing exon 8 and 9 and surrounding sequences. Minigene vectors were transfected into cultured cells, and mRNA was analyzed. In silico analysis was performed. RESULTS: Splicing assays revealed that one of the nine variants caused aberrant splicing, with exon 8 skipping. One previously reported case with this variant showed particularly severe phenotype, progressing to kidney failure within 3 months. CONCLUSIONS: One WT1 variant in exon 8 or 9 disrupted the splice site, leading to aberrant splicing in vitro and potentially contributing to an unexpectedly severe phenotype for a missense variant outside the DNA binding domain and C2H2 sites. In vitro splicing assays may help clarify the genotype-phenotype correlation in WT1-related disorders, especially for variants outside canonical functional domains.
    Oct. 2025, Clinical and experimental nephrology, 29(10) (10), 1489 - 1495, English, Domestic magazine
    Scientific journal

  • Shingo Ishimori, Shinya Ishiko, Junya Fujimura, Asahi Yamamoto, Shuhei Aoyama, Yuka Kimura, Yuta Inoki, Atsushi Kondo, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, China Nagano, Kazumichi Fujioka, Masafumi Oka, Wataru Shimabukuro, Koichi Nakanishi, Kandai Nozu
    AIM: To examine the relationship between children with multicystic dysplastic kidney (MCDK) that persists or spontaneously regresses over time and local renin-angiotensin-aldosterone system (RAAS) activity in children. METHODS: We conducted a multicentre, cross-sectional study of patients who were diagnosed with unilateral MCDK or a solitary kidney. The controls were age- and sex-matched children who underwent evaluation for short stature without any clinical kidney symptoms. We evaluated urinary angiotensinogen (AGT) as a biomarker of local RAAS activity, which acts specifically within the kidneys and differs from systemic RAAS. RESULTS: We included 52 children who were divided into the following four groups: 11 children with residual MCDK (MCDK persisted), 11 with regressed MCDK (MCDK spontaneously regressed), 12 with a solitary kidney and 18 were controls. Hypertension was identified in six patients, all of whom were in the residual or regressed MCDK groups. The urinary AGT/creatinine ratio was significantly higher in children in the residual MCDK group than in those in the regressed MCDK, solitary and control groups (p = 0.02, p < 0.01, p < 0.01, respectively). A logistic regression model showed that the only significant independent factor for regression of MCDK was urinary AGT/creatinine (odds ratio: 16.0, p < 0.01). CONCLUSION: Our data suggest that local RAAS activation could be associated with persistence of MCDK, but causality cannot be inferred because of the cross-sectional study design. Whether RAAS activation in residual MCDK is involved in the pathogenesis of MCDK or AGT is secreted from the MCDK kidney itself remains unknown.
    Oct. 2025, Nephrology (Carlton, Vic.), 30(10) (10), e70132, English, International magazine
    Scientific journal

  • Yuta Ichikawa, Nana Sakakibara, Shuhei Aoyama, Yuka Kimura, Yuta Inoki, Yu Tanaka, Chika Ueda, Hideaki Kitakado, China Nagano, Tomohiko Yamamura, Shingo Ishimori, Yuko Shima, Hayaki Okamoto, Hideki Fujii, Hironobu Maruyama, Kazumoto Iijima, Kandai Nozu, Tomoko Horinouchi
    Abstract Background Increased serum anti-nephrin antibody titers and co-localization of nephrin and IgG in kidney tissues have been reported in minimal change disease (MCD) and post-transplant recurrent focal segmental glomerulosclerosis (FSGS). These results indicate an association of anti-nephrin antibodies with nephrotic syndrome (NS); however, the exact relationship remains unclear. Herein, we evaluated nephrin/IgG co-localization in the glomeruli of patients with various kidney diseases, including monogenic NS, to clarify the association between idiopathic nephrotic syndrome (INS) and anti-nephrin antibodies. Methods IgG and nephrin co-localization was investigated in 52 kidney tissue biopsy samples, comprising INS in the active phase ( n  = 26; MCD, n  = 19; FSGS, n  = 7) and remission ( n  = 6), monogenic NS ( n  = 3), and other kidney diseases ( n  = 17). Double-immunofluorescence staining for nephrin/IgG was performed in unfixed frozen sections for 2 h at room temperature with Alexa Fluor-labeled nephrin/IgG cocktail antibodies. Nephrin/IgG co-localization was assessed using optical sectioning under a fluorescence microscope. Results Nephrin/IgG co-localization was observed in 81% (21/26, children: 15/17, adults: 6/9) of active INS cases, 84% (16/19) of MCD cases, and 71% (5/7) of FSGS cases. No co-localization was observed in NS with monogenic variants or other kidney diseases. Conclusion Nephrin/IgG co-localization in the kidney tissue is finding observed in active INS , strongly indicating an association between anti-nephrin antibodies and INS onset. The nephrin/IgG cocktail antibody is a rapid and effective approach for investigating INS pathogenesis that facilitates the differential diagnosis of immune-mediated NS from other kidney diseases, including monogenic NS.
    Springer Science and Business Media LLC, Aug. 2025, Clinical and Experimental Nephrology, 29(12) (12), 1821 - 1828
    Scientific journal

  • Atsushi Kondo, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Yu Tanaka, Hideaki Kitakado, Chika Ueda, Nana Sakakibara, China Nagano, Kandai Nozu
    BACKGROUND: Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is caused by medication and lifestyle factors, leading to hypokalemia and potentially impairing kidney function. Treatment primarily involves eliminating the underlying causes, which typically results in rapid improvement. However, PBS/PGS findings may persist long after the removal of causative factors, and its pathogenesis remains unclear. METHODS: This study focused on 49 cases diagnosed with PBS/PGS. All cases presented with hypokalemia, attributed to apparent causes, and comprehensive genetic testing detected no pathogenic variants associated with hereditary kidney diseases. They were categorized into two groups: the current group (n = 39), where causative factors persisted, and the past group (n = 10), where more than 1 year had elapsed since the elimination of the causative factors at the time of examination. A retrospective comparative analysis was conducted between these groups. RESULTS: All patients were female, except for two in the current group. The median time since the elimination of causes in the past group was 7.5 years. Hypokalemia and kidney dysfunction were observed in both groups without statistically significant differences. Both groups exhibited overactivation of renin-angiotensin systems. CONCLUSION: This study is the first to reveal the possibility of persistent PBS/PGS findings even after the removal of causative factors. While swift removal of the cause of PBS/PGS is crucial, long-term post-removal monitoring is essential to improve renal prognosis.
    Jul. 2025, Clinical and experimental nephrology, English, Domestic magazine
    Scientific journal

  • Yuki Nakata, China Nagano, Yukihito Imagawa, Keisuke Shirai, Yu Masuda, Takumi Kido, Mariko Ashina, Kandai Nozu, Kazumichi Fujioka
    Background/Objectives: Pseudohypoaldosteronism type 1 (PHA-1) is a rare disorder characterized by aldosterone resistance, leading to hyponatremia, hyperkalemia, and elevated renin and aldosterone levels in neonates and infants. While genetic mutations in NR3C2 (mineralocorticoid receptor, MR) and SCNN1A/B/G (epithelial sodium channel, ENaC) are established causes of primary PHA-1, cases without detectable mutations have also been reported. This study aimed to compare the clinical characteristics of genetically confirmed PHA-1 cases-with or without mutations-and to assess genotype-phenotype correlations. Methods: A literature review was conducted using the Medline database, covering studies published from 1966 to October 2023. Included cases were diagnosed with PHA-1 and had undergone genetic testing for NR3C2 and SCNN1A/B/G. Clinical and biochemical data were compared across three groups: MR, ENaC, and non-mutation. Additional subgroup analysis based on mutation type (truncating vs. non-truncating) was also performed. Results: A total of 164 patients from 64 studies met the inclusion criteria. The ENaC group showed significantly higher serum potassium levels than the MR and non-mutation groups. Serum aldosterone levels were significantly higher in the MR group compared to the non-mutation group. A genotype-phenotype correlation was evident in the ENaC group, with truncating variants associated with more severe hyperkalemia. No such correlation was observed in the MR group. Conclusions: This review highlights distinct clinical features of PHA-1 according to genetic status. Aldosterone levels may aid in guiding decisions regarding genetic testing. Furthermore, variant type in ENaC-related PHA-1 may predict biochemical severity and should be considered in clinical management strategies.
    Jun. 2025, Journal of clinical medicine, 14(13) (13), English, International magazine
    Scientific journal

  • ADTKD-MUC1診断における免疫蛍光染色の有用性
    青砥 悠哉, 藤井 秀毅, 丸山 順裕, 長野 智那, 兵頭 俊紀, 森貞 直哉, 原 重雄, 野津 寛大
    (一社)日本腎臓学会, Jun. 2025, 日本腎臓学会誌, 67(4) (4), 467 - 467, Japanese

  • Haruka Nozaki, Nana Sakakibara, Hiroaki Hanafusa, Yuta Inoki, Yu Tanaka, Hideaki Kitakado, Chika Ueda, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Hiroshi Yamaguchi, Kandai Nozu, Naoya Morisada
    BACKGROUND: Cases of unexplained neurodevelopmental disorder (NDD) are often accompanied by multiple congenital anomalies. With recent advances in genetic analysis technology, whole-exome sequencing (WES) has become a powerful diagnostic tool for unexplained NDD patients, but variants of unknown significance are sometimes detected in them. METHODS: WES identified a variant in a 2-year-old boy with NDD associated with multiple congenital anomalies who had no abnormal findings in G-banding and array comparative genomic hybridization (array CGH). mRNA analysis was performed on the variant using the patient's peripheral blood leukocytes following in silico analysis to confirm its effect on splicing. RESULTS: WES revealed a novel homozygous single base substituting variant of unknown significance (VUS), which was carried heterozygously by the patient's parents (DCPS, NM_014026.6: c.200A>G, p.(Lys67Arg)). In silico analysis predicted that this variant may cause aberrant splicing, and mRNA analysis revealed a 48-bp deletion from the 3' end of exon 1. Biallelic variants of DCPS are known to cause Al-Raqad syndrome, a quite rare disorder which presents NDD with multiple malformations. This disease has been reported in only eight individuals from five Middle Eastern or Caucasian families but never in the Japanese but the symptoms of the present case were similar to reported cases of this syndrome. DISCUSSION: We successfully diagnosed a case of unexplained NDD as Al-Raqad syndrome by WES along with mRNA analysis. Single base substitution with judged VUS can be pathogenic by causing aberrant splicing and, therefore, in silico analysis and subsequent RNA sequence are necessary to prove its pathogenicity.
    May 2025, Brain & development, 47(4) (4), 104366 - 104366, English, International magazine
    Scientific journal

  • 青砥 悠哉, 長野 智那, 藤井 秀毅, 丸山 順裕, 兵頭 俊紀, 田中 悠, 上田 知佳, 北角 英晶, 榊原 菜々, 堀之内 智子, 山村 智彦, 石森 真吾, 森貞 直哉, 原 重雄, 野津 寛大
    (一社)日本小児腎臓病学会, May 2025, 日本小児腎臓病学会雑誌, 38(Suppl.) (Suppl.), 98 - 98, Japanese

  • Rini Rossanti, Eri Okada, Nana Sakakibara, Ryota Suzuki, Yuta Inoki, Yuta Ichikawa, Yu Tanaka, Hideaki Kitakado, Chika Ueda, Atsushi Kondo, Yuya Aoto, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Kandai Nozu
    INTRODUCTION: Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by oculocerebrorenal syndrome of Lowe (OCRL) abnormality. Previous genetic studies demonstrated that truncating variants in exons 1 to 7 results in Dent disease-2 and in exons 8 to 24, result in Lowe syndrome. Recently, we successfully identified a functional OCRL isoform, whose altered initiation codons (Met187 and Met206) in exon 8 can affect the OCRL-truncating variant phenotypes. However, the association between OCRL splicing variants and phenotypes is poorly understood. METHODS: We performed a detailed splicing pattern analysis of previously reported 28 OCRL splicing variants obtained from the Human Gene Mutation Database. We assessed the variant consequences at the mRNA level using an in vitro splicing assay with a minigene system, and examined their compatibility with in silico algorithms and correlation with disease phenotypes. RESULTS: Aberrant splicing was confirmed in all 27 variants, except for 1, in which splicing could not be experimentally confirmed in the minigene system, and therefore could not be concluded with certainty. Splicing variants in OCRL exons 1 to 7 resulted in Dent disease-2, and in exons 9 to 24 resulted in Lowe syndrome. In 1 case, c.561-2 A > G in exon 8 demonstrated Dent disease-2. CONCLUSION: This study provides significant data on the pathogenicity of OCRL splicing variants and genotype-phenotype correlations. In c.561-2 A > G, the latter altered initiation codon of the OCRL isoform (Met206) was preserved, potentially indicating the Dent disease-2 phenotype. This result supports our recent finding regarding the altered initiation codons in exon 8 of the OCRL isoform.
    May 2025, Kidney international reports, 10(5) (5), 1509 - 1517, English, International magazine
    Scientific journal

  • China Nagano, Naoya Morisada, Yuta Inoki, Yu Tanaka, Yuta Ichikawa, Chika Ueda, Hideaki Kitakado, Yuya Aoto, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Kandai Nozu
    BACKGROUND: Autosomal-dominant tubulointerstitial kidney disease caused by MUC1 (ADTKD-MUC1) is a rare disorder characterized by progressive kidney dysfunction. Pathogenic variants in MUC1 are difficult to detect owing to the variable number tandem repeat region. To address this issue, VNtyper-Kestrel, a bioinformatics pipeline for short-read sequencing data, was recently developed. In this study, the performance of VNtyper-Kestrel for detecting MUC1 variants in clinical settings was evaluated. METHODS: We used VNtyper-Kestrel to retrospectively analyze short-read sequencing data for 209 individuals with suspected ADTKD who were previously evaluated through long-read sequencing. Data from a panel including ~ 180 genes and an ADTKD-specific panel were used. In addition, the pipeline was applied to 976 patients with suspected hereditary kidney diseases other than ADTKD and positive cases were validated using long-read sequencing. Accuracy was assessed by comparisons with the results of long-read sequencing. RESULTS: Using VNtyper-Kestrel, we identified MUC1 variants in 16 of 19 confirmed cases of ADTKD-MUC1. Three initially negative cases were reanalyzed using the ADTKD-specific panel, yielding positive detection results with high confidence. We obtained two low-confidence positive results from 190 cases of suspected ADTKD and 10 low-confidence positive results among 976 non-ADTKD cases; however, all were classified as false positives upon long-read sequencing validation. CONCLUSIONS: VNtyper-Kestrel demonstrated high sensitivity in identifying MUC1 variants when sequencing coverage was adequate, supporting its potential as a rapid and cost-effective screening tool. However, confirmatory long-read sequencing is needed in uncertain cases. Optimizing coverage and refining patient selection criteria could improve the clinical utility of this approach.
    Apr. 2025, Clinical and experimental nephrology, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yu Tanaka, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, Shingo Ishimori, Tomohiko Yamamura, China Nagano, Kandai Nozu
    BACKGROUND: Isotonic fluids are becoming the standard for hydration and maintenance fluid therapy, but there is no consensus on the optional choice among the different types of isotonic solution. METHODS: This study is a single-center, non-randomized controlled trial at Kobe University Hospital, Japan, between April 2021 and March 2023. The study included pediatric patients aged 1-19 years who underwent kidney biopsies. From April 2021 to March 2022, 0.9% sodium chloride (saline) was administered, and from April 2022 to March 2023, balanced crystalloids were used. The primary outcome was the occurrence of hyponatremia (< 137 mEq/L) after a kidney biopsy. Secondary outcomes included other electrolyte balances, blood gas parameters, creatinine-based estimated glomerular filtration rate (Cr-eGFR), and arginine vasopressin concentrations (UMIN Clinical Trial Registry: UMIN 000044330). RESULTS: Of 61 patients enrolled, 2 were excluded, leaving 34 in the saline group and 25 in the balanced crystalloid group. No hyponatremia occurred, and serum sodium concentrations were similar between both groups (138.7 vs. 138.9 mEq/L, P = 0.08). The saline group showed a greater increase in serum chloride (+ 1.7 vs. + 0.2, P < 0.01) and a greater decrease in HCO3- concentrations (- 0.6 vs. + 0.9, P < 0.01). There were minimal changes in pH (- 0.01 vs. - 0.01, P = 0.99) and Cr-eGFR (- 1.5 vs. + 1.1 mL/min/1.73 m2, P = 0.96) in both groups. CONCLUSIONS: During pediatric kidney biopsy, both saline and balanced crystalloids were effective in preventing hyponatremia. Although saline infusion results in higher serum chloride concentrations and lower blood HCO3- concentrations than balanced crystalloids infusion, the clinical significance was minimal.
    Apr. 2025, Pediatric nephrology (Berlin, Germany), 40(4) (4), 1033 - 1040, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yuta Inoki, Tomoko Horinouchi, Shuhei Aoyama, Yuka Kimura, Yuta Ichikawa, Yu Tanaka, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, Koichi Kamei, Riku Hamada, Naoya Fujita, Yoshimitsu Gotoh, Yoshitsugu Kaku, Kei Nishiyama, Takayuki Okamoto, Yukiko Toya, Tomohiko Yamamura, Shingo Ishimori, China Nagano, Kandai Nozu
    BACKGROUND: More than half of patients with congenital nephrotic syndrome (CNS) or infantile nephrotic syndrome (infantile NS) have a monogenic aetiology. This study aimed to clarify differences in the clinical course, genetic background, and genotype-phenotype correlation between CNS and infantile NS. METHODS: We enrolled patients who were diagnosed with CNS or infantile NS and referred to our hospital for genetic analysis and investigated the clinical characteristics and genetic background of patients with identified causative genes. RESULTS: Among 74 patients enrolled, disease-causing genetic variants were detected in 50 patients. The median age for developing kidney failure in the genetic CNS (n = 33) and genetic infantile NS (n = 17) groups with monogenic variants was 13.2 and 19.0 months, respectively (P = 0.13). The age at developing kidney failure was significantly earlier in CNS patients with genes other than NPHS1 than in CNS patients with NPHS1 variants (1.0 vs. 31.0 months; P < 0.001). In patients with pathogenic variants other than NPHS1, there was a significant difference in the age at developing kidney failure between CNS and infantile NS patients (1.0 vs. 15.0 months; P < 0.001). Of patients with NPHS1 variants, no infants with NS had any truncating variants or developed kidney failure during follow-up. CONCLUSIONS: The onset of CNS or infantile NS affects the kidney prognosis in patients with genetic nephrotic syndrome. Among patients with pathogenic variants in the same gene, patients with infantile NS may have a milder genotype and better prognosis than those with CNS.
    Mar. 2025, Pediatric nephrology (Berlin, Germany), English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yu Tanaka, China Nagano, Nana Sakakibara, Eri Okada, Shuhei Aoyama, Yuka Kimura, Yuta Inoki, Yuta Ichikawa, Chika Ueda, Hideaki Kitakado, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Kazumoto Iijima, Kandai Nozu, Naoya Morisada
    BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by tubular atrophy, interstitial fibrosis, and progressive kidney dysfunction. Its causative genes include UMOD, MUC1, REN, HNF1B, and SEC61A1. ADTKD contributes to unexplained chronic kidney disease (CKD), and many cases remain genetically undiagnosed. This study aimed to elucidate the clinical features of patients genetically diagnosed with ADTKD in Japan. METHODS: We included individuals with suspected congenital anomalies of the kidney and urinary tract, nephronophthisis, polycystic kidney disease, or ADTKD. Genetic analyses using direct sequencing, short-read next-generation sequencing (SRS), and/or long-read next-generation sequencing (LRS) were performed on 1097 families. Patients with ADTKD-HNF1B were excluded due to prior reporting. RESULTS: Variants in UMOD, MUC1, REN, and SEC61A1 were identified in 52 patients from 40 families (18, 16, 5, and 1 family, respectively). The median age at diagnosis was 38.5 years, and the urinary protein-to-creatinine ratio was 0.05 g/gCr. End-stage kidney disease was present at diagnosis in 37% of patients. Genetic testing was performed in 58% due to suspected ADTKD based on pathology or clinical course and in 38% due to unexplained CKD. Kidney biopsies were performed in 55%, with ADTKD confirmed pathologically in 41%. SRS and LRS were used in 55% and 30% of all families, respectively; for ADTKD-MUC1, 75% of families were analyzed using LRS. CONCLUSIONS: Clinical and pathological diagnosis of ADTKD remains challenging, emphasizing the importance of comprehensive genetic testing. Enhanced access to advanced genetic testing such as LRS is essential to improve diagnostic precision and management.
    Feb. 2025, Clinical and experimental nephrology, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Takashi Uechi, Tomoko Horinouchi, Yuta Inoki, Yu Tanaka, Hideaki Kitakado, Chika Ueda, China Nagano, Masato Yamaguchi, Yoriko Tsuji, Kandai Nozu
    Systemic lupus erythematosus (SLE) can present with various symptoms, including rare manifestations such as gangrene. This report describes a 12-year-old girl with SLE who presented with intermittent claudication and gangrene. Although intermittent claudication is rare in paediatric cases, it is essential to consider vascular diseases including those associated with SLE as a potential cause. The patient initially experienced pain, redness, and cold sensations in the right great toe accompanied by intermittent claudication, with symptoms worsening over time. Diagnostic imaging, including contrast-enhanced CT and MRI, revealed occlusion of the right popliteal artery with associated vasculitis and thrombosis. The diagnosis of SLE and antiphospholipid syndrome was confirmed based on clinical criteria. Treatment included prednisone, methylprednisolone pulse therapy, mycophenolate mofetil, hydroxychloroquine, and anticoagulants. The patient showed significant improvement, with resolution of the claudication and effective management of her gangrene through immunosuppressive therapy and careful wound care. This case highlights the importance of considering vascular complications in paediatric SLE and underscores the need for early diagnosis and comprehensive treatment.
    Feb. 2025, Modern rheumatology case reports, English, International magazine
    Scientific journal

  • Hideaki Kitakado, Tomoko Horinouchi, Shuhei Aoyama, Yuka Kimura, Yuta Inoki, Yu Tanaka, Chika Ueda, Yuya Aoto, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Shingo Ishimori, Rini Rossanti, Masafumi Matsuo, Kandai Nozu
    INTRODUCTION: Alport syndrome (AS) is an inherited kidney disease caused by variants in the COL4A3, COL4A4, or COL4A5 genes, resulting in type IV collagen abnormalities. Although autosomal dominant variants in COL4A3 and COL4A4 are increasingly being diagnosed, X-linked AS (XLAS) caused by COL4A5 variants predominates. Single nucleotide substitutions in introns positioned at first and second from the last nucleotide (called a consensus sequence) of exons always cause aberrant splicing. However, whether intronic variants at the third to fifth positions from the last nucleotide of exons can cause aberrant splicing is unclear. METHODS: We identified 11 intronic variants positioned at the third, fourth, and fifth nucleotides from the exon 3' end in COL4A5 from our AS cohort (January 2006-July 2022). We conducted in vitro splicing assays using minigenes and in silico splicing analysis using commercial splicing prediction software and evaluated mRNA sequences obtained from patients' samples when available. RESULTS: All 11 patients showed aberrant splicing patterns in the minigene splicing assays. In vivo analysis of 6 patients corroborated these findings. The commercial splicing prediction software accurately predicted splicing changes in 10 variants. CONCLUSIONS: This study shows that 11 intronic variants at the third to fifth positions in COL4A5 introns cause aberrant splicing. This finding highlights the importance of evaluating such variants for the diagnosis and prognosis of XLAS. Further investigation is warranted to confirm the pathogenicity of these variants and their effect on the prognosis of the kidney in XLAS.
    Feb. 2025, Kidney international reports, 10(2) (2), 516 - 521, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Shingo Ishimori, Shinya Ishiko, Junya Fujimura, Shuhei Aoyama, Yuka Kimura, Hideaki Kitakado, Chika Ueda, Yuta Inoki, Yu Tanaka, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, China Nagano, Kandai Nozu
    BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in kidney development and the progression of chronic kidney disease (CKD). OBJECTIVES: To identify children with low birth weight (LBW) at risk of CKD who have RAAS activation. DESIGN: We conducted a prospective cohort study to evaluate whether a history of LBW contributes to the development of latent RAAS activation using urine samples from patients with short stature with no clinical kidney symptoms. Additionally, among children who had idiopathic nephrotic syndrome (INS), we examined how a history of LBW contributes to the development of latent RAAS activation using residual kidney biopsy samples. METHODS: We prospectively evaluated angiotensinogen (AGT) using spot urine in children with and without a history of LBW, who required evaluation for short stature without kidney symptoms at registration. We also performed immunohistochemical staining of AGT using kidney biopsy specimens of subjects with and without a history of LBW who had INS. Urinary AGT was assessed as a marker of intrarenal RAAS. RESULTS: In 45 children (median age 5 years), urinary AGT/creatinine (Cr) levels were significantly higher in children with a history of LBW (n = 24) than in those without (n = 21, median: 12.6 vs 6.7 µg/g･Cr, mean: 15.4 vs 9.1 µg/g･Cr, P < .01). The unadjusted mean difference between the 2 groups and the 95% confidence interval were 6.3 and (1.6, 11.1), respectively. In the immunohistochemical kidney pathological study, the positive area of AGT staining in the kidney tubules of 3 subjects with a history of LBW was more extensive than that of 3 additional subjects without a history of LBW. CONCLUSION: Our results indicated that latent intrarenal RAAS activation in children with a history of LBW persists until early school age and may contribute to the progression of CKD.
    2025, Biomarker insights, 20, 11772719251379198 - 11772719251379198, English, International magazine
    Scientific journal

  • 難治性ネフローゼ症候群として加療され,遺伝子検査によりLAMA5関連腎炎の診断に至った症例の10年の経過
    清水 翔一, 諸橋 環, 大島 正成, 中崎 公隆, 齋藤 宏, 北角 英晶, 長野 智那, 野津 寛大, 森岡 一朗
    (一社)日本小児腎臓病学会, 2025, 日本小児腎臓病学会雑誌, 38, 4 - 4, Japanese

  • China Nagano, Kandai Nozu
    The Wilms tumor 1 (WT1) gene was first identified in 1990 as a strong candidate for conferring a predisposition to Wilms tumor. The WT1 protein has four zinc finger structures (DNA binding domain) at the C-terminus, which bind to transcriptional regulatory sequences on DNA, and acts as a transcription factor. WT1 is expressed during kidney development and regulates differentiation, and is also expressed in glomerular epithelial cells after birth to maintain the structure of podocytes. WT1-related disorders are a group of conditions associated with an aberrant or absent copy of the WT1 gene. This group of conditions encompasses a wide phenotypic spectrum that includes Denys-Drash syndrome (DDS), Frasier syndrome (FS), Wilms-aniridia-genitourinary-mental retardation syndrome, and isolated manifestations of nephropathy or Wilms tumor. The genotype-phenotype correlation is becoming clearer: patients with missense variants in DNA binding sites including C2H2 sites manifest DDS and develop early-onset and rapidly developing end-stage kidney disease. A deeper understanding of the genotype-phenotype correlation has also been obtained in DDS, but no such correlation has been observed in FS. The incidence of Wilms tumor is higher in patients with DDS and exon-truncating variants than in those with non-truncating variants. Here, we briefly describe the genetic background of this highly complicated WT1-related disorders.
    Jan. 2025, Clinical and experimental nephrology, 29(1) (1), 1 - 9, English, Domestic magazine
    Scientific journal

  • Yuta Ichikawa, Nana Sakakibara, China Nagano, Yuta Inoki, Yu Tanaka, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Shingo Ishimori, Tomoko Horinouchi, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: In patients with steroid-resistant nephrotic syndrome (SRNS), the presence of monogenic variants influences therapeutic strategies. Large cohort studies reported the detection of monogenic variants in approximately 30% of patients with SRNS. However, these cohorts included many patients, such as those with symptomatic proteinuria, who did not meet the strict diagnostic criteria for pediatric nephrotic syndrome (NS). Therefore, we investigated the proportion of causative monogenic variants detected in patients who strictly met the diagnostic criteria of SRNS and explored their clinical characteristics. METHODS: We examined pediatric SRNS cases with genetic analysis conducted in our hospital. Cases satisfying all of the following criteria were included: (1) age at onset 1-18 years, (2) serum albumin at onset ≤ 2.5 g/dl, (3) persistent heavy proteinuria, and (4) no complete remission after 4 weeks of steroid monotherapy. RESULTS: The proportion of detected monogenic variants was 12% (22/185) among all patients. The proportion was only 7% (9/129) in patients with edema at disease onset compared with 38% (9/24) in those without (p < 0.0001). Monogenic variants were rare in patients with acute kidney injury associated with NS (1% (1/11)) or a history of complete remission (4% (2/51)). CONCLUSIONS: Our study revealed a monogenic cause in 12% of individuals with strictly defined SRNS, a much smaller proportion than previously reported. The presence or absence of edema at the onset was an important factor to distinguish SRNS with monogenic cause from SRNS without. Our results provide further evidence of the SRNS types attributable to monogenic causes.
    Dec. 2024, Pediatric nephrology (Berlin, Germany), 39(12) (12), 3497 - 3503, English, International magazine
    Scientific journal

  • Atsushi Kondo, Kunihiko Yoshiya, Nana Sakakibara, China Nagano, Tomoko Horinouchi, Kandai Nozu
    Pseudo-Bartter/Gitelman syndrome (PBS/PGS) is a disorder that presents with hypokalemia and metabolic alkalosis resembling Gitelman syndrome (GS) due to secondary factors, such as lifestyle and /or medicines. Notably, PBS/PGS is more likely to cause renal dysfunction than GS. We report the first case of PBS/PGS due to long-term laxative abuse leading to end-stage kidney disease (ESKD). The patient was a 49-year-old woman with a history of constipation since school, who had used excessive doses of laxatives on her own judgment for nine years at least from 22 years of age. Two years later, blood tests revealed hypokalemia (serum K 3.1 mEq/L), and nine years later, the patient's renal function began to deteriorate (Cr-eGFR 48.7 mL/min/1.73 m2). Since abuse of laxatives was suspected as the cause, it was changed to the proper dosage of laxatives. At 33 years, the patient developed acute kidney injury (AKI), due to a urinary tract infection, and required intensive treatment, including hemodialysis. Although the patient was eventually weaned off dialysis, the renal function did not recover to pre-AKI levels. In suspected GS, comprehensive genetic testing for renal disease-related genes was performed; however, no obvious pathogenic variants were identified. Thereafter, despite decreasing the laxative doses and potassium supplementation, her renal function continued to decline. At 49 years, the patient developed ESKD and was started on maintenance hemodialysis. PBS/PGS is a disease that can lead to ESKD. An early diagnosis of PBS/PGS is crucial to prevent renal function deterioration, and the underlying causes should be removed immediately.
    Oct. 2024, CEN case reports, 13(5) (5), 326 - 329, English, Domestic magazine
    Scientific journal

  • Yuta Inoki, Tomoko Horinouchi, Tomohiko Yamamura, Shingo Ishimori, Yuta Ichikawa, Yu Tanaka, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, China Nagano, Kandai Nozu
    KEY POINTS: Patients with both COL4A3 and COL4A4 variants exhibited poor renal prognosis compared with those with autosomal dominant Alport syndrome. The proportion of patients with digenic Alport syndrome was 1.7% among all patients with Alport syndrome. BACKGROUND: Digenic Alport syndrome could be associated with poor renal prognosis. However, the characteristics of patients with digenic Alport syndrome remain ambiguous. METHODS: We retrospectively investigated the clinical symptoms, pathological findings, genetic variants, and proportions of patients with digenic Alport syndrome. The ages at detection of proteinuria and development of ESKD were compared between patients with digenic Alport syndrome with disease-causing variants in COL4A3 and COL4A4 and those with autosomal dominant Alport syndrome (ADAS) previously analyzed by our group. RESULTS: Eighteen patients from nine families with digenic variants in COL4A3 and COL4A4 and four male and five female patients with digenic variants in COL4A5 and COL4A3 or COL4A4 were enrolled in this study. Next-generation sequencing revealed that the proportion of patients with digenic Alport syndrome was 1.7% among all patients with Alport syndrome. In patients with digenic variants in COL4A3 and COL4A4, the median ages at detection of proteinuria and ESKD were 10.0 and 57.0 years, respectively. Compared with the patients with ADAS, the age at detection of proteinuria tended to be earlier (10.0 versus 20.0 years; P = 0.073) and that at development of ESKD was significantly earlier (57.0 versus 72.0 years; P = 0.045) in patients with digenic Alport syndrome. CONCLUSIONS: Overall, patients with digenic Alport syndrome harboring COL4A3 and COL4A4 variants exhibited poor renal compared with the patients with ADAS. Therefore, timely identification of the two disease-causing variants is critical for the renal prognostic assessment and early treatment of patients with digenic Alport syndrome.
    Oct. 2024, Kidney360, 5(10) (10), 1510 - 1517, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Ryota Suzuki, Nana Sakakibara, Sae Murakami, Yuta Ichikawa, Hideaki Kitakado, Chika Ueda, Yu Tanaka, Eri Okada, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Shingo Ishimori, China Nagano, Tomohiko Yamamura, Tomoko Horinouchi, Takayuki Okamoto, Kandai Nozu
    BACKGROUND AND HYPOTHESIS: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. Female patients, however, show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. However, the factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort. METHODS: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leukocytes using the human androgen receptor assay method and analyzed two cohorts. In 74 adult female patients, we evaluated the correlation between kidney function (creatinine-estimated glomerular filtration rate [Cr-eGFR] optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis, and in 65 pediatric female patients, we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein-to-creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazard analysis. RESULTS: In adult female patients, XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate = -0.53, P = 0.004), whereas genotype was not (P = 0.892). In pediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria (hazard ratio [HR], 3.702; 95% confidence interval [CI], 1.681-8.150; P = 0.001 and HR, 1.043; 95% CI, 1.061-1.070; P = 0.001, respectively), whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = 0.20, P = 0.67, respectively). CONCLUSION: Genotype and XCI are factors associated with the severity in females with XLAS.
    Aug. 2024, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, English, International magazine
    [Refereed]
    Scientific journal

  • Mari Kurokawa, Manao Nishimura, Kei Nishiyama, Kentaro Matsuoka, China Nagano, Yoshitsugu Kaku
    A 6-year-old boy was diagnosed with chromosomal abnormalities (48,XYY, + 21[11]/46,XY[19]) at 4 months of age after a physical examination revealed an undescended testis and a dwarf penis. He also had mild renal dysfunction and severe proteinuria, and kidney biopsy at 2 years of age revealed focal segmental glomerulosclerosis. Genetic analysis to investigate suspected WT1 gene abnormalities revealed a novel variant in NM_024426.6:exon10:c.1506 T > A (p.(Asp502Glu)). His kidney function deteriorated rapidly, leading to the induction of peritoneal dialysis at 5 years of age. Although this variant had not been previously reported, bilateral nephrectomy was performed to prevent any progression of the tumor. Histopathology showed all the glomeruli observed within the observation area to be completely sclerotic, while also showing evidence of embryonal hyperplasia. This case was not a hot spot for Denys-Drash syndrome, but it had a similar phenotype and pathology that could have been derived from a WT1 gene abnormality.
    Jul. 2024, Pediatric nephrology (Berlin, Germany), 39(7) (7), 2083 - 2085, English, International magazine
    Scientific journal

  • 本邦のネフローゼ患者における抗ネフリン抗体の発現について
    長野 智那, 市川 裕太, 堀之内 智子, 藤井 秀毅, 飯島 一誠, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 568 - 568, Japanese

  • 原因除去後長期にわたり維持する偽性Gitelman症候群の検討
    近藤 淳, 猪野木 雄太, 市川 裕太, 田中 悠, 上田 知佳, 北角 英昌, 榊原 菜々, 長野 智那, 堀之内 智子, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 574 - 574, Japanese

  • Alport症候群患者の診断における3歳児検尿の役割の検討
    北角 英晶, 猪野木 雄太, 市川 裕太, 田中 悠, 上田 知佳, 近藤 淳, 榊原 菜々, 長野 智那, 堀之内 智子, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 576 - 576, Japanese

  • Digenic Alport syndromeの重症度に関する検討
    猪野木 雄太, 堀之内 智子, 田中 悠, 市川 裕太, 上田 知佳, 北角 英晶, 近藤 淳, 榊原 菜々, 長野 智那, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 576 - 576, Japanese

  • 腎生検時輸液における生理食塩水とリンゲル液の安全性の比較に関する検討
    田中 悠, 堀之内 智子, 猪野木 雄太, 市川 裕太, 上田 知佳, 北角 英晶, 近藤 淳, 榊原 菜々, 長野 智那, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 577 - 577, Japanese

  • ネフリン/IgGカクテル抗体を用いた小児特発性ネフローゼ症候群腎組織の抗ネフリン抗体検出とその有用性
    市川 裕太, 榊原 菜々, 猪野木 雄太, 田中 悠, 上田 知佳, 北角 英晶, 近藤 淳, 長野 智那, 堀之内 智子, 丸山 順裕, 飯島 一誠, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 579 - 579, Japanese

  • OCRL異常症の表現型は,phosphatidylinositol 4,5-bisphosphate 5-phosphatase活性と相関する
    鈴木 諒太, 榊原 菜々, 市川 裕太, 北角 英晶, 上田 知佳, 田中 悠, 岡田 絵里, 近藤 淳, 長野 智那, 堀之内 智子, 岡本 孝之, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 599 - 599, Japanese

  • 検尿異常により発見された蛋白尿症と単一遺伝子異常との関連
    榊原 菜々, 猪野木 雄太, 市川 裕太, 田中 悠, 北角 英晶, 上田 知佳, 近藤 淳, 長野 智那, 堀之内 智子, 野津 寛大
    (一社)日本腎臓学会, Jun. 2024, 日本腎臓学会誌, 66(4) (4), 676 - 676, Japanese

  • 青砥 悠哉, 藤井 秀毅, 丸山 順裕, 兵頭 俊紀, 市川 裕太, 田中 悠, 北角 英晶, 近藤 淳, 榊原 菜々, 長野 智那, 堀之内 智子, 森貞 直哉, 原 重雄, 野津 寛大
    (一社)日本小児腎臓病学会, May 2024, 日本小児腎臓病学会雑誌, 37(Suppl.) (Suppl.), 188 - 188, Japanese

  • Chika Ueda, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Yu Tanaka, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Junya Fujimura, Naohiro Kamiyoshi, Shingo Ishimori, Takeshi Ninchoji, Hiroshi Kaito, Yuko Shima, Kazumoto Iijima, Kandai Nozu, Norishige Yoshikawa
    BACKGROUND: Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. METHODS: In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. RESULTS: Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. CONCLUSIONS: Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.
    Apr. 2024, Pediatric nephrology (Berlin, Germany), English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yu Tanaka, Tomoko Horinouchi, Yuta Inoki, Yuta Ichikawa, Chika Ueda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, China Nagano, Yoshihiko Yano, Norishige Yoshikawa, Naoya Morisada, Kandai Nozu
    We present a case of nephronophthisis 13 that resulted from WDR19 variants. The patient, a nine-year-old Japanese boy, had detection of mild proteinuria during a school urine screening. Urinalysis revealed mild proteinuria without hematuria. Blood tests indicated pancytopenia, mild elevation of liver enzymes, and kidney dysfunction. Ultrasound examination disclosed hepatosplenomegaly. Abdominal computed tomography and bone marrow assessments ruled out malignant tumors. Subsequent kidney and liver biopsies suggested nephronophthisis and congenital hepatic fibrosis. Furthermore, comprehensive genetic analysis through next-generation sequencing revealed compound heterozygous variants in WDR19 (NM_025132.4), including the previously reported c.3533G > A, p.(Arg1178Gln), and c.3703G > A, p.(Glu1235Lys) variants, confirming the diagnosis of nephronophthisis 13. There is potential need for liver and kidney transplantation in patients with nephronophthisis and hepatic fibrosis. Early diagnosis is therefore crucial to mitigate delays in treating complications associated with kidney and hepatic insufficiency and to facilitate preparation of transplantation. To achieve early diagnosis of nephronophthisis, it is imperative to consider it as a differential diagnosis when extrarenal symptoms and kidney dysfunction coexist, particularly when mild proteinuria is observed through opportunistic urinalysis. Genetic testing is important because nephronophthisis manifests as diverse symptoms, necessitating an accurate diagnosis. Next-generation sequencing was shown to be invaluable for the genetic diagnosis of nephronophthisis, given the numerous identified causative genes.
    Apr. 2024, CEN case reports, English, Domestic magazine
    Scientific journal

  • 検尿を契機とし持続する蛋白尿を指摘された症例における単一遺伝子異常同定に関する検討
    榊原 菜々, 猪野木 雄太, 市川 裕太, 田中 悠, 北角 英晶, 上田 知佳, 近藤 淳, 長野 智那, 堀之内 智子, 野津 寛大
    (公社)日本小児科学会, Feb. 2024, 日本小児科学会雑誌, 128(2) (2), 205 - 205, Japanese

  • 腎生検時における生理食塩水とリンゲル液の安全性の比較に関する検討
    田中 悠, 堀之内 智子, 猪野木 雄太, 市川 裕太, 北角 英晶, 上田 知佳, 近藤 淳, 榊原 菜々, 長野 智那, 野津 寛大
    (公社)日本小児科学会, Feb. 2024, 日本小児科学会雑誌, 128(2) (2), 207 - 207, Japanese

  • Minigeneを用いたIn vitro splicing解析によるWT1遺伝子におけるIntron variantの病原性評価
    井上 誠也, 近藤 敦, 猪野木 雄太, 市川 裕太, 田中 悠, 上田 知佳, 北角 英晶, 榊原 菜々, 長野 智那, 堀之内 智子, 野津 寛大
    (公社)日本小児科学会, Feb. 2024, 日本小児科学会雑誌, 128(2) (2), 233 - 233, Japanese

  • 全エクソーム解析およびmRNA解析により診断に至ったAl-Raqad症候群の1例
    野崎 晴花, 榊原 菜々, 猪野木 雄太, 市川 裕太, 田中 悠, 北角 英晶, 上田 知佳, 近藤 淳, 長野 智那, 堀之内 智子, 森貞 直哉, 野津 寛大
    (公社)日本小児科学会, Feb. 2024, 日本小児科学会雑誌, 128(2) (2), 234 - 234, Japanese

  • Alport症候群患者の診断における3歳児検尿の役割に関する検討
    北角 英晶, 猪野木 雄太, 市川 裕太, 田中 悠, 上田 知佳, 近藤 淳, 青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 野津 寛大
    (公社)日本小児科学会, Feb. 2024, 日本小児科学会雑誌, 128(2) (2), 236 - 236, Japanese

  • 【腎臓学この1年の進歩】ネフリンとネフローゼ症候群
    飯島 一誠, 堀之内 智子, 長野 智那, 野津 寛大
    (一社)日本腎臓学会, Jan. 2024, 日本腎臓学会誌, 66(1) (1), 303 - 309, Japanese

  • 猪野木 雄太, 堀之内 智子, 田中 悠, 市川 裕太, 上田 知佳, 北角 英晶, 近藤 淳, 榊原 菜々, 長野 智那, 野津 寛大
    (一社)日本小児腎臓病学会, 2024, 日本小児腎臓病学会雑誌, 37, 92 - 93, Japanese

  • 花房 宏昭, 森貞 直哉, 長坂 美和子, 叶 明娟, 野口 裕子, 長野 智那, 野津 寛大, 粟野 宏之
    (一社)日本小児神経学会, Jul. 2023, 脳と発達, 55(4) (4), 279 - 282, English

  • 花房 宏昭, 森貞 直哉, 長坂 美和子, 叶 明娟, 野口 裕子, 長野 智那, 野津 寛大, 粟野 宏之
    (一社)日本小児神経学会, Jul. 2023, 脳と発達, 55(4) (4), 279 - 282, English

  • Ryota Suzuki, Nana Sakakibara, Yuta Ichikawa, Hideaki Kitakado, Chika Ueda, Yu Tanaka, Eri Okada, Atsushi Kondo, Shinya Ishiko, Shingo Ishimori, China Nagano, Tomohiko Yamamura, Tomoko Horinouchi, Takayuki Okamoto, Kandai Nozu
    Elsevier {BV}, Jul. 2023, Kidney International Reports, English
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Eri Okada, Tomoko Horinouchi, Tomohiko Yamamura, Yuya Aoto, Ryota Suzuki, Yuta Ichikawa, Yu Tanaka, Chika Masuda, Hideaki Kitakado, Atsushi Kondo, Nana Sakakibara, Shinya Ishiko, China Nagano, Shingo Ishimori, Joichi Usui, Kunihiro Yamagata, Masafumi Matsuo, Kandai Nozu
    BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by insufficient α-galactosidase A (GLA) activity resulting from variants in the GLA gene, which leads to glycosphingolipid accumulation and life-threatening, multi-organ complications. Approximately 50 variants have been reported that cause splicing abnormalities in GLA. Most were found within canonical splice sites, which are highly conserved GT and AG splice acceptor and donor dinucleotides, whereas one-third were located outside canonical splice sites, making it difficult to interpret their pathogenicity. In this study, we aimed to investigate the genetic pathogenicity of variants located in non-canonical splice sites within the GLA gene. METHODS: 13 variants, including four deep intronic variants, were selected from the Human Gene Variant Database Professional. We performed an in vitro splicing assay to identify splicing abnormalities in the variants. RESULTS: All candidate non-canonical splice site variants in GLA caused aberrant splicing. Additionally, all but one variant was protein-truncating. The four deep intronic variants generated abnormal transcripts, including a cryptic exon, as well as normal transcripts, with the proportion of each differing in a cell-specific manner. CONCLUSIONS: Validation of splicing effects using an in vitro splicing assay is useful for confirming pathogenicity and determining associations with clinical phenotypes.
    May 2023, Clinical and experimental nephrology, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Eri Okada, Naoya Morisada, Tomoko Horinouchi, Hideki Fujii, Takayuki Tsuji, Masayoshi Miura, Hideyuki Katori, Masashi Kitagawa, Kunio Morozumi, Takanobu Toriyama, Yuki Nakamura, Ryuta Nishikomori, Sadayuki Nagai, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Shingo Ishimori, Joichi Usui, Kunihiro Yamagata, Kazumoto Iijima, Toshiyuki Imasawa, Kandai Nozu
    [This corrects the article DOI: 10.1016/j.ekir.2021.12.037.].
    May 2023, Kidney international reports, 8(5) (5), 1127 - 1129, English, International magazine

  • Georgia Malakasioti, Daniela Iancu, Anastasiia Milovanova, Alexey Tsygin, Tomoko Horinouchi, China Nagano, Kandai Nozu, Koichi Kamei, Shuichiro Fujinaga, Kazumoto Iijima, Rajiv Sinha, Biswanath Basu, William Morello, Giovanni Montini, Aoife Waters, Olivia Boyer, Zeynep Yürük Yıldırım, Sibel Yel, İsmail Dursun, Hugh J McCarthy, Marina Vivarelli, Larisa Prikhodina, Martine T P Besouw, Eugene Yu-Hin Chan, Wenyan Huang, Markus J Kemper, Sebastian Loos, Chanel Prestidge, William Wong, Galia Zlatanova, Rasmus Ehren, Lutz T Weber, Hassib Chehade, Nakysa Hooman, Marcin Tkaczyk, Małgorzata Stańczyk, Michael Miligkos, Kjell Tullus
    While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.
    May 2023, Kidney international, 103(5) (5), 962 - 972, English, International magazine
    Scientific journal

  • Alexandra Barry, Michelle T McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A E van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs E Silva, Ruth J F Loos, Eimear E Kenny, Michiel F Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Cheong 2nd, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Dongwon Lee, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, Matthew G Sampson
    Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
    Apr. 2023, Nature communications, 14(1) (1), 2481 - 2481, English, International magazine
    Scientific journal

  • Katsuaki Kasahara, Yoshimitsu Gotoh, Yoshiyuki Kuroyanagi, China Nagano, Satoshi Yamakawa, Kazuki Tanaka, Asami Takeda, Osamu Uemura
    BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest initially using angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs) to treat Henoch-Schönlein purpura nephritis (HSPN). However, these guidelines might overlook the potential benefits of aggressive therapy. Therefore, we evaluated the efficacy of an HSPN protocol that primarily uses steroids and immunosuppressants, without ACE-Is or ARBs. METHODS: We determine treatment intensity based on International Study of Kidney Diseases in Children (ISKDC) grading. Fifty-one patients were treated with our protocol that primarily uses steroids and immunosuppressants. ACE-Is and ARBs were not used in the acute phase, including before renal biopsy. We evaluated the proteinuria disappearance rate, duration to proteinuria disappearance, and estimated glomerular filtration rate (eGFR) at the time of last observation and compared them to those in previous reports. RESULTS: Proteinuria disappeared in 49 patients (96%) within a median of 5 months. The median eGFR was 116.0 mL/min/1.73 m2 at the time of last observation. Six of 51 patients had acute kidney injury (eGFR<90 mL/min/1.73 m2) before treatment, but all recovered during the observation period (median 52 months). CONCLUSIONS: Our steroid- and immunosuppressant-based protocol without ACE-Is or ARBs in the acute phase of HSPN had almost equivalent efficacy to that in previous studies that used ACE-Is and/or ARBs with steroids and immunosuppressants.
    Apr. 2023, Minerva pediatrics, 75(2) (2), 201 - 209, English, International magazine
    Scientific journal

  • 近藤 淳, 長野 智那, 北角 英晶, 増田 知佳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 佐々木 聡, 飯島 一誠, 野津 寛大
    (一社)日本小児腎臓病学会, Nov. 2022, 日本小児腎臓病学会雑誌, 35(2) (2), 159 - 159, Japanese

  • Rini Rossanti, Tomoko Horinouchi, Nana Sakakibara, Tomohiko Yamamura, China Nagano, Shinya Ishiko, Yuya Aoto, Atsushi Kondo, Sadayuki Nagai, Hiroyuki Awano, Hiroaki Nagase, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    Gitelman syndrome (GS) is a rare, autosomal recessive, salt-losing tubulopathy caused by loss of function in the SLC12A3 gene (NM_000339.2), which encodes the natrium chloride cotransporter. The detection of homozygous or compound heterozygous SLC12A3 variants is expected in GS, but 18%-40% of patients with clinical GS carry only one mutant allele. Previous reports identified some pathogenic deep intronic variants in SLC12A3. Here, we report the screening of SLC12A3 deep intronic variants in 13 patients with suspected GS carrying one mutated SLC12A3 allele. Variant screening used the HaloPlex Target Enrichment System Kit capturing whole introns and the promotor region of SLC12A3, followed by SureCall variant analysis. Rare intronic variants (<1% frequency) were identified, and pathogenicity evaluated by the minigene system. Deep intronic variant screening detected seven rare SLC12A3 variants from six patients. Only one variant showed pathogenicity in the minigene system (c.602-16G>A, intron 4) through activation of a cryptic acceptor site. No variants were detected in the promotor region. Deep intronic screening identified only one pathogenic variant in patients with suspected GS carrying monoallelic SLC12A3 variants. Our results suggest that deep intronic variants partially explain the cause of monoallelic variants in patients with GS.
    Sep. 2022, American journal of medical genetics. Part A, 188(9) (9), 2576 - 2583, English, International magazine
    Scientific journal

  • 近藤 淳, 堀之内 智子, 山村 智彦, 増田 知佳, 北角 英昌, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 吉川 徳茂, 野津 寛大
    日本小児腎不全学会, Aug. 2022, 日本小児腎不全学会雑誌, 42, 97 - 100, Japanese

  • 早期の遺伝学的検査が治療方針選択に有用であったステロイド抵抗性ネフローゼ症候群の1例
    近藤 淳, 堀之内 智子, 山村 智彦, 増田 知佳, 北角 英昌, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 吉川 徳茂, 野津 寛大
    日本小児腎不全学会, Aug. 2022, 日本小児腎不全学会雑誌, 42, 97 - 100, Japanese

  • 【ポドサイトパチー】ポドサイト疾患の遺伝学的要因 遺伝性ポドサイト疾患とそのリスク因子
    青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 野津 寛大
    (有)科学評論社, Jun. 2022, 腎臓内科, 15(6) (6), 633 - 643, Japanese

  • Yuya Aoto, Takeshi Ninchoji, Hiroshi Kaito, Yuko Shima, Junya Fujimura, Naohiro Kamiyoshi, Shingo Ishimori, Koichi Nakanishi, Shogo Minamikawa, Shinya Ishiko, Nana Sakakibara, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Sadayuki Nagai, Atsushi Kondo, Yosuke Inaguma, Ryojiro Tanaka, Norishige Yoshikawa, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Patients with immunoglobulin A nephropathy who present with focal mesangial proliferation (focal IgAN) can have a relatively good prognosis, and renin-angiotensin system inhibitor (RAS-i) is commonly used as the initial treatment. However, there are some complicated focal IgAN cases with resistance to RAS-i treatment or nephrotic-range proteinuria. Thus, combination therapy including corticosteroids is often used. This study aimed to evaluate the efficacy of combination therapy for complicated focal IgAN cases by comparing to diffuse mesangial proliferation (diffuse IgAN). METHODS: We conducted a multicenter retrospective study on 88 children who received 2-year combination therapy. The participants were classified based on pathological severity: focal IgAN (n = 26) and diffuse IgAN (n = 62). RESULTS: In total, 26 patients with focal IgAN and 52 with diffuse IgAN achieved proteinuria disappearance within 2 years (100 vs. 83.9%, P = 0.03). Moreover, the time to proteinuria disappearance was significantly shorter in the focal IgAN group than in the diffuse IgAN group (2.9 vs. 4.2 months, P < 0.01) and all patients with focal IgAN achieved proteinuria disappearance within 8 months. At the last observation (8.6 vs. 10.4 years, P = 0.13), only patients with diffuse IgAN (n = 12) had greater than stage 2 chronic kidney disease. In terms of irreversible adverse events, one patient exhibited cataracts. CONCLUSION: Combination therapy was significantly effective in patients with complicated focal IgAN. Moreover, the long-term prognosis was good, and the duration of combination therapy for complicated focal IgAN can be decreased to reduce adverse events.
    Jun. 2022, Clinical and experimental nephrology, 26(6) (6), 561 - 570, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • China Nagano, Shigeo Hara, Norishige Yoshikawa, Asami Takeda, Yoshimitsu Gotoh, Riku Hamada, Kentaro Matsuoka, Masaki Yamamoto, Shuichiro Fujinaga, Koji Sakuraya, Koichi Kamei, Yuko Hamasaki, Hideyo Oguchi, Yoshinori Araki, Yayoi Ogawa, Takayuki Okamoto, Shuichi Ito, Seiji Tanaka, Hiroshi Kaito, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Hiroaki Nagase, Kazumoto Iijima, K, ai Nozu
    Background: Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histological variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. Methods: This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathological findings were obtained from referring clinicians. We analyzed the associations of histological variants with clinical characteristics, kidney survival, and gene variant detection rates. Results: The distribution of histological variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end-stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), andACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; p<0.001). Conclusions: We revealed the distributions of histological variants of genetic FSGS and non-genetic FSGS in a large patient population. Detailed data concerning gene variants and pathological findings are important for understanding the etiology of FSGS.
    American Society of Nephrology ({ASN}), May 2022, Kidney360, 3(8) (8), 1384 - 1393, English, International magazine
    [Refereed]
    Scientific journal

  • Akiko Hayakawa-Iwamoto, Daisuke Aotani, Yuki Shimizu, Shota Kakoi, Chie Hasegawa, Shunsuke Itoh, Asami Fujii, Katsushi Takeda, Takashi Yagi, Hiroyuki Koyama, Kenro Imaeda, Kandai Nozu, China Nagano, Hiromi Kataoka, Tomohiro Tanaka
    A 34-year-old man visited our Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss. His plasma glucose level was 32.8 mmol/L and serum levels of ketone bodies were increased, but with metabolic alkalemia. He was also suffering from renal tubular hypomagnesemia and hypokalemia. Abdominal computed tomography showed bilateral renal cysts. These findings were suggestive of maturity-onset diabetes of the young type 5. Genetic testing showed heterozygous hepatocyte nuclear factor 1 beta gene deletion. In the present case, it seemed reasonable to view hepatocyte nuclear factor 1 beta gene deletion as the common cause of maturity-onset diabetes of the young type 5-associated diabetic ketoacidosis and tubular malfunction-induced hypokalemic alkalosis. This case exemplifies the importance of hepatocyte nuclear factor 1 beta gene abnormality as a potential cause of diabetic ketoacidosis with alkalemia.
    May 2022, Journal of diabetes investigation, 13(5) (5), 923 - 926, English, Domestic magazine

  • 近藤 淳, 長野 智那, 北角 英晶, 増田 知佳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 佐々木 聡, 飯島 一誠, 野津 寛大
    (一社)日本小児腎臓病学会, Apr. 2022, 日本小児腎臓病学会雑誌, 35(1Suppl.) (1Suppl.), 105 - 105, Japanese

  • Eri Okada, Naoya Morisada, Tomoko Horinouchi, Hideki Fujii, Takayuki Tsuji, Masayoshi Miura, Hideyuki Katori, Masashi Kitagawa, Kunio Morozumi, Takanobu Toriyama, Yuki Nakamura, Ryuta Nishikomori, Sadayuki Nagai, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Shingo Ishimori, Joichi Usui, Kunihiro Yamagata, Kazumoto Iijima, Toshiyuki Imasawa, Kandai Nozu
    Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD)-MUC1 is predominantly caused by frameshift mutations owing to a single-base insertion into the variable number tandem repeat (VNTR) region in MUC1. Because of the complexity of the variant hotspot, identification using short-read sequencers (SRSs) is challenging. Although recent studies have revealed the usefulness of long-read sequencers (LRSs), the prevalence of MUC1 variants in patients with clinically suspected ADTKD remains unknown. We aimed to clarify this prevalence and the genetic characteristics and clinical manifestations of ADTKD-MUC1 in a Japanese population using an SRS and an LRS. Methods: From January 2015 to December 2019, genetic analysis was performed using an SRS in 48 patients with clinically suspected ADTKD. Additional analyses were conducted using an LRS in patients with negative SRS results. Results: Short-read sequencing results revealed MUC1 variants in 1 patient harboring a cytosine insertion in the second repeat unit of the VNTR region; however, deeper VNTR regions could not be read by the SRS. Therefore, we conducted long-read sequencing analysis of 39 cases and detected MUC1 VNTR variants in 8 patients (in total, 9 patients from unrelated families). With the inclusion of family-affected patients (n = 31), the median age at the development of end-stage kidney disease (ESKD) was 45 years (95% CI: 40-40 years). Conclusion: In Japan, the detection rate of MUC1 variants in patients with clinically suspected ADTKD was 18.8%. More than 20% of patients with negative SRS results had MUC1 variants detected by an LRS.
    Apr. 2022, Kidney international reports, 7(4) (4), 857 - 866, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Rini Rossanti, Tomoko Horinouchi, Tomohiko Yamamura, China Nagano, Nana Sakakibara, Shinya Ishiko, Yuya Aoto, Atsushi Kondo, Sadayuki Nagai, Eri Okada, Shingo Ishimori, Hiroaki Nagase, Satoshi Matsui, Keiichi Tamagaki, Yoshifumi Ubara, Masahiko Nagahama, Yuko Shima, Koichi Nakanishi, Takeshi Ninchoji, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    Background: Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in COL4A3 and COL4A4 have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified. Methods: We conducted in silico splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed in vitro splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome (COL4A3 [c.693G>A (p.Val231=)] and COL4A4 [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)]). Results: Both in vivo and in vitro splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in COL4A4). Prediction analysis of wild-type and mutated COL4A4 sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, e.g., in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing. Conclusions: This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome.
    Mar. 2022, Kidney360, 3(3) (3), 497 - 505, English, International magazine
    Scientific journal

  • 肉眼的血尿をきたした膜性増殖性糸球体腎炎(MPGN)(C3腎症)の1例
    邱 智前, 忍頂寺 毅史, 永井 貞之, 近藤 淳, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 山村 智彦, 堀之内 智子, 平嶋 良章, 貫名 貞之, 吉川 徳茂, 野津 寛大, 飯島 一誠
    (公社)日本小児科学会, Mar. 2022, 日本小児科学会雑誌, 126(3) (3), 545 - 546, Japanese

  • Kojima-Ishii Kanako, Nana Sakakibara, Kei Murayama, Koji Nagatani, Satoshi Murata, Akira Otake, Yasutoshi Koga, Hisato Suzuki, Tomoko Uehara, Kenjiro Kosaki, Koh-Ichiro Yoshiura, Hiroyuki Mishima, Yuko Ichimiya, Yuichi Mushimoto, Tomoko Horinouchi, China Nagano, Tomohiko Yamamura, Kazumoto Iijima, Kandai Nozu
    Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.
    Mar. 2022, Journal of human genetics, 67(3) (3), 143 - 148, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Nana Sakakibara, Kandai Nozu, Tomohiko Yamamura, Tomoko Horinouchi, China Nagano, Ming Juan Ye, Shinya Ishiko, Yuya Aoto, Rini Rossanti, Riku Hamada, Nobuhiko Okamoto, Yuko Shima, Koichi Nakanishi, Masafumi Matsuo, Kazumoto Iijima, Naoya Morisada
    Nephronophthisis is an autosomal-recessive kidney disease that is caused by abnormalities in primary cilia. Nephronophthisis-related ciliopathies (NPHP-RCs) are a common cause of end-stage kidney disease (ESKD) in children and adolescents. NPHP-RCs are often accompanied by extrarenal manifestations, including intellectual disability, retinitis pigmentosa, or polydactyly. Although more than 100 causative genes have been identified, its diagnosis is difficult because the clinical features of each mutation often overlap. From September 2010 to August 2021, we performed genetic analysis, including next-generation sequencing (NGS), in 574 probands with kidney dysfunction and retrospectively studied cases genetically diagnosed with NPHP-RCs. RESULTS: We detected mutations related to NPHP-RCs in 93 patients from 83 families. Members of 60 families were diagnosed using NGS, and the mutations and the corresponding number of families are as follows: NPHP1 (24), NPHP3 (10), OFD1 (7), WDR35 (5), SDCCAG8 (4), BBS10 (3), TMEM67 (3), WDR19 (3), BBS1 (2), BBS2 (2), IFT122 (2), IFT140 (2), IQCB1 (2), MKKS (2), SCLT1 (2), TTC21B (2), ALMS1 (1), ANKS6 (1), BBS4 (1), BBS12 (1), CC2D2A (1), DYNC2H1 (1), IFT172 (1), and MAPKBP1 (1). A total of 39 cases (41.9%) progressed to ESKD at the time of genetic analysis, whereas 58 cases (62.3%) showed extrarenal manifestations, the most common being developmental delay, intellectual disability, and autism spectrum disorder in 44 patients. Comprehensive genetic analysis using NGS is useful for diagnosing patients with NPHP-RCs.
    Feb. 2022, Journal of human genetics, 67(7) (7), 427 - 440, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Miki Murakoshi, Koichi Kamei, Masao Ogura, Mai Sato, Taishi Nada, Ryutaro Suzuki, Chikako Kamae, Kentaro Nishi, Toru Kanamori, China Nagano, Kandai Nozu, Koichi Nakanishi, Kazumoto Iijima
    BACKGROUND: The management of congenital nephrotic syndrome of the Finnish type (CNF) is challenging. It is difficult to withdraw intravenous albumin infusions, resulting in long-term hospitalization. In addition, fatal hypotension after bilateral nephrectomy has been reported. In our center, we have performed unilateral nephrectomy during early infancy. METHODS: Infants diagnosed with CNF between 2011 and 2020 in our institution were enrolled. We examined the clinical course before and after unilateral nephrectomy and evaluated the effectiveness of this strategy. RESULTS: Seven patients (all showing NPHS1 mutations) were enrolled. All required daily intravenous albumin infusion via central venous catheter (CVC). Unilateral nephrectomy was performed at a median of 76 days of age (59-208 days). Surgical complications did not occur in any of patients. The mean albumin dose was decreased after unilateral nephrectomy (2.0 vs 0.4 g/kg/day; p = 0.02). Intravenous albumin infusion could be withdrawn at a median of 17 days, the CVC removed at a median of 21 days, and they discharged at a median of 82 days after unilateral nephrectomy. Although bacterial infections were noted seven times before unilateral nephrectomy, only one episode occurred after surgery. Four patients initiated peritoneal dialysis at two to three years of age and all of them underwent kidney transplantation thereafter. CONCLUSIONS: Unilateral nephrectomy during early infancy may be an effective treatment allowing for withdrawal from albumin infusion, prevention of complications, withdrawal from CVCs and shortening hospital stay for patients with CNF.
    Feb. 2022, Clinical and experimental nephrology, 26(2) (2), 162 - 169, English, Domestic magazine
    Scientific journal

  • Megumi Nagai-Sangawa, Atsushi Fukunaga, Chihiro Takeuchi, Satoshi Nishiyama, Tatsuya Horikawa, China Nagano, Kandai Nozu, Hideki Fujii, Chikako Nishigori
    Fabry disease (FD), which is a lysosomal storage disease resulting from a deficiency of α-galactosidase A, leads to the accumulation of globotriaosylceramide in various tissues and multiorgan impairment. Early diagnosis is important to improve long-term prognosis. Early clinical manifestations of FD include neuropathic pain, vascular skin lesions, and sweating abnormalities. Hypohidorosis is one of the clinical findings in the early stage of FD. However, there have been no studies on prospective screening of FD in patients with definitive diagnosis of hypohidrosis. We examined α-galactosidase A activity in white blood cells in 17 (one female and 16 male) patients with generalized hypohidorosis. Among 17 patients, one male patient (approximately 5.8%) had significantly reduced α-galactosidase A activity. He presented with a history of hypohidrosis with heat intolerance and neuropathic tingling pain in a warm environment from 6 years ago. He had a few angiokeratoma on the trunk and extremities. Ultrastructural examination of skin biopsy from the angiokeratoma revealed lamellar inclusions in endothelial cells. Kidney biopsy revealed swollen podocytes and Gb3 deposition in the glomerulus, and urinalysis revealed mulberry bodies. He was finally diagnosed with FD and started on enzyme replacement therapy with agalsidase alpha in the early stage. In addition, his family screening led to find the patients of four additional FD. Screening for FD in patients with hypohidrosis may lead to efficient early detection of FD.
    Feb. 2022, The Journal of dermatology, 49(2) (2), 308 - 312, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Shinya Ishiko, Naoya Morisada, Atsushi Kondo, Sadayuki Nagai, Yuya Aoto, Eri Okada, Rini Rossanti, Nana Sakakibara, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Takeshi Ninchoji, Hiroshi Kaito, Riku Hamada, Yuko Shima, Koichi Nakanishi, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population. METHODS: We conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes. RESULTS: PKHD1 pathogenic variants were identified in 32 patients (0-46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1-2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities. CONCLUSION: Clinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.
    Feb. 2022, Clinical and experimental nephrology, 26(2) (2), 140 - 153, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Sadayuki Nagai, Tomoko Horinouchi, Takeshi Ninchoji, Atsushi Kondo, Yuya Aoto, Shinya Ishiko, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Hiroshi Kaito, Ryojiro Tanaka, Yuko Shima, Junya Fujimura, Naohiro Kamiyoshi, Shingo Ishimori, Koichi Nakanishi, Norishige Yoshikawa, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Cases of Henoch-Schönlein purpura nephritis (HSPN) with moderate severity were demonstrated to achieve good prognosis after treatment with renin-angiotensin system (RAS) inhibitors. However, some patients required additional treatment for recurrence after remission. This study aimed to clarify the effect of RAS inhibitors in HSPN cases with moderate severity, including the proportion of cases with recurrence and their response to additional treatment. METHODS: Among 126 patients diagnosed with HSPN between 1996 and 2019, 71 patients with clinicopathologically diagnosed HSPN of moderate severity, defined as ISKDC grade II-IIIa and serum albumin ≥ 2.5 g/dL, were investigated. RESULTS: Proteinuria became negative after RAS inhibitor treatment alone in all 71 cases. However, 16 (22.5%) had recurrence. Eleven recurrent cases achieved negative proteinuria again following additional treatment. At the last follow-up (median 46.5 months; IQR, 23.2-98.2), 5 patients had persistent mild proteinuria; no patients had estimated glomerular filtration rate < 90 mL/min/1.73 m2. The pathological findings in all recurrent cases were ISKDC grade IIIa. The 16 recurrent cases had significantly higher proportions of glomeruli with global/segmental sclerosis (25.0 vs. 0%, P < 0.001) and tubular atrophy/interstitial fibrosis (37.5 vs. 12.7%, P =0.0 24) than 55 cases without recurrence. CONCLUSIONS: Japanese childhood HSPN cases with moderate severity had good outcomes without need for corticosteroids or immunosuppressants, when prescribed RAS inhibitor treatment. Even in recurrent cases, abnormal proteinuria was transient, and prognosis was excellent. A higher resolution version of the Graphical abstract is available as Supplementary information.
    Jan. 2022, Pediatric nephrology (Berlin, Germany), 37(8) (8), 1845 - 1853, English, International magazine
    Scientific journal

  • Hiroshi Yamaguchi, Kandai Nozu, Shinya Ishiko, Hiroaki Nagase, Takeshi Ninchoji, China Nagano, Hiroki Takeda, Ai Unzaki, Kazuto Ishibashi, Ichiro Morioka, Kazumoto Iijima, Akihito Ishida
    INTRODUCTION: Previous studies reported a dramatic decline in the incidence of varicella and varicella-related deaths after implementing universal varicella vaccination (VarV). Although previous studies reported the effectiveness and economic impact of VarV, they were unknown in the emergency department (ED) setting. METHODS: To determine the effectiveness and economic impact of VarV in the ED, Kobe, Japan, we retrospectively reviewed the clinical database of consecutive patients younger than 16 years presenting to our primary ED from 2011 to 2019. RESULTS: Of the 265,191 children presenting to our ED, 3,092 patients were clinically diagnosed with varicella. The number of patients with varicella was approximately 500 annually, before introducing the universal two-dose VarV for children aged 1 to <3 years in October 2014, in the Japanese national immunization program, and decreased to approximately 200 in 2019. The number of patients with varicella younger than 1 year (ineligible for the vaccination) also decreased. Regarding the economic impact, the medical cost in our ED reduced after the introduction of VarV was JPY 4.1 million (US$ 40,049) annually. From the central data, approximately 95% of children were vaccinated after October 2014; however, a relatively large percentage of infected unvaccinated children (59.0%) presented to ED in this study. After the implementation of the universal VarV, infection was mainly observed in older children (i.e., the unvaccinated generation). CONCLUSIONS: Our data showed the effectiveness and economic impact of VarV in the ED setting. Additionally, our data suggested that the public vaccination program should include older unvaccinated children and other unvaccinated individuals.
    Jan. 2022, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 28(1) (1), 35 - 40, English, International magazine
    Scientific journal

  • 堀之内 智子, 山村 智彦, 永井 貞之, 近藤 淳, 青砥 悠哉, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 飯島 一誠, 野津 寛大
    (一社)日本小児腎臓病学会, Nov. 2021, 日本小児腎臓病学会雑誌, 34(2) (2), 177 - 177, Japanese

  • 近藤 淳, 堀之内 智子, 山村 智彦, 永井 貞之, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 野津 寛大, 吉川 徳茂, 飯島 一誠
    (一社)日本小児腎臓病学会, Nov. 2021, 日本小児腎臓病学会雑誌, 34(2) (2), 204 - 205, Japanese

  • 近藤 淳, 堀之内 智子, 山村 智彦, 永井 貞之, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 野津 寛大, 吉川 徳茂, 飯島 一誠
    (一社)日本小児腎臓病学会, Nov. 2021, 日本小児腎臓病学会雑誌, 34(2) (2), 204 - 205, Japanese

  • Hiroshi Yamaguchi, Kandai Nozu, Shinya Ishiko, Atsushi Kondo, Takeshi Ninchoji, China Nagano, Hiroki Takeda, Ai Unzaki, Kazuto Ishibashi, Ichiro Morioka, Hiroaki Nagase, Kazumoto Iijima, Akihito Ishida
    The coronavirus disease (COVID-19) pandemic altered environmental factors. We studied the impact of these changes on asthma exacerbation (AE) by comparing the AE-related environmental factors between COVID-19 (2020) and pre-COVID-19 (2011-2019) eras. Between 2011 and 2020, 278,465 children (<16 years old) visited our emergency department, and 7476 were diagnosed with AE. The number of patients showed spring and fall peaks in 2011-2019. Multivariate analyses showed significant positive relationships of the number of AE patients with the average temperature among all patients and 0-5-year-olds and with sulfur dioxide (SO2) levels in 2011-2019 among 0-5-year-olds. Although the spring peak in the number of patients was not observed in 2020 after declaration of a state of emergency, the fall peak was again observed after the state of emergency was lifted. No changes in average temperature were detected, but SO2 was significantly reduced following declaration of the state of emergency in 2020. Therefore, SO2 reduction might have contributed to the disappearance of the peak of AE. However, a fall peak was observed again in 2020, although SO2 levels continued to be low. These data suggest that person to person interaction seems to be associated with AE, presumably due to unknown viral infections.
    Oct. 2021, International journal of environmental research and public health, 18(21) (21), English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yukimasa Taniguchi, China Nagano, Kiyotoshi Sekiguchi, Atsushi Tashiro, Noriko Sugawara, Haruhide Sakaguchi, Chisato Umeda, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Atsushi Kondo, Sadayuki Nagai, Hiroaki Nagase, Kazumoto Iijima, Jeffrey H. Miner, Kandai Nozu
    Background: Pathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only 7 patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome and one SRNS case with biallelic LAMA5 missense variants. Methods: We conducted comprehensive gene screening of Japanese patients with severe proteinuria. Using targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays. Results: Biallelic truncating variants in the LAMA5 gene (NM_005560) were detected in 3 patients from 2 families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.(Arg3078*)) and a splice site variant (c.1282+1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.(Arg2720*)) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin β1 and γ1 chains. Patient 4 showed SRNS at the age of eight and carried compound heterozygous missense variants (c.1493C>T, p.(Ala498Val) and c.8399G>A, p.(Arg2800His)). Conclusions: Our patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathological characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in congenital/infantile nephrotic syndrome patients.
    American Society of Nephrology (ASN), Oct. 2021, Kidney360, 10.34067/KID.0004952021 - 10.34067/KID.0004952021
    Scientific journal

  • Satoshi Takemori, Shinji Tanigaki, Kandai Nozu, Hiroshi Yoshihashi, Yutaro Uchiumi, Kyoko Sakaguchi, Kana Tsushima, Aya Kitamura, Chie Kobayashi, Miho Matsuhima, Atsushi Tajima, China Nagano, Yoichi Kobayashi
    Transient antenatal Bartter syndrome due to melanoma-associated antigen D2 gene mutation is a newly reported type of Bartter syndrome. Its characteristics include an X-linked inheritance pattern, early-onset hydramnios, and spontaneous disappearance of symptoms after childbirth. To date, there have been no reports of prenatally diagnosed cases. We herein present the case of a preterm male born to a mother with early-onset hydramnios and a family history of X-linked idiopathic hydramnios. We suspected melanoma-associated antigen D2 gene mutation and performed direct sequencing. As a result, we were able to prenatally establish a diagnosis of transient Bartter syndrome due to a melanoma-associated antigen D2 gene mutation.
    Oct. 2021, European journal of medical genetics, 64(10) (10), 104308 - 104308, English, International magazine
    Scientific journal

  • Yurika Tsuji, Tomohiko Yamamura, China Nagano, Tomoko Horinouchi, Nana Sakakibara, Shinya Ishiko, Yuya Aoto, Rini Rossanti, Eri Okada, Eriko Tanaka, Koji Tsugawa, Takayuki Okamoto, Toshihiro Sawai, Yoshinori Araki, Yuko Shima, Koichi Nakanishi, Hiroaki Nagase, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    INTRODUCTION: Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of WT1. For wild-type WT1, 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or -KTS]), and imbalance of the +KTS/-KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated. METHODS: We conducted an in vitro minigene splicing assay for 6 reported causative variants and in vivo RNA sequencing to determine the +KTS/-KTS ratio using patients' samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype. RESULTS: The in vitro assay revealed that although all mutant alleles produced -KTS transcripts only, the wild-type allele produced both +KTS and -KTS transcripts at a 1:1 ratio. In vivo RNA sequencing showed that patients' samples with all heterozygous variants produced similar ratios of +KTS to -KTS (1:3.2-1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period. CONCLUSION: Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS.
    Oct. 2021, Kidney international reports, 6(10) (10), 2585 - 2593, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yuya Aoto, Tomoko Horinouchi, Tomohiko Yamamura, Atsushi Kondo, Sadayuki Nagai, Shinya Ishiko, Eri Okada, Rini Rossanti, Nana Sakakibara, China Nagano, Hiroyuki Awano, Hiroaki Nagase, Yuko Shima, Koichi Nakanishi, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    Elsevier BV, Oct. 2021, Kidney International Reports
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Nana Sakakibara, Takeshi Ijuin, Tomoko Horinouchi, Tomohiko Yamamura, China Nagano, Eri Okada, Shinya Ishiko, Yuya Aoto, Rini Rossanti, Takeshi Ninchoji, Hiroyuki Awano, Hiroaki Nagase, Shogo Minamikawa, Ryojiro Tanaka, Takeshi Matsuyama, Koji Nagatani, Koichi Kamei, Kumiko Jinnouchi, Yasufumi Ohtsuka, Masafumi Oka, Yoshinori Araki, Toju Tanaka, Mari S Harada, Toru Igarashi, Hikaru Kitahara, Naoya Morisada, Shun-ichi Nakamura, Taro Okada, Kazumoto Iijima, Kandai Nozu
    Abstract Background Although Lowe syndrome and Dent disease-2 are both caused by OCRL mutations, their clinical severities differ substantially, and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1 through 7 lead to Dent disease-2, whereas those in exons 8 through 24 lead to Lowe syndrome. Herein, we identified the mechanism underlying the action of novel OCRL protein isoforms. Methods mRNA samples extracted from cultured urine-derived cells from a healthy control and the Dent disease-2 patient were examined to detect the 5′ end of the OCRL isoform. For protein expression and functional analysis, vectors containing (1) the full-length OCRL transcripts, (2) the isoform transcripts, and (3) transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. Results We successfully cloned the novel isoform transcripts from OCRL exons 6–24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained &gt; 50% enzyme activity, whereas the Lowe syndrome variants retained &lt; 20% activity. Conclusions We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.
    Oxford University Press (OUP), Sep. 2021, Nephrology Dialysis Transplantation, 37(2) (2), 262 - 270
    Scientific journal

  • Takeshi Ninchoji, Kandai Nozu, Atsushi Kondo, Shinya Ishiko, Ai Unzaki, China Nagano, Hiroshi Yamaguchi, Hiroki Takeda, Takuro Hayashi, Ryojiro Tanaka, Hiroaki Nagase, Kazumoto Iijima, Akihito Ishida
    OBJECTIVES: Accidental foreign body ingestion (FBI) and toxic agent ingestion (TAI) are commonly encountered among children in primary emergency settings. Early detection and appropriate medical intervention are crucial to improve outcomes. Although many reports from tertiary institutions have shown improvements in therapy, data are still lacking from primary emergency facilities. METHODS: We performed a retrospective analysis based on medical records of FBI/TAI over 4 years at the Kobe Children's Primary Emergency Medical Center. We collected patient information, including age, sex, time between FBI/TAI occurrence and centre visit, provision of first aid, symptoms, type of FBI/TAI, examinations, treatments, and outcomes. RESULTS: A total of 580 children were enrolled. The median age was 1.3 years, and patients under 2 years old accounted for 70% of total cases. Cigarettes (17.5%) were the most common ingested foreign body, followed by medicines (15.3%), detergents (8.1%), in TAI, plastics (14.1%), metal (13.4%), batteries (9.0%) in FBI, and others (22.6%). A total of 42 patients were transferred to advanced hospitals; among these, 22 patients were hospitalised but the foreign body was removed in only 3 (0.9%) patients. Transferred patients were significantly older (P<0.05) in FBI and had a higher rate of any of symptoms (P<0.05) in FBI/TAI. CONCLUSIONS: This large-scale retrospective study of accidental FBI/TAI conducted at a primary emergency facility clarified current management, including treatment at a primary facility. Very few cases of FBI/TAI were treated, even when they were transferred to an advanced treatment hospital. Unified protocols should be established, to improve the management of FBI/TAI.
    Sep. 2021, Minerva pediatrics, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 長野 智那, 野津 寛大
    (有)科学評論社, Sep. 2021, 腎臓内科, 14(3) (3), 329 - 335, Japanese

  • Atsushi Kondo, China Nagano, Shinya Ishiko, Takashi Omori, Yuya Aoto, Rini Rossanti, Nana Sakakibara, Tomoko Horinouchi, Tomohiko Yamamura, Sadayuki Nagai, Eri Okada, Yuko Shima, Koichi Nakanishi, Takeshi Ninchoji, Hiroshi Kaito, Hiroki Takeda, Hiroaki Nagase, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    Gitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy-Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.
    Aug. 2021, Scientific reports, 11(1) (1), 16099 - 16099, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Kyaw San Lin, Suguru Uemura, Khin Kyae Mon Thwin, Naoko Nakatani, Toshiaki Ishida, Nobuyuki Yamamoto, Akihiro Tamura, Atsuro Saito, Takeshi Mori, Daiichiro Hasegawa, Yoshiyuki Kosaka, Nanako Nino, China Nagano, Satoru Takafuji, Kazumoto Iijima, Noriyuki Nishimura
    Neuroblastoma (NB) is the most common extracranial solid tumor in children and originates from sympathoadrenal or Schwann cell precursors derived from neural crest. These neural crest derivatives also constitute the hematopoietic and mesenchymal stem cells in bone marrow (BM) that is the most frequent site of NB metastasis and relapse. In NB patients, NB cells have been pathologically detected in BM and peripheral blood (PB), and minimal residual disease (MRD) in BM and PB (BM-MRD and PB-MRD) can be monitored by quantitating several sets of NB-associated mRNAs (NB-mRNAs). Although previous studies have shown varying degrees of correlation between BM-MRD and PB-MRD, the underlying factors and/or mechanisms remains unknown. In the present study, we determined the levels of BM-MRD and PB-MRD by quantitating seven NB-mRNAs in 133 pairs of concurrently collected BM and PB samples from 19 high-risk NB patients with clinical disease evaluation, and examined their correlation in overall and subgroups of sample pairs. The levels of BM-MRD and PB-MRD were moderately (r = 0.418, p < 0.001) correlated with each other in overall sample pairs. The correlation became strong (r = 0.725, p < 0.001), weak (r = 0.284, p = 0.008), and insignificant (p = 0.194) in progression, stable, and remission subgroups of sample pairs, respectively. It also became stronger in subgroups of sample pairs with poor treatment responses and poor prognostic factors. Present study suggests that MRD in high-risk NB shows a dynamic and disease burden-dependent correlation between BM and PB.
    Aug. 2021, Translational oncology, 14(8) (8), 101019 - 101019, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Suguru Uemura, Kyaw San Lin, Khin Kyae Mon Thwin, Naoko Nakatani, Toshiaki Ishida, Nobuyuki Yamamoto, Akihiro Tamura, Atsuro Saito, Takeshi Mori, Daiichiro Hasegawa, Yoshiyuki Kosaka, Nanako Nino, China Nagano, Satoru Takafuji, Kazumoto Iijima, Noriyuki Nishimura
    Vanillylmandelic acid (VMA), homovanillic acid (HVA), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) are classical tumor markers and are used as standard clinical evaluations for patients with neuroblastoma (NB). Minimal residual disease (MRD) can be monitored by quantifying several sets of NB-associated mRNAs in the bone marrow (BM) and peripheral blood (PB) of patients with NB. Although MRD in BM and PB has been revealed to be a strong prognostic factor that is independent of standard clinical evaluations, its interrelation with tumor markers remains uncharacterized. The present study determined the levels of tumor markers (VMA, HVA, NSE and LDH) and MRD (BM-MRD and PB-MRD) in 133 pairs of concurrently collected BM, PB and urine samples from 19 patients with high-risk NB. The patients were evaluated during the entire course of treatment, which included 10 diagnoses, 32 treatments, 36 post-treatment, 9 relapses and 46 post-relapse sample pairs. The level of BM-MRD and PB-MRD was determined by quantifying 7 NB-mRNAs (collapsin response mediator protein 1, dopamine beta-hydroxylase, dopa decarboxylase, growth-associated protein 43, ISL LIM homeobox 1, pairedlike homeobox 2b and tyrosine hydroxylase) using droplet digital PCR. In overall sample pairs, tumor markers (VMA, HVA, NSE and LDH) demonstrated weak but significant correlations (P<0.011) with BM-MRD and PB-MRD. In subgroups according to each patient evaluation, the degree of correlation between tumor markers and MRD became stronger in patients with adrenal gland tumors, BM metastasis at diagnosis and relapse/regrowth compared with overall sample pairs. In contrast, tumor markers demonstrated variable correlations with MRD in subgroups according to each sample evaluation (BM infiltration at sampling, collection time point and disease status). The results suggested that tumor markers may demonstrate limited correlation with MRD in patients with high-risk NB.
    Jul. 2021, Molecular and clinical oncology, 15(1) (1), 137 - 137, English, International magazine
    Scientific journal
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  • Shinya Ishiko, Akihito Tanaka, Asami Takeda, Masayuki Hara, Naoto Hamano, Masahiro Koizumi, Toshinori Ueno, Hiroki Hayashi, Atsushi Kondo, Sadayuki Nagai, Yuya Aoto, Nana Sakakibara, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Takeshi Ninchoji, Yuko Shima, Koichi Nakanishi, Norishige Yoshikawa, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Pathological findings in Alport syndrome frequently show mesangial proliferation and sometimes incidental IgA deposition, in addition to unique glomerular basement membrane (GBM) changes including thin basement membrane and/or lamellation. However, similar GBM abnormalities are also often observed in IgA nephropathy. Both diseases are also known to show hematuria, proteinuria, and sometimes macrohematuria when associated with viral infection. Therefore, it can be difficult to make a differential diagnosis, even based on clinical and pathological findings. Some recent articles demonstrated that galactose-deficient IgA1 (Gd-IgA1)-specific monoclonal antibody (KM55) could potentially enable incidental IgA deposition to be distinguished from IgA nephropathy. METHODS: We performed comprehensive gene screening and glomerular Gd-IgA1 and type IV collagen α5 chain immunostaining for five cases with both IgA deposition and GBM changes to confirm that Gd-IgA1 can help to distinguish these two diseases. RESULTS: Four of the cases were genetically diagnosed with Alport syndrome (Cases 1-4) and one was IgA nephropathy with massive GBM changes, which had a negative gene test result (Case 5). In Cases 1-4, glomerular Gd-IgA1 deposition was not detected, although there was positivity for IgA in the mesangial area. In Case 5, glomerular Gd-IgA1 deposition was observed. CONCLUSION: Gd-IgA1 expression analysis could clearly differentiate these two disorders. This approach can be applied to identify these two diseases showing identical clinical and pathological findings.
    Jul. 2021, Clinical and experimental nephrology, 25(7) (7), 779 - 787, English, Domestic magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Rini Rossanti, Kandai Nozu, Atsushi Fukunaga, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, Shogo Minamikawa, Shinya Ishiko, Yuya Aoto, Eri Okada, Takeshi Ninchoji, Noritoshi Kato, Shoichi Maruyama, Keiji Kono, Shinichi Nishi, Kazumoto Iijima, Hideki Fujii
    BACKGROUND: Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. METHODS: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity. RESULTS: Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%). CONCLUSION: We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
    Jun. 2021, Clinical and experimental nephrology, 25(11) (11), 1224 - 1230, English, Domestic magazine
    Scientific journal

  • 石森 真吾, 藤村 順也, 堀之内 智子, 山村 智彦, 榊原 菜々, 長野 智那, 西田 浩輔, 藤岡 一路, 忍頂寺 毅史, 野津 寛大
    日本小児泌尿器科学会, Jun. 2021, 日本小児泌尿器科学会雑誌, 30(2) (2), 202 - 202, Japanese

  • 小児から成人へのシームレスなネフローゼ診療 単一遺伝子異常と小児および成人におけるネフローゼ症候群
    堀之内 智子, 野津 寛大, 長野 智那, 飯島 一誠
    (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 396 - 396, Japanese

  • ゲノムデータベースに基づく民族によるGitelman症候群の推定有病率の検討
    近藤 淳, 野津 寛大, 永井 貞之, 青砥 悠哉, Rini Rosanti, 榊原 菜々, 長野 智那, 堀之内 智子, 忍頂寺 毅史, 飯島 一誠
    (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 435 - 435, Japanese

  • COL4A5遺伝子collagenous domain内のnon-Glyミスセンス変異によるX染色体連鎖型Alport症候群発症メカニズムの解明
    青砥 悠哉, 野津 寛大, 近藤 淳, 永井 貞之, Rini Rosanti, 榊原 菜々, 長野 智那, 堀之内 智子, 忍頂寺 毅史, 飯島 一誠
    (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 456 - 456, Japanese

  • CLCN5遺伝子を含むX染色体微細欠失により発症したDent disease-1女性の2例
    榊原 菜々, 野津 寛大, 青砥 悠哉, 長野 智那, 堀之内 智子, 忍頂寺 毅史, 岡田 絵里, 川口 武彦, 今澤 俊之, 稲垣 徹史, 飯島 一誠
    (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 456 - 456, Japanese

  • 堀之内 智子, 山村 智彦, 永井 貞之, 近藤 淳, 青砥 悠哉, 榊原 菜々, 長野 智那, 忍頂寺 毅史, 飯島 一誠, 野津 寛大
    (一社)日本小児腎臓病学会, May 2021, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 92 - 92, Japanese

  • 青砥 悠哉, 高岡 裕, 近藤 淳, 永井 貞之, 岡田 絵里, Rossanti Rini, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 忍頂寺 毅史, 飯島 一誠, 野津 寛大
    (一社)日本小児腎臓病学会, May 2021, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 92 - 92, Japanese

  • 近藤 淳, 野津 寛大, 永井 貞之, 青砥 悠哉, Rossanti Rini, 榊原 菜々, 長野 智那, 堀之内 智子, 忍頂寺 毅史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2021, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 98 - 98, Japanese

  • 榊原 菜々, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rossanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 忍頂寺 毅史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2021, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 126 - 126, Japanese

  • Tomohiko Inoue, China Nagano, Masafumi Matsuo, Tomohiko Yamamura, Nana Sakakibara, Tomoko Horinouchi, Yugo Shibagaki, Daisuke Ichikawa, Yuya Aoto, Shinya Ishiko, Shingo Ishimori, Rini Rossanti, Kazumoto Iijima, Kandai Nozu
    May 2021, Clinical and experimental nephrology, 25(5) (5), 564 - 564, English, Domestic magazine

  • China Nagano, Yutaka Takaoka, Koichi Kamei, Riku Hamada, Daisuke Ichikawa, Kazuki Tanaka, Yuya Aoto, Shinya Ishiko, Rini Rossanti, Nana Sakakibara, Eri Okada, Tomoko Horinouchi, Tomohiko Yamamura, Yurika Tsuji, Yuko Noguchi, Shingo Ishimori, Hiroaki Nagase, Takeshi Ninchoji, Kazumoto Iijima, Kandai Nozu
    Elsevier BV, May 2021, Kidney International Reports
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Hiroaki Hanafusa, Yoshihiko Hidaka, Tomomi Yamaguchi, Hisashi Shimojo, Takanori Tsukahara, Tsubasa Murase, Daisuke Matsuoka, Nao Chiba, Shun Shimada, Hirokazu Morokawa, Norio Omori, Hironori Minoura, China Nagano, Kyoko Takano, Katsuya Nakamura, Keiko Wakui, Yoshimitsu Fukushima, Takeshi Uehara, Yozo Nakazawa, Kazumoto Iijima, Kandai Nozu, Tomoki Kosho
    Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.
    Apr. 2021, American journal of medical genetics. Part A, 185(7) (7), 2175 - 2179, English, International magazine

  • Hiroshi Yamaguchi, Kandai Nozu, Shinya Ishiko, Hiroaki Nagase, Takeshi Ninchoji, China Nagano, Hiroki Takeda, Ai Unzaki, Kazuto Ishibashi, Ichiro Morioka, Kazumoto Iijima, Akihito Ishida
    OBJECTIVES: To examine the association between the number of visits to the emergency department (ED) by children for night-time headaches and exposure to multifaceted factors, such as meteorological conditions and air pollution. DESIGN: We conducted a clinical observational time-series analysis study. SETTING: We reviewed consecutive patients younger than 16 years of age at the primary ED centre in Kobe city, Japan, during the night shift (19:30-7:00 hours) between 1 January 2011 and 31 December 2019. PARTICIPANTS: In total, 265 191 children visited the ED; 822 presented with headache during the study period. PRIMARY OUTCOME MEASURES: We investigated the effects of meteorological factors and air pollutants by multivariate analysis of Poisson regression estimates. A subanalysis included the relationship between the number of patients with night-time headaches and the above factors by sex. Furthermore, the effect of typhoon landing on patient visits for headache was also analysed. Headache was not classified because examinations were performed by general paediatricians (non-specialists). RESULTS: The number of patients with night-time headaches displayed distinct seasonal changes, with peaks during the summer. Multivariate analysis of Poisson regression estimates revealed a significant positive relationship between the number of patients for headache and mean temperature. Subanalysis by sex indicated a positive relationship between the number of patients with headache and mean temperature in both sexes; however, it was significant only for females. No relationship was found between the number of patients with headache and air pollution. There was no change in the number of patients for night-time headaches 3 days before and after typhoon landing. CONCLUSIONS: High temperature is the main factor for visiting ED for night-time headaches among children in Kobe city. Our results suggest that preventive measures against night-time headaches may be possible by reducing time spent outside during summer.
    Apr. 2021, BMJ open, 11(4) (4), e046520, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 榊原 菜々, 岡本 孝之, 野津 寛大, 佐藤 泰征, 林 麻子, 高橋 俊行, 上田 泰弘, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rossanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, Apr. 2021, 日本小児腎臓病学会雑誌, 34(1) (1), 93 - 93, Japanese

  • 榊原 菜々, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rossanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 田中 亮二郎, 飯島 一誠
    (一社)日本小児腎臓病学会, Apr. 2021, 日本小児腎臓病学会雑誌, 34(1) (1), 87 - 87, Japanese

  • 長野 智那, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, Apr. 2021, 日本小児腎臓病学会雑誌, 34(1) (1), 91 - 91, Japanese

  • 高リスク神経芽腫における微小残存病変(MRD)と腫瘍マーカーの相関に関する臨床的検討(Clinical analysis of the correlation between minimal residual disease and tumor markers in high-risk neuroblastoma)
    植村 優, Lin Kyaw San, Thwin Khin Kyaemon, 中谷 尚子, 石田 敏章, 山本 暢之, 田村 彰広, 斉藤 敦郎, 森 健, 長谷川 大一郎, 小阪 嘉之, 二野 菜々子, 高藤 哲, 青砥 悠哉, 長野 智那, 飯島 一誠, 西村 範行
    (公社)日本小児科学会, Feb. 2021, 日本小児科学会雑誌, 125(2) (2), 250 - 250, English

  • 当科で経験した寡巨大糸球体症(Oligomeganephronia)の臨床病理学的検討
    北角 英晶, 忍頂寺 毅史, 増田 知佳, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 長野 智那, 榊原 菜々, 堀之内 智子, 山村 智彦, 野津 寛大, 飯島 一誠
    (公社)日本小児科学会, Feb. 2021, 日本小児科学会雑誌, 125(2) (2), 260 - 260, Japanese

  • Lowe症候群とDent disease-2における分子生物学的発症機序の解明
    榊原 菜々, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rosanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 忍頂寺 毅史, 飯島 一誠
    (公社)日本小児科学会, Feb. 2021, 日本小児科学会雑誌, 125(2) (2), 284 - 284, Japanese

  • 異なる臨床像を呈したSLC4A1遺伝子による常染色体優性遠位尿細管性アシドーシスの姉弟例
    佐藤 望, 櫻谷 浩二, 長野 智那, 丘 宏逸, 吉田 登, 辻脇 篤志, 鈴木 恭子, 野津 寛大, 飯島 一誠, 大友 義之
    (公社)日本小児科学会, Feb. 2021, 日本小児科学会雑誌, 125(2) (2), 285 - 285, Japanese

  • Rini Rossanti, Toshio Watanabe, China Nagano, Shigeo Hara, Tomoko Horinouchi, Tomohiko Yamamura, Nana Sakakibara, Takeshi Ninchoji, Kazumoto Iijima, Kandai Nozu
    The identification of monogenic causes in patients with proteinuria has revealed that the encoded proteins functionally participate in distinct cellular tasks and signaling pathways in the slit diaphragms of the glomerular basement membrane. FAT1 is a member of a small family of vertebrate-cadherin-like genes, which is a crucial component in slit diaphragms and has a vital role in tubular regeneration. Only 5 cases with glomerulonephritis having FAT1 gene biallelic variants have been reported. However, only one had the biallelic truncating variant, and others had missense variants. Therefore, we need further evidence of this gene being responsible for steroid-resistant nephrotic syndrome (SRNS) or glomerulonephritis. Here we describe a 5-year-old boy in who proteinuria was detected at the age of 3 years without any extrarenal symptom. The pathological findings were examined, and targeted exome sequencing was performed. We also conducted reviews for all previously-reported cases of glomerulonephritis possessing FAT1 biallelic gene variants. We found two novel truncating variants in FAT1 (NM_005245.3), c.12867dup in exon 10, and, c.5480_5483del in exon 25. Our case showed mild proteinuria compared to previously-reported cases who showed SRNS and extrarenal symptoms that might have been because the latter variant in our patient was located on out of cadherin domains; however, our follow up period is short and we further need careful follow up. Our findings corroborate the evidence that individuals with FAT1-truncating variants can show isolated mild proteinuria. Further studies are needed to investigate the genotype-phenotype correlation in this disease. Therefore, our case will provide vital information regarding this rare condition.
    Feb. 2021, CEN case reports, 10(1) (1), 100 - 105, English, Domestic magazine
    Scientific journal

  • Tomoko Fujikawa, Suguru Uemura, Yuya Aoto, Yoshinori Nambu, China Nagano, Naoko Nakatani, Nanako Nino, Nobuyuki Yamamoto, Takeshi Mori, Noriyuki Nishimura, Kazumoto Iijima
    Rapidly growing nontuberculous mycobacteria should be considered if GPRs gram-positive rods are detected in blood cultures 2-3 days after the blood sample collection.
    Feb. 2021, Clinical case reports, 9(2) (2), 835 - 840, English, International magazine
    Link to Kobe Univ. Repository (Kernel)

  • Koji Sakuraya, Kandai Nozu, Hitohiko Murakami, China Nagano, Tomoko Horinouchi, Shuichiro Fujinaga, Kazumoto Iijima, Yoshiyuki Ohtomo
    Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.
    Jan. 2021, CEN case reports, 10(3) (3), 359 - 363, English, Domestic magazine
    Scientific journal

  • 遺伝性腎疾患における遺伝学的検査方法の進歩
    野津 寛大, 森貞 直哉, 長野 智那, 堀之内 智子, 榊原 菜々, 山村 智彦, 飯島 一誠
    (有)科学評論社, Jan. 2021, 腎臓内科, 13(1) (1), 105 - 112, Japanese

  • Kandai Nozu, Yutaka Takaoka, Hirofumi Kai, Minoru Takasato, Kensuke Yabuuchi, Tomohiko Yamamura, Tomoko Horinouchi, Nana Sakakibara, Takeshi Ninchoji, China Nagano, Kazumoto Iijima
    Alport syndrome (AS) is a progressive inherited kidney disease characterized by hearing loss and ocular abnormalities. There are three forms of AS depending on inheritance mode: X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, which encodes type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode type IV collagen α3 or α4 chain, respectively. In male XLAS or ARAS cases, end-stage kidney disease (ESKD) develops around a median age of 20 to 30 years old, while female XLAS or ADAS cases develop ESKD around a median age of 60 to 70 years old. The diagnosis of AS is dependent on either genetic or pathological findings. However, determining the pathogenicity of the variants detected by gene tests can be difficult. Recently, we applied the following molecular investigation tools to determine pathogenicity: 1) in silico and in vitro trimer formation assay of α345 chains to assess triple helix formation ability, 2) kidney organoids constructed from patients' induced pluripotent stem cells to identify α5 chain expression on the glomerular basement membrane, and 3) in vitro splicing assay to detect aberrant splicing to determine the pathogenicity of variants. In this review article, we discuss the genetic background and novel assays for determining the pathogenicity of variants. We also discuss the current treatment approaches and introduce exon skipping therapy as one potential treatment option.
    Dec. 2020, Kidney research and clinical practice, 39(4) (4), 402 - 413, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 榊原 菜々, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rossanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 田中 亮二郎, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 76 - 76, Japanese

  • 石河 慎也, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 石森 真吾, 貝藤 裕史, 田中 亮二郎, 島 友子, 中西 浩一, 吉川 徳茂, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 77 - 77, Japanese

  • 長野 智那, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 81 - 81, Japanese

  • 石河 慎也, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 82 - 82, Japanese

  • 長岡 由修, 若林 知宏, 矢吹 郁美, 飯塚 裕典, 稲澤 奈津子, 木澤 敏毅, 伊藤 希美, 東舘 義仁, 小川 弥生, 石河 慎也, 長野 智那, 野津 寛大, 飯島 一誠, 川崎 幸彦
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 86 - 86, Japanese

  • 堀之内 智子, 長野 智那, 山村 智彦, 香山 雅子, 野津 寛大, 飯島 一誠, 荒瀬 尚
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 88 - 88, English

  • Rini Rossanti, 山村 智彦, 堀之内 智子, 長野 智那, 榊原 菜々, 石河 慎也, 青砥 悠哉, 近藤 淳, 永井 貞之, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 88 - 88, English

  • 永井 貞之, 山村 智彦, 近藤 淳, 青砥 悠哉, 石河 慎也, 榊原 菜々, 長野 智那, 堀之内 智子, 忍頂寺 毅史, 島 友子, 中西 浩一, 吉川 徳茂, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 107 - 107, Japanese

  • 石見 壮史, 北岡 太一, 山田 知絵子, 宮田 京, 中山 尋文, 武鑓 真司, 山本 賢一, 中野 由佳子, 藤原 誠, 大幡 泰久, 窪田 拓生, 山本 威久, 長野 智那, 野津 寛大, 飯島 一誠, 大薗 恵一
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 145 - 145, Japanese

  • 村越 未希, 小椋 雅夫, 釜江 智佳子, 西 健太朗, 鈴木 竜太郎, 金森 透, 佐藤 舞, 長野 智那, 野津 寛大, 飯島 一誠, 亀井 宏一
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 176 - 176, Japanese

  • 榊原 菜々, 岡本 孝之, 野津 寛大, 佐藤 泰征, 林 麻子, 高橋 俊行, 上田 泰弘, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, Rossanti Rini, 長野 智那, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, Dec. 2020, 日本小児腎臓病学会雑誌, 33(1Suppl.) (1Suppl.), 85 - 85, Japanese

  • Hiroshi Yamaguchi, Hiroaki Nagase, Shoichi Tokumoto, Kazumi Tomioka, Masahiro Nishiyama, Hiroki Takeda, Takeshi Ninchoji, China Nagano, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene. In 1984, Scheinberg and Sternlieb estimated the prevalence of WD to be 1:30,000. However, recent epidemiological studies have reported increasing prevalence rates in different populations. The carrier frequency of ATP7B variants and the prevalence of WD in the Japanese population have not been reported using multiple databases. METHODS: Multiple public databases were used. First, we included mutations in the ATP7B gene that were registered in the Human Gene Mutation Database (HGMD) Professional, where 885 ATP7B variants were identified as pathogenic. Next, we investigated the allele frequencies of these 885 variants in Japanese individuals using the Human Genetic Variation Database (HGVD) and the Japanese Multi Omics Reference Panel (jMorp). RESULTS: Of the 885 variants of ATP7B, 7 and 12 missense and nonsense variants, 0 and 3 splicing variants, and 0 and 2 small deletions were found in the HGVD and in jMorp, respectively. The total allele frequencies of the ATP7B mutations were 0.011 in the HGVD and 0.014 in the jMorp. According to these data, the carrier frequencies were 0.022 (2.2%) and 0.028 (2.8%), respectively, and patient frequencies were 0.000121 (1.21/10,000 individuals) and 0.000196 (1.96/10,000 individuals), respectively. CONCLUSION: This is the first study to report the carrier frequency of ATP7B variants and the prevalence of WD in Japan using multiple databases. The calculated prevalence of WD was comparatively higher than that of previous reports, indicating previous underdiagnosis or the existence of less severe phenotypes.
    Dec. 2020, Pediatrics international : official journal of the Japan Pediatric Society, 63(8) (8), 918 - 922, English, International magazine
    Scientific journal

  • Nana Sakakibara, China Nagano, Shinya Ishiko, Tomoko Horinouchi, Tomohiko Yamamura, Shogo Minamikawa, Yuko Shima, Koichi Nakanishi, Shingo Ishimori, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Dent disease is associated with low molecular weight proteinuria and hypercalciuria and caused by pathogenic variants in either of two genes: CLCN5 (Dent disease 1) and OCRL (Dent disease 2). It is generally not accompanied by extrarenal manifestations and it is difficult to distinguish Dent disease 1 from Dent disease 2 without gene testing. We retrospectively compared the characteristics of these two diseases using one of the largest cohorts to date. METHODS: We performed gene testing for clinically suspected Dent disease, leading to the genetic diagnosis of 85 males: 72 with Dent disease 1 and 13 with Dent disease 2. A retrospective review of the clinical findings and laboratory data obtained from questionnaires submitted in association with the gene testing was conducted for these cases. RESULTS: The following variables had significantly higher levels in Dent disease 2 than in Dent disease 1: height standard deviation score (height SDS), serum creatinine-based estimated GFR (Cr-eGFR) (median: 84 vs. 127 mL/min/1.73 m2, p < 0.01), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum lactate dehydrogenase (LDH), serum creatine phosphokinase (CK), serum potassium, serum inorganic phosphorus, serum uric acid, urine protein/creatinine ratio (median: 3.5 vs. 1.6 mg/mg, p < 0.01), and urine calcium/creatinine ratio. There were no significant differences in serum sodium, serum calcium, alkaline phosphatase (ALP), urine β2-microglobulin, incidence of nephrocalcinosis, and prevalence of intellectual disability or autism spectrum disorder. CONCLUSIONS: The clinical and laboratory features of Dent disease 1 and Dent disease 2 were shown in this study. Notably, patients with Dent disease 2 showed kidney dysfunction at a younger age, which should provide a clue for the differential diagnosis of these diseases.
    Dec. 2020, Pediatric nephrology (Berlin, Germany), 35(12) (12), 2319 - 2326, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Tomohiko Yamamura, Tomoko Horinouchi, China Nagano, Takashi Omori, Nana Sakakibara, Yuya Aoto, Shinya Ishiko, Koichi Nakanishi, Yuko Shima, Hiroaki Nagase, Hiroki Takeda, Rini Rossanti, Ming Juan Ye, Yoshimi Nozu, Shingo Ishimori, Takeshi Ninchoji, Hiroshi Kaito, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    Early kidney failure in the hereditary type IV collagen disease, Alport syndrome, can be delayed by renin-angiotensin inhibitors. However, whether all patients and all different genotypes respond equally well to this kidney-protective therapy remains unclear. Here, we performed a retrospective study on 430 patients with male X-linked Alport syndrome to examine the relationships among kidney prognosis, genotype, and treatment effect in a large cohort of Japanese patients. We analyzed the clinical features, genotype-phenotype correlation, and kidney survival period for patients treated with or without renin-angiotensin inhibitors. As a result, the median kidney survival period of patients in this cohort was found to be at 35 years with a strong genotype-phenotype correlation. The median age at the onset of end stage kidney disease (ESKD) significantly differed between patients treated with and without renin-angiotensin inhibitors (over 50 years versus 28 years, respectively). Moreover, these drugs delayed the onset of ESKD in patients with truncating variants for 12 years, extending the median age from 16 years to 28 years. Thus, our results confirmed a strong genotype-phenotype correlation in patients with male X-linked Alport syndrome. Additionally, it was suggested that renin-angiotensin inhibitors could significantly delay ESKD progression. Despite these therapies, patients with truncating variants developed ESKD at the median age of 28 years.
    Dec. 2020, Kidney international, 98(6) (6), 1605 - 1614, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yoshinori Araki, Azusa Kawaguchi, Nana Sakakibara, Yoshinobu Nagaoka, Tomohiko Yamamura, Tomoko Horinouchi, China Nagano, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    Alport syndrome (AS) is a progressive kidney disease. Male cases with X-linked AS (XLAS) are reported to develop end-stage kidney disease (ESKD) at the age of around 20-30 years. One risk factor for developing ESKD at a young age is a genotype of having truncating variants in the COL4A5 gene. However, to date, other such factors have remained unclear. Here, we describe a 15-year-old Japanese boy with XLAS who had a missense variant in the COL4A5 gene. He presented with gross hematuria, severe proteinuria, oliguria, systemic edema, body weight gain, and hypertension after pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and elevated antistreptolysin-O level. We diagnosed him with poststreptococcal acute glomerulonephritis (PSAGN) and he was stopped treatment by lisinopril, and received supportive treatment. However, he showed an unusual clinical course for PSAGN and, consequently, developed ESKD 15 months after the onset of PSAGN without recovery from the kidney dysfunction. This case showed that the onset of PSAGN can be a risk factor for AS patients to develop ESKD at a young age.
    Nov. 2020, CEN case reports, 9(4) (4), 418 - 422, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Yuya Aoto, Tomoo Kise, Koichi Nakanishi, China Nagano, Tomoko Horinouchi, Tomohiko Yamamura, Shinya Ishiko, Nana Sakakibara, Yuko Shima, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    X-linked Alport syndrome (XLAS) is a progressive hereditary kidney disease caused by mutations in the COL4A5 gene encoding the type IV collagen α5 chain. To date, 11 cases having somatic mosaic variants in COL4A5 have been reported; however, all of them involved single-nucleotide variations (SNVs). Here, we report a female XLAS patient with somatic mosaicism identified by copy number variation (CNV) in COL4A5. The case was a 35-year-old female, the mother of the proband, whose only clinical symptom was hematuria. The proband, who was the son of this patient, was diagnosed with XLAS by gene testing, which showed a large hemizygous deletion from exon 3-51 in COL4A5 detected by next-generation sequencing and then confirmed by multiplex ligation-dependent probe amplification (MLPA). Then, MLPA analysis revealed that the female patient had the same deletion with only a 20% copy number reduction compared with a normal female control; she was thus diagnosed with XLAS with somatic mosaicism. CNVs in COL4A5 are relatively rare and, to the best of our knowledge, somatic mosaic variants with CNVs have never been reported. This case clearly featured a germline variant because the patient's son exhibited XLAS. This is thus the first case report on an XLAS patient having CNV in COL4A5 with somatic mosaicism. The obtained findings were very important for the genetic counseling of this family.
    Nov. 2020, CEN case reports, 9(4) (4), 431 - 436, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Koji Sakuraya, Kandai Nozu, Itsuhiro Oka, Shuichiro Fujinaga, China Nagano, Yoshiyuki Ohtomo, Kazumoto Iijima
    Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger known as anion exchanger 1, have been reported as the sole genetic cause of autosomal dominant distal renal tubular acidosis (dRTA). This disorder is extremely rare and most patients show no clinical symptoms during childhood. Here, we report a case of an infant with early-onset autosomal dominant dRTA caused by SLC4A1 mutation p.Gly609Arg that is detected as a hot spot world widely. Despite the fact that the patient's mother and sister had the same SLC4A1 mutation, all family members presented different clinical courses. A 9-month-old boy was referred to our hospital because of insufficient body weight gain. At the initial visit, his height and weight were 68.2 cm (-1.0 SD) and 6.4 kg (-2.2SD) respectively. Metabolic acidosis with a normal serum anion gap and inappropriate alkaline urine were detected. Abdominal ultrasound indicated bilateral renal medullary high-echoic lesions which suspected nephrocalcinosis. The genetic test revealed a heterozygous mutation c.1825G > A (p.Gly609Arg) in SLC4A1 that directed his diagnosis of autosomal dominant dRTA. The genetic test was performed on the patient's family members, indicating that the same SLC4A1 mutation was detected in his mother and sister. His mother had nephrocalcinosis and metabolic acidosis at the age of 35 years. However, his sister had no clinical symptoms at the age of 6 years without any laboratory abnormalities. This familial case demonstrated that the significant heterogeneity in clinical manifestations may develop even among familial members sharing the same variant.
    Nov. 2020, CEN case reports, 9(4) (4), 442 - 445, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Xiaoyuan Jia, Tomohiko Yamamura, Rasheed Gbadegesin, Michelle T McNulty, Kyuyong Song, China Nagano, Yuki Hitomi, Dongwon Lee, Yoshihiro Aiba, Seik-Soon Khor, Kazuko Ueno, Yosuke Kawai, Masao Nagasaki, Eisei Noiri, Tomoko Horinouchi, Hiroshi Kaito, Riku Hamada, Takayuki Okamoto, Koichi Kamei, Yoshitsugu Kaku, Rika Fujimaru, Ryojiro Tanaka, Yuko Shima, Jiwon Baek, Hee Gyung Kang, Il-Soo Ha, Kyoung Hee Han, Eun Mi Yang, Asiri Abeyagunawardena, Brandon Lane, Megan Chryst-Stangl, Christopher Esezobor, Adaobi Solarin, Claire Dossier, Georges Deschênes, Marina Vivarelli, Hanna Debiec, Kenji Ishikura, Masafumi Matsuo, Kandai Nozu, Pierre Ronco, Hae Il Cheong, Matthew G Sampson, Katsushi Tokunaga, Kazumoto Iijima
    To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).
    Nov. 2020, Kidney international, 98(5) (5), 1308 - 1322, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Takayuki Okamoto, Nana Sakakibara, Kandai Nozu, Toshiyuki Takahashi, Asako Hayashi, Yasuyuki Sato, China Nagano, Masafumi Matsuo, Kazumoto Iijima, Atsushi Manabe
    BACKGROUND: Approximately 15% of patients with Dent disease have pathogenic variants in the OCRL gene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported. METHODS: In this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of an OCRL variant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygous OCRL variant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis. RESULTS: Our patient had an OCRL heterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient's Dent-2 phenotype. CONCLUSIONS: This is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by an OCRL heterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.
    Oct. 2020, Clinical and experimental nephrology, 24(10) (10), 946 - 954, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Tomoko Horinouchi, Tomohiko Yamamura, China Nagano, Nana Sakakibara, Shinya Ishiko, Yuya Aoto, Rini Rossanti, Koichi Nakanishi, Yuko Shima, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: Autosomal recessive Alport syndrome (ARAS) is an inherited renal disorder caused by homozygous and compound heterozygous mutations in COL4A3 or COL4A4, but the prognostic predictors for this disorder are not yet fully understood. Recently, the magnitude of the clinical spectrum of the COL4A3 and COL4A4 heterozygous state has attracted attention. This spectrum includes asymptomatic carriers of ARAS, benign familial hematuria, thin basement membrane disease, and autosomal dominant Alport syndrome. METHODS: We retrospectively analyzed 49 patients with ARAS from 41 families with a median age of 19 years to examine the clinical features and prognostic factors of ARAS, including the associated genotypes. RESULTS: The median age of patients with ARAS at ESKD onset was 27 years. There was no significant association between the presence or absence of hearing loss or truncating mutations and renal prognosis. However, there was a statistically significant correlation between renal prognosis and heterozygous variants that cause urinary abnormalities. Where the urinary abnormality-causing variant was absent or present in only one allele, the median age of ESKD onset was 45 years, whereas the same variant present on both alleles was associated with an age of onset of 15 years (P<0.001). CONCLUSIONS: This study was the first to demonstrate the clinical importance in ARAS of focusing on variants in COL4A3 or COL4A4 that cause urinary abnormalities in both the homozygous or heterozygous state. Although heterozygous mutation carriers of COL4A3 and COL4A4 comprise a broad clinical spectrum, clinical information regarding each variant is important for predicting ARAS prognosis.
    Sep. 2020, Kidney360, 1(9) (9), 936 - 942, English, International magazine
    Scientific journal

  • Kentaro Nishi, Koichi Kamei, Masao Ogura, Mai Sato, Miki Murakoshi, Chikako Kamae, Ryutaro Suzuki, Toru Kanamori, China Nagano, Kandai Nozu, Kenji Ishikura, Shuichi Ito
    Denys-Drash syndrome is characterized by progressive nephropathy, gonadal dysgenesis, and Wilms tumor caused by a WT1 gene mutation. Infants with Denys-Drash syndrome frequently experience severe hypertension, but detailed clinical manifestations have yet to be clarified. Cases of infantile-onset Denys-Drash syndrome with severe hypertension at our hospital were retrospectively analyzed and the pathogenesis of hypertension was investigated. Six infants who received the diagnosis of Denys-Drash syndrome at the median age of 10 days (range: 2-182 days) were enrolled. Five infants had the complication of severe hypertension within a few days of diagnosis. All the patients showed rapid progression to end-stage renal disease and urgently required dialysis due to anuria/oliguria and hypervolemia with a median duration of 7.5 days (range: 0-17 days) on the day after diagnosis. Even under dialysis, all the patients continued to need antihypertensive treatment. Five patients underwent a preventive nephrectomy for Wilms tumor, and one patient underwent a nephrectomy due to progression to Wilms tumor. Two patients developed hypotension after a nephrectomy. The main causes of hypertension were hypervolemia in the predialysis stage, renin-associated hypertension in the dialysis stage, and multiple factors, including increased plasma catecholamine-associated hypertension in the postnephrectomy dialysis stage. At last the follow-up after bilateral nephrectomy, four of the five patients required antihypertensive treatment. Not all the patients showed target organ complications caused by hypertension. Severe hypertension is a common complication of infantile-onset Denys-Drash syndrome. The possibility of hypotension after nephrectomy should be considered in patients with Denys-Drash syndrome.
    Sep. 2020, The Tohoku journal of experimental medicine, 252(1) (1), 45 - 51, English, Domestic magazine
    Scientific journal

  • Shinya Ishiko, Tomoko Horinouchi, Rika Fujimaru, Yuko Shima, Hiroshi Kaito, Ryojiro Tanaka, Shingo Ishimori, Atsushi Kondo, Sadayuki Nagai, Yuya Aoto, Nana Sakakibara, China Nagano, Tomohiko Yamamura, Momoka Yoshimura, Koichi Nakanishi, Junya Fujimura, Naohiro Kamiyoshi, Hiroaki Nagase, Norishige Yoshikawa, Kazumoto Iijima, Kandai Nozu
    Galactose-deficient IgA1 (Gd-IgA1) is important in the pathogenesis of IgA nephropathy (IgAN). A Gd-IgA1-specific monoclonal antibody (KM55) has revealed glomerular Gd-IgA1 deposition solely in patients with IgAN and IgA vasculitis with nephritis (IgAV-N). However, this specificity is controversial and has not been demonstrated in pediatric patients. Here, we conducted double-immunofluorescence staining of IgA and Gd-IgA1 in 60 pediatric patients with various glomerular diseases. We divided patients into four groups: (1) patients with IgAN and IgAV-N (n = 23); (2) patients with immunocomplex-mediated glomerulonephritis accompanied by IgA deposition, including lupus nephritis, membranoproliferative glomerulonephritis, and membranous nephropathy (n = 14); (3) patients with other glomerular diseases involving IgA deposition, including idiopathic nephrotic syndrome (INS), oligomeganephronia, Alport syndrome, dense deposit disease, and crescentic glomerulonephritis (n = 11); and (4) patients with IgA-negative diseases including INS, membranoproliferative glomerulonephritis, membranous nephropathy, oligomeganephronia, Alport syndrome, C3 glomerulonephritis, poststreptococcal acute glomerulonephritis, and hemolytic uremic syndrome (n = 12). KM55 staining revealed Gd-IgA1-positive findings in 23/23 patients in Group 1 and 13/14 patients in Group 2, but not in patients in Groups 3 or 4. Therefore, KM55 may detect incidental IgA deposition in pediatric patients. Gd-IgA1 may be involved in the pathogenesis of these immune-related diseases; alternatively, KM55 may recognize IgA-related immunocomplexes in a non-specific manner.
    Aug. 2020, Scientific reports, 10(1) (1), 14026 - 14026, English, International magazine
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Tomoko Horinouchi, Tomohiko Yamamura, Shogo Minamikawa, China Nagano, Nana Sakakibara, Koichi Nakanishi, Yuko Shima, Naoya Morisada, Shinya Ishiko, Yuya Aoto, Hiroaki Nagase, Hiroki Takeda, Rini Rossanti, Shingo Ishimori, Hiroshi Kaito, Masafumi Matsuo, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive, hereditary glomerular nephritis of variable severity caused by pathogenic COL4A5 variants. Currently, genetic testing is widely used for diagnosing XLAS; however, determining the pathogenicity of variants detected by such analyses can be difficult. Intronic variants or synonymous variants may cause inherited diseases by inducing aberrant splicing. Transcript analysis is necessary to confirm the pathogenicity of such variants, but it is sometimes difficult to extract mRNA directly from patient specimens. METHODS: In this study, we conducted in vitro splicing analysis using a hybrid minigene assay and specimens from three XLAS patients with synonymous variants causing aberrant splicing, including previously reported pathogenic mutations in the same codon. The variants were c.876 A>T (p.Gly292=), c.2358 A>G (p.Pro786=), and c.3906 A>G (p.Gln1302=). RESULTS: The results from our hybrid minigene assay were sufficient to predict splicing abnormalities; c.876 A>T cause 17-bp del and 35-bp del, c.2358 A>G cause exon 29 skipping, c.3906 A>G cause exon 42 skipping, which are very likely to cause pathogenicity. Further, patients carrying c.2358 A>G exhibited a mild phenotype that may have been associated with the presence of both normal and abnormally spliced transcripts. CONCLUSION: The minigene system was shown to be a sensitive assay and a useful tool for investigating the pathogenicity of synonymous variants.
    Aug. 2020, Molecular genetics & genomic medicine, 8(8) (8), e1342, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 小児における糖鎖不全IgA1免疫染色
    石河 慎也, 野津 寛大, 永井 貞之, 青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 石森 真吾, 貝藤 裕史, 田中 亮二郎, 飯島 一誠
    (一社)日本腎臓学会, Jul. 2020, 日本腎臓学会誌, 62(4) (4), 255 - 255, Japanese

  • スプライシング異常が疑われるCLCN5遺伝子変異のDent病発症メカニズムの解明
    井上 友彦, 長野 智那, 山村 智彦, 榊原 菜々, 堀之内 智子, 青砥 悠哉, 石河 慎也, 野津 寛大, 飯島 一誠
    (一社)日本腎臓学会, Jul. 2020, 日本腎臓学会誌, 62(4) (4), 257 - 257, Japanese

  • WT1遺伝子exon8-9ミスセンス変異における遺伝子型-臨床型の相関に関する検討
    長野 智那, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 飯島 一誠
    (一社)日本腎臓学会, Jul. 2020, 日本腎臓学会誌, 62(4) (4), 293 - 293, Japanese

  • Lowe症候群とDent disease-2の2疾患における分子生物学的発症機序の解明
    榊原 菜々, 野津 寛大, 永井 貞之, 青砥 悠哉, 石河 慎也, 長野 智那, 堀之内 智子, 飯島 一誠
    (一社)日本腎臓学会, Jul. 2020, 日本腎臓学会誌, 62(4) (4), 293 - 293, Japanese

  • 森下 俊真, 渡邊 佳孝, 遠藤 翔太, 宮野 洋希, 梅田 千里, 西野 智彦, 仲川 真由, 村上 仁彦, 藤永 周一郎, 長野 智那, 野津 寛大, 飯島 一誠
    日本小児腎不全学会, Jul. 2020, 日本小児腎不全学会雑誌, 40, 261 - 264, Japanese

  • Tomohiko Inoue, China Nagano, Masafumi Matsuo, Tomohiko Yamamura, Nana Sakakibara, Tomoko Horinouchi, Yugo Shibagaki, Daisuke Ichikawa, Yuya Aoto, Shinya Ishiko, Shingo Ishimori, Rini Rossanti, Kazumoto Iijima, Kandai Nozu
    BACKGROUND: In recent years, the elucidation of splicing abnormalities as a cause of hereditary diseases has progressed. However, there are no comprehensive reports of suspected splicing variants in the CLCN5 gene in Dent disease cases. We reproduced gene mutations by mutagenesis, inserted the mutated genes into minigene vectors, and investigated the pathogenicity and onset mechanisms of these variants. METHODS: We conducted functional splicing assays using a hybrid minigene for six suspected splicing variants (c.105G>A, c.105+5G>C, c.106-17T>G, c.393+4A>G, c.517-8A>G, c.517-3C>A) in CLCN5. We extracted information on these variants from the Human Gene Mutation Database. We reproduced minigene vectors with the insertion of relevant exons with suspected splicing variants. We then transfected these minigene vectors into cultured cells and extracted and analyzed the mRNA. In addition, we conducted in silico analysis to confirm our minigene assay results. RESULTS: We successfully determined that five of these six variants are pathogenic via the production of splicing abnormalities. One showed only normal transcript production and was thus suspected of not being pathogenic (c.106-17T>G). CONCLUSION: We found that five CLCN5 variants disrupted the original splice site, resulting in aberrant splicing. It is sometimes difficult to obtain mRNA from patient samples because of the fragility of mRNA or its low expression level in peripheral leukocytes. Our in vitro system can be used as an alternative to in vivo assays to determine the pathogenicity of suspected splicing variants.
    Jul. 2020, Clinical and experimental nephrology, 24(7) (7), 606 - 612, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Tomohiko Yamamura, Tomoko Horinouchi, Tomomi Adachi, Maki Terakawa, Yutaka Takaoka, Kohei Omachi, Minoru Takasato, Kiyosumi Takaishi, Takao Shoji, Yoshiyuki Onishi, Yoshito Kanazawa, Makoto Koizumi, Yasuko Tomono, Aki Sugano, Akemi Shono, Shogo Minamikawa, China Nagano, Nana Sakakibara, Shinya Ishiko, Yuya Aoto, Misato Kamura, Yutaka Harita, Kenichiro Miura, Shoichiro Kanda, Naoya Morisada, Rini Rossanti, Ming Juan Ye, Yoshimi Nozu, Masafumi Matsuo, Hirofumi Kai, Kazumoto Iijima, Kandai Nozu
    Currently, there are no treatments for Alport syndrome, which is the second most commonly inherited kidney disease. Here we report the development of an exon-skipping therapy using an antisense-oligonucleotide (ASO) for severe male X-linked Alport syndrome (XLAS). We targeted truncating variants in exon 21 of the COL4A5 gene and conducted a type IV collagen α3/α4/α5 chain triple helix formation assay, and in vitro and in vivo treatment efficacy evaluation. We show that exon skipping enabled trimer formation, leading to remarkable clinical and pathological improvements including expression of the α5 chain on glomerular and the tubular basement membrane. In addition, the survival period was clearly prolonged in the ASO treated mice group. This data suggests that exon skipping may represent a promising therapeutic approach for treating severe male XLAS cases.
    Jun. 2020, Nature communications, 11(1) (1), 2777 - 2777, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 母児間輸血症候群後に慢性腎臓病(CKD)に至った3例
    青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 藤岡 一路, 野津 寛大, 飯島 一誠
    (公社)日本小児科学会, Jun. 2020, 日本小児科学会雑誌, 124(6) (6), 1036 - 1036, Japanese

  • Rini Rossanti, Naoya Morisada, Kandai Nozu, Koichi Kamei, Tomoko Horinouchi, Tomohiko Yamamura, Shogo Minamikawa, Junya Fujimura, China Nagano, Nana Sakakibara, Takeshi Ninchoji, Hiroshi Kaito, Shuichi Ito, Ryojiro Tanaka, Kazumoto Iijima
    Pathogenic variants of paired box gene 2 (PAX2) cause autosomal-dominant PAX2-related disorder, which includes renal coloboma syndrome (RCS). Patients with PAX2-related disorder present with renal and ophthalmological pathologies, as well as with other abnormalities, including developmental problems and hearing loss. We sequenced PAX2 in 457 patients with congenital anomalies of the kidney and urinary tract or with renal dysfunction of unknown cause and identified 19 different pathogenic variants in 38 patients from 30 families (6.5%). Thirty-four patients had renal hypodysplasia or chronic kidney disease of unknown cause, and three had focal segmental glomerulosclerosis. Although no obvious genotype-phenotype correlation was observed, six of the seven patients who developed end-stage renal disease in childhood had truncating variants. Twenty-three patients had ocular disabilities, mostly optic disc coloboma. Non-renal and non-ophthalmological manifestations included developmental disorder, electrolyte abnormality, and gonadal abnormalities. Two unrelated patients had congenital cystic adenomatoid malformations in their lungs. Six of ten probands with PAX2 mutation identified by next-generation sequencing did not show typical RCS manifestations. We conclude that PAX2-related disorder has a variable clinical presentation and can be diagnosed by next-generation sequencing even in the absence of typical RCS manifestations.
    Jun. 2020, Journal of human genetics, 65(6) (6), 541 - 549, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • WT1遺伝子異常症
    長野 智那, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 野津 寛大, 飯島 一誠
    発達腎研究会, Apr. 2020, 発達腎研究会誌, 28(1) (1), 29 - 32, Japanese

  • 長尾 佳樹, 石原 正行, 石塚 喜世伸, 三浦 健一郎, 服部 元史, 長野 智那, 野津 寛大, 飯島 一誠, 藤枝 幹也
    (一社)日本小児腎臓病学会, Apr. 2020, 日本小児腎臓病学会雑誌, 33(1) (1), 105 - 105, Japanese

  • Shogo Minamikawa, Saori Miwa, Tetsuji Inagaki, Kei Nishiyama, Hiroshi Kaito, Takeshi Ninchoji, Tomohiko Yamamura, China Nagano, Nana Sakakibara, Shingo Ishimori, Shigeo Hara, Norishige Yoshikawa, Daishi Hirano, Ryoko Harada, Riku Hamada, Natsuki Matsunoshita, Michio Nagata, Yuko Shima, Koichi Nakanishi, Hiroaki Nagase, Hiroki Takeda, Naoya Morisada, Kazumoto Iijima, Kandai Nozu
    Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.
    Apr. 2020, Journal of human genetics, 65(4) (4), 355 - 362, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Kandai Nozu, Tomohiko Yamamura, Tomoko Horinouchi, China Nagano, Nana Sakakibara, Kenji Ishikura, Riku Hamada, Naoya Morisada, Kazumoto Iijima
    Bartter syndrome (BS) and Gitelman syndrome (GS) are syndromes associated with congenital tubular dysfunction, characterized by hypokalemia and metabolic alkalosis. Clinically, BS is classified into two types: the severe antenatal/neonatal type, which develops during the fetal period with polyhydramnios and preterm delivery; and the relatively mild classic type, which is usually found during infancy with failure to thrive. GS can be clinically differentiated from BS by its age at onset, usually after school age, or laboratory findings of hypomagnesemia and hypocalciuria. Recent advances in molecular biology have shown that these diseases can be genetically classified into type 1 to 5 BS and GS. As a result, it has become clear that the clinical classification of antenatal/neonatal BS, classic BS, and GS does not always correspond to the clinical symptoms associated with the genotypes in a one-to-one manner; and there is clinically no clear differential border between type 3 BS and GS. This has caused confusion among clinicians in the diagnosis of these diseases. It has been proposed that the disease name "inherited salt-losing tubulopathy" can be used for cases of tubulopathies accompanied by hypokalemia and metabolic alkalosis. It is reasonable to use this term prior to genetic typing into type 1-5 BS or GS, to avoid confusion in a clinical setting. In this article, we review causative genes and phenotypic correlations, diagnosis, and treatment strategies for salt-losing tubulopathy as well as the clinical characteristics of pseudo-BS/GS, which can also be called a "salt-losing disorder".
    Apr. 2020, Pediatrics international : official journal of the Japan Pediatric Society, 62(4) (4), 428 - 437, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • X染色体連鎖型Alport症候群患者におけるサイレント変異の病的意義の検討
    堀之内 智子, 野津 寛大, 近藤 淳, 永井 貞之, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 山村 智彦, 森貞 直哉, 飯島 一誠
    (公社)日本小児科学会, Feb. 2020, 日本小児科学会雑誌, 124(2) (2), 237 - 237, Japanese

  • Dent disease-1とDent disease-2の臨床像の差異に関する検討
    榊原 菜々, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 長野 智那, 堀之内 智子, 山村 智彦, 飯島 一誠
    (公社)日本小児科学会, Feb. 2020, 日本小児科学会雑誌, 124(2) (2), 238 - 238, Japanese

  • 日本人における遺伝性ネフローゼ症候群の網羅的遺伝子診断体制
    長野 智那, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 石河 慎也, 榊原 菜々, 堀之内 智子, 山村 智彦, 飯島 一誠
    (公社)日本小児科学会, Feb. 2020, 日本小児科学会雑誌, 124(2) (2), 305 - 305, Japanese

  • 糖鎖不全IgA1免疫染色が診断に有用であったステロイド抵抗性ネフローゼ症候群の1例
    石河 慎也, 野津 寛大, 近藤 淳, 永井 貞之, 青砥 悠哉, 榊原 菜々, 長野 智那, 堀之内 智子, 山村 智彦, 飯島 一誠
    (公社)日本小児科学会, Feb. 2020, 日本小児科学会雑誌, 124(2) (2), 305 - 305, Japanese

  • 小児IgA腎症の組織学的軽症例と重症例における多剤併用療法の効果に関する比較
    青砥 悠哉, 野津 寛大, 近藤 淳, 石河 慎也, 榊原 菜々, 長野 智那, 藤村 順也, 堀之内 智子, 山村 智彦, 神吉 直宙, 石森 真吾, 島 友子, 中西 浩一, 吉川 徳茂, 貝藤 裕史, 飯島 一誠
    (公社)日本小児科学会, Feb. 2020, 日本小児科学会雑誌, 124(2) (2), 303 - 303, Japanese

  • China Nagano, Tomohiko Yamamura, Tomoko Horinouchi, Yuya Aoto, Shinya Ishiko, Nana Sakakibara, Yuko Shima, Koichi Nakanishi, Hiroaki Nagase, Kazumoto Iijima, Kandai Nozu
    Numerous disease-causing gene mutations have been identified in proteinuric diseases, such as nephrotic syndrome and glomerulosclerosis. This report describes the results of comprehensive genetic diagnosis of Japanese patients with severe proteinuria. In addition, the report describes the clinical characteristics of patients with monogenic disease-causing mutations. We conducted comprehensive gene screening of patients who had either congenital nephrotic syndrome, infantile nephrotic syndrome, steroid-resistant nephrotic syndrome, or focal segmental glomerular sclerosis. Using targeted next-generation sequencing, 60 podocyte-related genes were screened in 230 unrelated patients with proteinuria. A retrospective review of clinical data was conducted for these patients. We detected monogenic disease-causing mutations in 30% (69 of 230) of patients among 19 of the screened genes. Common genes with disease-causing mutations were WT1 (25%), NPHS1 (12%), INF2 (12%), TRPC6 (10%), and LAMB2 (9%). With various immunosuppressive or renoprotective therapies, remission of proteinuria in patients with unknown causative mutations was observed in 26% of patients, whereas only 5% of patients with monogenic disease-causing mutations exhibited complete remission. We assessed the genetic backgrounds of Japanese patients with severe proteinuria. The proportion of patients with gene defects was similar to that of other reports, but the disease-causing gene mutation frequency was considerably different.
    Jan. 2020, Scientific reports, 10(1) (1), 270 - 270, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 堀之内 智子, 野津 寛大, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 南川 将吾, 山村 智彦, 貝藤 裕史, 森貞 直哉, 飯島 一誠
    (一社)日本小児腎臓病学会, Nov. 2019, 日本小児腎臓病学会雑誌, 32(2) (2), 139 - 139, Japanese

  • Tomoko Horinouchi, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, China Nagano, Nana Sakakibara, Koichi Nakanishi, Yuko Shima, Naoya Morisada, Shinya Ishiko, Yuya Aoto, Hiroaki Nagase, Hiroki Takeda, Rini Rossanti, Hiroshi Kaito, Masafumi Matsuo, Kazumoto Iijima
    X-linked Alport syndrome (XLAS) is a congenital renal disease caused by mutations in COL4A5. In XLAS cases suspected of being caused by aberrant splicing, transcript analysis needs to be conducted to determine splicing patterns and assess the pathogenicity. However, such analysis is not always available. We conducted a functional splicing assay using a hybrid minigene for seven COL4A5 intronic mutations: one was identified by us and six were found in the Human Gene Mutation Database. The minigene assay revealed exon skipping in four variants, exon skipping and a 10-bp insertion in one variant, and no change in one variant, which appeared not to be pathogenic. For one variant, our assay did not work. The results of all three cases for which transcript data were available were consistent with our assay results. Our findings may help to increase the accuracy of genetic test results and clarify the mechanisms causing aberrant splicing.
    Sep. 2019, Scientific reports, 9(1) (1), 12696 - 12696, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • China Nagano, Naoya Morisada, Kandai Nozu, Koichi Kamei, Ryojiro Tanaka, Shoichiro Kanda, Shinichi Shiona, Yoshinori Araki, Shinichiro Ohara, Chieko Matsumura, Katsuaki Kasahara, Yukiko Mori, Akane Seo, Kenichiro Miura, Miki Washiyama, Keisuke Sugimoto, Ryoko Harada, Satoshi Tazoe, Hiroyo Kourakata, Mayumi Enseki, Daisuke Aotani, Takeshi Yamada, Nana Sakakibara, Tomohiko Yamamura, Shogo Minamikawa, Kenji Ishikura, Shuichi Ito, Motoshi Hattori, Kazumoto Iijima
    BACKGROUND: Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.
    Sep. 2019, Clinical and experimental nephrology, 23(9) (9), 1119 - 1129, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Tomohiko Yamamura, Kandai Nozu, Shogo Minamikawa, Tomoko Horinouchi, Nana Sakakibara, China Nagano, Yuya Aoto, Shinya Ishiko, Koichi Nakanishi, Yuko Shima, Hiroaki Nagase, Rini Rossanti, Ming J Ye, Yoshimi Nozu, Shingo Ishimori, Naoya Morisada, Hiroshi Kaito, Kazumoto Iijima
    BACKGROUND: Alport syndrome (AS) is a hereditary disease caused by mutations in COL4A3-5 genes. Recently, comprehensive genetic analysis has become the first-line diagnostic tool for AS. However, no reports comparing mutation identification rates between conventional sequencing and comprehensive screening have been published. METHODS: In this study, 441 patients clinically suspected of having AS were divided into two groups and compared. The initial mutational analysis method involved targeted exome sequencing using next-generation sequencing (NGS) (n = 147, NGS group) or Sanger sequencing for COL4A3/COL4A4/COL4A5 (n = 294, Sanger group). RESULTS: In the NGS group, 126 patients (86%) were diagnosed with AS by NGS, while two had pathogenic mutations in other genes, NPHS1 and EYA1. Further, 239 patients (81%) were diagnosed with AS by initial analysis in the Sanger group. Thirteen patients who were negative for mutation detection in the Sanger group were analyzed by NGS; three were diagnosed with AS. Two had mutations in CLCN5 or LAMB2. The final variant detection rate was 90%. DISCUSSION: Our results reveal that Sanger sequencing and targeted exome sequencing have high diagnostic ability. NGS also has the advantage of detecting other inherited kidney diseases and pathogenic mutations missed by Sanger sequencing.
    Sep. 2019, Molecular genetics & genomic medicine, 7(9) (9), e883, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 生後3ヵ月時発症のステロイド感受性ネフローゼ症候群の一例
    梅田 千里, 藤永 周一郎, 長野 智那, 野津 寛大, 飯島 一誠
    (一社)日本腎臓学会, Aug. 2019, 日本腎臓学会誌, 61(6) (6), 747 - 747, Japanese

  • Nagano C, Sako M, Kamei K, Ishikura K, Nakamura H, Nakanishi K, Omori T, Nozu K, Iijima K
    BACKGROUND: Eighty percent of children with idiopathic nephrotic syndrome respond well to steroid therapy, but up to 50% of patients with steroid-sensitive nephrotic syndrome exhibit frequently relapsing (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Several studies identified the chimeric anti-CD20 monoclonal antibody rituximab as an effective treatment for patients with complicated FRNS/SDNS. Recent studies suggested that rituximab could also be a first-line treatment for early-stage uncomplicated FRNS/SDNS, although further studies are required to confirm its efficacy and safety. METHODS/DESIGN: We are conducting a multicenter, double-blind, randomized placebo controlled trial to investigate the efficacy and safety of rituximab for the treatment of childhood-onset early-stage uncomplicated FRNS/SDNS. Patients will be allocated to receive two 375 mg/m2 doses (maximum dose: 500 mg) of either rituximab or placebo. Investigators are permitted to request the disclosure of a subject's allocation code if he or she exhibits treatment failure. Additionally, if placebo-treated subjects display early relapse (a sign of treatment failure), they have the option to receive rituximab in an unblinded phase. The primary endpoint is relapse-free survival during the observation period. DISCUSSION: The results will provide important data on the use of rituximab for patients with uncomplicated FRNS/SDNS. In the future, rituximab treatment will enable most patients with uncomplicated FRNS/SDNS to discontinue or reduce steroid therapy without relapse, and it is possible that rituximab could represent an immunosuppressive therapy for these diseases. TRIAL REGISTRATION: This trial was prospectively registered to the JMACCT Clinical Trials Registry on September 6, 2018 (Trial ID: JMA-IIA00380 ).
    Aug. 2019, BMC nephrology, 20(1) (1), 293 - 293, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 当科における24時間自由行動下血圧測定(ABPM)の使用経験
    榊原 菜々, 青砥 悠哉, 石河 慎也, 長野 智那, 南川 将吾, 山村 智彦, 野津 寛大, 飯島 一誠
    日本小児高血圧研究会, Jul. 2019, 日本小児高血圧研究会誌, 16(1) (1), 14 - 21, Japanese

  • Rini Rossanti, Akemi Shono, Kenichiro Miura, Motoshi Hattori, Tomohiko Yamamura, Keita Nakanishi, Shogo Minamikawa, Junya Fujimura, Tomoko Horinouchi, China Nagano, Nana Sakakibara, Hiroshi Kaito, Hiroaki Nagase, Naoya Morisada, Katsuhiko Asanuma, Masafumi Matsuo, Kandai Nozu, Kazumoto Iijima
    Advances in molecular genetics have revealed that approximately 30% of cases with steroid-resistant nephrotic syndrome (SRNS) are caused by single-gene mutations. More than 50 genes are responsible for SRNS. One such gene is the nucleoporin, 93-KD (NUP93). Thus far, few studies have reported mutations of NUP93 in SRNS. Here, we describe an NUP93 biallelic mutation in a 9-year-old boy with focal segmental glomerular sclerosis (FSGS). Notably, one mutation comprised an intronic variant; we conducted in vivo and in vitro analysis to characterize this variant. We found two heterozygous mutations in NUP93: c.2137-18G>A in intron 19 and a novel nonsense mutation c.727A>T (p.Lys243*) in exon 8. We conducted RNA sequencing and in vitro splicing assays by using minigene construction, combined with protein expression analysis to determine the pathogenicity of the intronic variant. Both RNA sequencing and in vitro splicing assay showed exon 20-skipping by the intronic variant. In protein expression analysis, aberrant subcellular localization with small punctate vesicles in the cytoplasm was observed for the intronic variant. Taken together, we concluded that c.2137-18G>A was linked to pathogenicity due to aberrant splicing. NUP93 variants are quite rare; however, we have shown that even intronic variants in NUP93 can cause SRNS. This study provides a fundamental approach to validate the intronic variant, as well as new insights regarding the clinical spectrum of SRNS caused by rare gene variants.
    Jul. 2019, Journal of human genetics, 64(7) (7), 673 - 679, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • NPHS1は小児ステロイド感受性ネフローゼ症候群の疾患感受性遺伝子である
    山村 智彦, 長野 智那, 堀之内 智子, 野津 寛大, 飯島 一誠
    (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 298 - 298, Japanese

  • 常染色体劣性Alport症候群39家系46人の臨床遺伝学的検討
    堀之内 智子, 野津 寛大, 榊原 菜々, 長野 智那, 南川 将吾, 山村 智彦, 飯島 一誠
    (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 318 - 318, Japanese

  • 遺伝性ネフローゼ症候群における臨床的特徴の検討
    長野 智那, 野津 寛大, 青砥 悠哉, 石河 慎也, 榊原 菜々, 南川 将吾, 山村 智彦, 飯島 一誠
    (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 303 - 303, Japanese

  • Dent病およびLowe症候群の臨床遺伝学的検討
    榊原 菜々, 野津 寛大, 青砥 悠哉, 石河 慎也, 長野 智那, 南川 将吾, 山村 智彦, 飯島 一誠
    (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 355 - 355, Japanese

  • 長野 智那, 野津 寛大, 青砥 悠哉, 石河 慎也, 榊原 菜々, 南川 将吾, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 91 - 91, Japanese

  • 堀之内 智子, 野津 寛大, 石河 慎也, 青砥 悠哉, 榊原 菜々, 長野 智那, 南川 将吾, 山村 智彦, 貝藤 裕史, 森貞 直哉, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 92 - 92, Japanese

  • 榊原 菜々, 野津 寛大, 青砥 悠哉, 石河 慎也, 長野 智那, 南川 将吾, 山村 智彦, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 180 - 180, Japanese

  • 石河 慎也, 野津 寛大, 青砥 悠哉, 榊原 菜々, 長野 智那, 南川 将吾, 山村 智彦, 島 友子, 中西 浩一, 吉川 徳茂, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 119 - 119, Japanese

  • 青砥 悠哉, 野津 寛大, 石河 慎也, 榊原 菜々, 長野 智那, 藤村 順也, 南川 将吾, 山村 智彦, 神吉 直宙, 石森 真吾, 島 友子, 中西 浩一, 吉川 徳茂, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 120 - 120, Japanese

  • 三輪 沙織, 山田 哲史, 川上 雄平, 徳永 愛, 武政 洋一, 梅田 千里, 掛川 大輔, 伊藤 亮, 長野 智那, 野津 寛大, 飯島 一誠, 平野 大志
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 179 - 179, Japanese

  • 飯島 一誠, Xiaoyuan Jia, 山村 智彦, 人見 祐基, 長野 智那, 堀之内 智子, 野津 寛大, 徳永 勝士
    (一社)日本小児腎臓病学会, May 2019, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 56 - 56, Japanese

  • Keita Nakanishi, Takayuki Okamoto, Kandai Nozu, Shigeo Hara, Yasuyuki Sato, Asako Hayashi, Toshiyuki Takahashi, China Nagano, Nana Sakakibara, Tomoko Horinouchi, Junya Fujimura, Shogo Minamikawa, Tomohiko Yamamura, Rini Rossanti, Hiroaki Nagase, Hiroshi Kaito, Tadashi Ariga, Kazumoto Iijima
    BACKGROUND: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS. METHODS: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case. RESULTS: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1-2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission. CONCLUSIONS: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.
    May 2019, Clinical and experimental nephrology, 23(5) (5), 669 - 675, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • オリゴメガネフロニアと角膜ジストロフィ
    長野 智那, 青砥 悠哉, 石河 慎也, 榊原 菜々, 南川 将吾, 山村 智彦, 野津 寛大, 飯島 一誠
    発達腎研究会, Apr. 2019, 発達腎研究会誌, 27(1) (1), 7 - 8, Japanese
    [Refereed]

  • 無症候性血尿にて長期経過の後に蛋白尿が出現し常染色体劣性Alport症候群の診断に至った1例
    青砥 悠哉, 南川 将吾, 石河 慎也, 榊原 菜々, 長野 智那, 藤村 順也, 山村 智彦, 野津 寛大, 飯島 一誠
    (公社)日本小児科学会, Mar. 2019, 日本小児科学会雑誌, 123(3) (3), 621 - 621, Japanese

  • クラリスロマイシンによりカルシニューリン阻害薬血中濃度の異常上昇をきたした2例
    市川 裕太, 南川 将吾, 青砥 悠哉, 石河 慎也, 榊原 菜々, 長野 智那, 山村 智彦, 野津 寛大, 飯島 一誠
    (公社)日本小児科学会, Mar. 2019, 日本小児科学会雑誌, 123(3) (3), 628 - 628, Japanese

  • 腎生検後のADH上昇と生理食塩水輸液の安全性に関する検討
    石河 慎也, 野津 寛大, 青砥 悠哉, 榊原 菜々, 長野 智那, 南川 将吾, 山村 智彦, 飯島 一誠
    (公社)日本小児科学会, Feb. 2019, 日本小児科学会雑誌, 123(2) (2), 217 - 217, Japanese

  • 先天性/乳児およびステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制
    長野 智那, 野津 寛大, 青砥 悠哉, 石河 慎也, 榊原 菜々, 南川 将吾, 山村 智彦, 飯島 一誠
    (公社)日本小児科学会, Feb. 2019, 日本小児科学会雑誌, 123(2) (2), 217 - 217, Japanese

  • China Nagano, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Junya Fujimura, Nana Sakakibara, Keita Nakanishi, Tomoko Horinouchi, Yoichi Iwafuchi, Sentaro Kusuhara, Wataru Matsumiya, Norishige Yoshikawa, Kazumoto Iijima
    Transforming growth factor beta-induced (TGFBI)-associated corneal dystrophies are a group of inherited progressive corneal diseases. One of these TGFBI-associated corneal dystrophies is Avellino corneal dystrophy, an autosomal dominant corneal dystrophy characterized by multiple asymmetric stromal opacities that potentially impair vision. Recently, a case with corneal dystrophy complicated by nephropathy possessing a pathogenic variant of the TGFBI gene was reported for the first time. Here, we report the second case with the same condition and the same mutation in the TGFBI gene. The patient was an 18-year-old male. He and his father had already been diagnosed with corneal dystrophy. Proteinuria was revealed in the patient during urine screening at school. Since his serum creatinine level was raised, a percutaneous renal biopsy was performed. Light microscopy demonstrated oligomeganephronia. Electron microscopy demonstrated an irregular basement membrane. TGFBI was analyzed by direct sequencing. A heterozygous mutation c.371G > A in exon 4, which caused an amino acid substitution from arginine to histidine at codon 124, was identified in the patient and his father. Although only one case of TGFBI-associated corneal dystrophy and nephropathy has been reported, our case's clinical and pathological findings were almost identical to those in that reported case. Further investigations of this new disease entity should be reported to all nephrologists and ophthalmologists.
    Feb. 2019, CEN case reports, 8(1) (1), 14 - 17, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Nana Sakakibara, Naoya Morisada, Kandai Nozu, Koji Nagatani, Toshiyuki Ohta, Junya Shimizu, Takuzo Wada, Yuko Shima, Tomohiko Yamamura, Shogo Minamikawa, Junya Fujimura, Tomoko Horinouchi, China Nagano, Akemi Shono, Ming Juan Ye, Yoshimi Nozu, Koichi Nakanishi, Kazumoto Iijima
    Oral-facial-digital syndrome type 1 (OFD1) is a ciliopathy characterized by oral, facial, and digital malformations that are often accompanied by polycystic lesion of the kidney and central nervous involvement. OFD1 shows an X-linked recessive inheritance caused by mutation in the OFD1 gene (Xp22.2). The disease is generally considered embryonic lethal for hemizygous males. However, males with OFD1 mutations were recently reported. Here, we report four additional Japanese male patients with OFD1 variants and describe the variable clinical manifestation and disease severity among the four patients. Patient 1 with pathogenic indels including a 19-bp deletion and 4-bp insertion (c.2600-18_2600delinsACCT) had end-stage renal disease (ESRD) with bilateral cystic kidneys and sensory hearing loss. He showed neither intellectual disability nor facial or digital dysmorphism. Patient 2 with a missense variant in exon 7 (c.539 A > T, p.Asp180Val) presented head circumference enlargement, brachydactyly, high-arched palate, micropenis, severe global developmental delay, and ESRD. Patient 3 had a single base substitution at the splice donor site of intron 16 (c.2260 + 2 T > G) causing a 513-bp deletion at the transcript level. The patient had chronic kidney disease and speech delay, but no oral, facial, or digital dysmorphism. His uncle (patient 4) carried the same OFD1 variant and showed ESRD with extra-renal malformations including obesity and micropenis, which was previously diagnosed as Bardet-Biedl syndrome. The OFD1 mutations were not lethal in these four male patients, likely because the three mutations were in-frame or missense. This report provided insights into the onset mechanism and phenotype-genotype association in patients with OFD1 mutations.
    Jan. 2019, Journal of human genetics, 64(1) (1), 3 - 9, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Junya Fujimura, Kandai Nozu, Tomohiko Yamamura, Shogo Minamikawa, Keita Nakanishi, Tomoko Horinouchi, China Nagano, Nana Sakakibara, Koichi Nakanishi, Yuko Shima, Kenichi Miyako, Yoshimi Nozu, Naoya Morisada, Hiroaki Nagase, Takeshi Ninchoji, Hiroshi Kaito, Kazumoto Iijima
    Introduction: Gitelman syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most often diagnosed by chance blood test. Aside from that, some cases are also diagnosed from tetanic symptoms associated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroid dysfunction and short stature are known, but the incidence rates for these complications have not yet been elucidated. In addition, no genotype-phenotype correlation has been identified in GS. Methods: We examined the clinical characteristics and genotype-phenotype correlation in genetically proven GS cases with homozygous or compound heterozygous variants in SLC12A3 (n = 185). Results: In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), or short stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrile convulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT prolongation was detected. Among 29 cases with short stature, 10 were diagnosed with growth hormone (GH) deficiency and GH replacement therapy started. Interestingly, there was a strong correlation in serum magnesium levels between cases with p.Arg642Cys and/or p.Leu858His and cases without these variants, which are mutational hotspots in the Japanese population (1.76 mg/dl vs. 1.43 mg/dl, P < 0.001). Conclusion: This study has revealed, for the first time, clinical characteristics in genetically proven GS cases in the Japanese population, including prevalence of complications. Patients with hypokalemia detected by chance blood test should have gene tests performed. Patients with GS need attention for developing extrarenal complications, such as short stature, febrile convulsion, thyroid dysfunction, epilepsy, or QT prolongation. It was also revealed for the first time that hypomagnesemia was not severe in some variants in SLC12A3.
    Jan. 2019, Kidney international reports, 4(1) (1), 119 - 125, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • Suguru Uemura, Takeshi Mori, China Nagano, Satoru Takafuji, Noriyuki Nishimura, Tsutomu Toki, Kiminori Terui, Etsuro Ito, Kazumoto Iijima
    Dec. 2018, Pediatric blood & cancer, 65(12) (12), e27414, English, International magazine
    [Refereed]

  • Shogo Minamikawa, Kandai Nozu, Shingo Maeta, Tomohiko Yamamura, Keita Nakanishi, Junya Fujimura, Tomoko Horinouchi, China Nagano, Nana Sakakibara, Hiroaki Nagase, Hideaki Shima, Kenta Noda, Takeshi Ninchoji, Hiroshi Kaito, Kazumoto Iijima
    CD80, which regulates T cell activation, may provide a differential diagnostic marker between minimal change disease (MCD) and other renal diseases, including focal segmental glomerular sclerosis (FSGS). However, recent reports show contrasting results. Therefore, we evaluated the utility of urinary CD80 as a diagnostic biomarker. We collected 65 urine samples from 55 patients with MCD (n = 31), FSGS (n = 4), inherited nephrotic syndrome (n = 4), Alport syndrome (n = 5) and other glomerular diseases (n = 11), and control samples (n = 30). We measured urinary CD80 levels by ELISA. Urinary CD80 (ng/gCr) (median, interquartile range) levels were significantly higher in patients with MCD in relapse (91.5, 31.1-356.0), FSGS (376.2, 62.7-1916.0), and inherited nephrotic syndrome (220.1, 62.9-865.3), than in patients with MCD in remission (29.5, 21.7-52.8) (p < 0.05). Elevation of urinary CD80 was observed, even in patients with inherited nephrotic syndrome unrelated to T cell activation. Additionally, urinary CD80 was positively correlated with urinary protein levels. Our results suggest that urinary CD80 is unreliable as a differential diagnostic marker between MCD in relapse and FSGS or inherited kidney diseases. Increased urinary CD80 excretion was present in all patients with active kidney disease.
    Nov. 2018, Scientific reports, 8(1) (1), 17322 - 17322, English, International magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 榊原 菜々, 森貞 直哉, 長野 智那, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 山村 智彦, 貝藤 裕史, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, Nov. 2018, 日本小児腎臓病学会雑誌, 31(2) (2), 175 - 175, Japanese

  • 長野 智那, 野津 寛大, 森貞 直哉, 松村 千恵子, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, Nov. 2018, 日本小児腎臓病学会雑誌, 31(2) (2), 176 - 176, Japanese

  • Kasahara K, Gotoh Y, Kuroyanagi Y, Nagano C, Yamakawa S, Tanaka K, Takeda A, Uemura O
    Nov. 2018, Minerva pediatrica
    [Refereed]

  • China Nagano, Kandai Nozu, Naoya Morisada, Masahiko Yazawa, Daisuke Ichikawa, Keita Numasawa, Hiroyo Kourakata, Chieko Matsumura, Satoshi Tazoe, Ryojiro Tanaka, Tomohiko Yamamura, Shogo Minamikawa, Tomoko Horinouchi, Keita Nakanishi, Junya Fujimura, Nana Sakakibara, Yoshimi Nozu, Ming Juan Ye, Hiroshi Kaito, Kazumoto Iijima
    BACKGROUND: Comprehensive genetic approaches for diagnosing inherited kidney diseases using next-generation sequencing (NGS) have recently been established. However, even with these approaches, we are still failing to detect gene defects in some patients who appear to suffer from genetic diseases. One of the reasons for this is the difficulty of detecting copy number variations (CNVs) using our current approaches. For such cases, we can apply methods of array-based comparative genomic hybridization (aCGH) or multiplex ligation and probe amplification (MLPA); however, these are expensive and laborious and also often fail to identify CNVs. Here, we report seven cases with CNVs in various inherited kidney diseases screened by NGS pair analysis. METHODS: Targeted sequencing analysis for causative genes was conducted for cases with suspected inherited kidney diseases, for some of which a definitive genetic diagnosis had not been achieved. We conducted pair analysis using NGS data for those cases. When CNVs were detected by pair analysis, they were confirmed by aCGH and/or MLPA. RESULTS: In seven cases, CNVs in various causative genes of inherited kidney diseases were detected by pair analysis. With aCGH and/or MLPA, pathogenic CNV variants were confirmed: COL4A5 or HNF1B in two cases each, and EYA1, CLCNKB, or PAX2 in one each. CONCLUSION: We presented seven cases with CNVs in various genes that were screened by pair analysis. The NGS-based CNV detection method is useful for comprehensive screening of CNVs, and our results revealed that, for a certain proportion of cases, CNV analysis is necessary for accurate genetic diagnosis.
    Aug. 2018, Clinical and experimental nephrology, 22(4) (4), 881 - 888, English, Domestic magazine
    [Refereed]
    Scientific journal
    Link to Kobe Univ. Repository (Kernel)

  • 治療方針の決定に疾患パネル解析を用いたステロイド抵抗性ネフローゼ症候群の1例
    NAGANO CHINA, KAITO HIROSHI, FUJIMURA JUNYA, HORINOUCHI TOMOKO, NAKANISHI KEITA, MINAMIKAWA SHOGO, YAMAMURA TOMOHIKO, NOZU KANDAI, IIJIMA KAZUMOTO, KAMIYOSHI NAOHIRO, 濱平 陽史
    Jul. 2018, 日本小児腎不全学会雑誌, 38, 148 - 151, Japanese
    [Refereed]
    Scientific journal

  • 骨肉腫に対する大量化学療法についての検討
    植村 優, 森 健, 二野 菜々子, 長野 智那, 高藤 哲, 西村 範行, 飯島 一誠
    (一社)日本小児血液・がん学会, Jun. 2018, 日本小児血液・がん学会雑誌, 55(1) (1), 60 - 60, Japanese
    [Refereed]

  • 高血圧を呈さず高度蛋白尿が遷延した溶連菌感染後急性糸球体腎炎の1例
    FUJIMURA JUNYA, KAITO HIROSHI, NAGANO CHINA, 榊原 菜々, NAKANISHI KEITA, HORINOUCHI TOMOKO, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, NOZU KANDAI, IIJIMA KAZUMOTO
    Jun. 2018, 日本小児高血圧研究会誌, 15(1) (1), 21 - 25, Japanese
    [Refereed]
    Scientific journal

  • 堀之内 智子, 山村 智彦, 榊原 菜々, 長野 智那, 藤村 順也, 中西 啓太, 南川 将吾, 貝藤 裕史, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 99 - 99, Japanese

  • 榊原 菜々, 森貞 直哉, 長野 智那, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 山村 智彦, 貝藤 裕史, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 100 - 100, Japanese

  • 長野 智那, 野津 寛大, 森貞 直哉, 松村 千恵子, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 101 - 101, Japanese

  • 辻 ゆり佳, 山村 智彦, 野津 寛大, 榊原 菜々, 長野 智那, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 147 - 147, Japanese

  • 南川 将吾, 野津 寛大, 前田 真吾, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 藤村 順也, 山村 智彦, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 156 - 156, Japanese

  • 藤村 順也, 野津 寛大, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 200 - 200, Japanese

  • 低身長を契機に診断に至ったGitelman症候群の2例
    FUJIMURA JUNYA, NOZU KANDAI, NAGANO CHINA, 榊原 菜々, NAKANISHI KEITA, HORINOUCHI TOMOKO, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, KAITO HIROSHI, IIJIMA KAZUMOTO
    May 2018, 日本小児体液研究会誌, 10, 67 - 72, Japanese
    [Refereed]
    Scientific journal

  • Shogo Minamikawa, Kandai Nozu, Yoshimi Nozu, Tomohiko Yamamura, Mariko Taniguchi-Ikeda, Keita Nakanishi, Junya Fujimura, Tomoko Horinouchi, Yuko Shima, Koichi Nakanishi, Masuji Hattori, Kyoko Kanda, Ryojiro Tanaka, Naoya Morisada, China Nagano, Nana Sakakibara, Hiroaki Nagase, Ichiro Morioka, Hiroshi Kaito, Kazumoto Iijima
    The pattern of X-chromosome inactivation (XCI) can affect the clinical severity of X-linked disorders in females. XCI pattern analysis has been conducted mainly by HUMARA assay, a polymerase chain reaction-based assay using a methylation-sensitive restriction enzyme. However, this assay examines the XCI ratio of the androgen receptor gene at the genomic DNA level and does not reflect the ratio of either targeted gene directly or at the mRNA level. Here, we report four females with Dent disease, and we clarified the correlation between XCI and female cases of Dent disease using not only HUMARA assay but also a novel analytical method by RNA sequencing. We constructed genetic analysis for 4 female cases showing high level of urinary low-molecular-weight proteinuria and their parents. Their XCI pattern was analyzed by both HUMARA assay and an ultra-deep targeted RNA sequencing of the CLCN5 gene using genomic DNA and mRNA extracted from both leukocytes and urine sediment. All four cases possessed pathogenic variants of the CLCN5 gene. XCI analysis revealed skewed XCI in only two cases, while the other two showed random XCI. All assay results of HUMARA and targeted RNA sequencing in both leukocytes and urinary sediment were clearly identical in all four cases. We developed a novel XCI analytical assay of ultra-deep targeted RNA sequencing and revealed that skewed XCI explains the mechanism of onset of female Dent disease in only half of such cases.
    May 2018, Journal of human genetics, 63(5) (5), 589 - 595, English, International magazine
    [Refereed]
    Scientific journal

  • X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
    山村 智彦, 野津 寛大, 長野 智那, 榊原 菜々, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 貝藤 裕史, 中西 浩一, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 336 - 336, Japanese

  • Gitelman症候群185例における臨床的特徴に関する検討
    藤村 順也, 野津 寛大, 長野 智那, 榊原 菜々, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, Japanese

  • 次世代シークエンサー解析データを用いたpair解析により診断に至った遺伝性腎疾患例に関する検討
    長野 智那, 野津 寛大, 森貞 直哉, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, Japanese

  • ステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制の構築
    中西 啓太, 野津 寛大, 榊原 菜々, 長野 智那, 藤村 順也, 堀之内 智子, 南川 将吾, 山村 智彦, 貝藤 裕史, 島 友子, 中西 浩一, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, Japanese

  • Yoshiyuki Kuroyanagi, Yoshimitsu Gotoh, Katsuaki Kasahara, China Nagano, Naoya Fujita, Satoshi Yamakawa, Masaki Yamamoto, Asami Takeda, Osamu Uemura
    Springer Tokyo, Jul. 2017, Clinical and Experimental Nephrology, 22(2) (2), 1 - 7, English
    [Refereed]
    Scientific journal

  • Kandai Nozu, Shogo Minamikawa, Shiro Yamada, Masafumi Oka, Motoko Yanagita, Naoya Morisada, Shuichiro Fujinaga, China Nagano, Yoshimitsu Gotoh, Eihiko Takahashi, Takahiro Morishita, Tomohiko Yamamura, Takeshi Ninchoji, Hiroshi Kaito, Ichiro Morioka, Koichi Nakanishi, Igor Vorechovsky, Kazumoto Iijima
    Jul. 2017, JOURNAL OF HUMAN GENETICS, 62(7) (7), 733 - 735, English
    [Refereed]
    Scientific journal

  • Katsuaki Kasahara, Yoshimitsu Gotoh, Yoshiyuki Kuroyanagi, China Nagano
    Jul. 2017, BMC NEPHROLOGY, 18(1) (1), 237, English
    [Refereed]
    Scientific journal

  • A case of Alport-leiomyomatosis syndrome with leiomyoma in the esophagus and rectum
    Shudo Yusaku, Nagano China, Kuroyanagi Yoshiyuki, Kasahara Katsuaki, Gotoh Yoshimitsu
    <p>Alport-leiomyomatosis syndrome (A-LS) is a rare disease, in which diffuse leiomyomatosis occurs in patients with Alport syndrome. Here, we report on a case of A-LS incidentally detected by radiographic examination performed for symptoms of the common cold. The case was a boy who was undergoing follow-up observation in the outpatient department after being diagnosed with Alport syndrome from a result of the detection of complete deficiency of the type IV collagen alpha 5 chain via renal biopsy performed at the age of 6. An abnormal shadow was observed on a chest x-ray performed for symptoms of the common cold at the age of 10. Follow-up examination indicated diffuse leiomyomatosis in the esophagus and he was diagnosed with A-LS. The fact that leiomyoma was observed in the rectum as well as the esophagus made this a rare case. Genetic analysis revealed extensive deficiency from COL4A5 to COL4A6, which was the same gene loss pattern as reported in previous studies. This case was considered sporadic because no gene mutation was detected in the patient's mother. This case was considered sporadic due to this result. Due to the possibility that leiomyomatosis may occur in multiple organs in the future, this case requires continued observation.</p>
    一般社団法人 日本小児腎臓病学会, 2017, Nihon Shoni Jinzobyo Gakkai Zasshi, 30(1) (1), 41 - 47, Japanese

  • 神経芽腫に対する集学的治療後の腎機能障害・尿細管障害症例の実態調査
    長野 智那, 後藤 芳充, 笠原 克明, 畔柳 佳幸, 西川 英里, 高橋 義行
    (一社)日本小児腎臓病学会, Nov. 2016, 日本小児腎臓病学会雑誌, 29(2) (2), 201 - 202, Japanese
    [Refereed]

  • Go Miyano, China Nagano, Keiichi Morita, Masaya Yamoto, Masakatsu Kaneshiro, Hiromu Miyake, Hiroshi Nouso, Hirotsugu Kitayama, Naohiro Wada, Koji Fukumoto, Mariko Koyama, Naoto Urushihara
    Mar. 2016, JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES, 26(3) (3), 235 - 238, English
    [Refereed]
    Scientific journal

  • China Nagano, Yoshimitu Goto, Katuaki Kasahara, Yoshiyuki Kuroyanagi
    Nov. 2015, BMC NEPHROLOGY, 16, 185, English
    [Refereed]
    Scientific journal

  • Nephrotic syndrome in a child receiving cord blood stem cell transplantation (CBSCT) for infant acute lymphoblastic leukemia
    Nagano China, Wada Naohiro, Kitayama Hirotsugu, Yamada Masahiro, Uno Yuichi, Kudo Kazuko, Horikoshi Yasuo, Ogura Taemi, Ito Rieko
    A 1-month-old boy was diagnosed with infant acute lymphoblastic leukemia. At age 6 months, he underwent CBSCT after achieving remission with induction chemotherapy. Cyclosporin (CsA) was tapered because acute graft versus host disease (GVHD) showed amelioration. He was discharged 101 days after CBSCT without evidence of chronic GVHD. At age 9 months, he developed nephrotic syndrome and prednisolone therapy was started. However, proteinuria persisted for more than four weeks. Steroid resistant nephrotic syndrome was diagnosed. Three steroid pulse therapy courses were administered after the diagnosis. Percutaneous renal biopsy then revealed minimal change disease. Subsequently, mizoribine was introduced and the CsA dosage was increased. Two further steroid pulse therapy courses were administered. However, complete remission was not achieved. Many immunosuppressant drug types were administered, raising concern about recurrence of the original hematologic malignancy. Since the primary disease was B-cell lymphoblastic leukemia, rituximab was administered four times. Proteinuria disappeared and he was discharged at age 1 year and 3 months. To date, he has remained in complete remission. This is a rare case report of nephrotic syndrome developing in a child after CBSCT.
    一般社団法人 日本小児腎臓病学会, 2014, Nihon Shoni Jinzobyo Gakkai Zasshi, 27(1) (1), 36 - 42, Japanese

  • インドメタシン投与が有効であったSalt-losing tubulopathyの1例
    鵜野 裕一, 和田 尚弘, 北山 浩嗣, 山田 昌由, 長野 智那
    日本小児体液研究会事務局, 2014, 日本小児体液研究会誌 = Japanese journal of pediatric body fluid and electrolyte, 6, 63 - 66, Japanese

■ MISC
  • 前部虚血性視神経症を合併した維持腹膜透析の1例
    石森真吾, 木村裕香, 青山周平, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 堀之内智子, 山村智彦, 榊原菜々, 長野智那, 上田香織, 中西裕子, 野津寛大
    2025, 日本小児腎不全学会雑誌, 45

  • Disease susceptibility genes for nephrotic syndrome
    長野智那, 堀之内智子, 野津寛大, 飯島一誠, 飯島一誠
    2025, 腎と透析, 98(3) (3)

  • Updates on minimal change nephrotic syndrome and anti-nephrin antibodies
    堀之内智子, 長野智那, 野津寛大, 飯島一誠, 飯島一誠
    2025, 腎と透析, 98(3) (3)

  • 小児特発性ネフローゼ症候群における腎糸球体ネフリン/IgG共局在陽性の治療感受性バイオマーカーとしての可能性
    猪野木雄太, 堀之内智子, 市川裕太, 木村裕香, 青山周平, 田中悠, 上田知佳, 北角英晶, 山村智彦, 石森真吾, 長野智那, 榊原菜々, 丸山順裕, 飯島一誠, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • 頻回再発型/ステロイド依存性ネフローゼ症候群の寛解維持療法におけるミコフェノール酸モフェチルの有用性の検討
    木村裕香, 山村智彦, 青山周平, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 石森真吾, 藤村順也, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • びまん性メサンギウム増殖を呈する特発性ネフローゼ症候群の臨床像及び長期予後に関する検討
    青山周平, 山村智彦, 木村裕香, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 石森真吾, 吉川徳茂, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • Alport症候群を疑い施行した遺伝学的検査でNPHS1遺伝子変異を同定し診断に至ったネフローゼ症候群
    武市実奈, 芳野三和, 片渕瑛介, 長野智那, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • ACTN4遺伝子関連巣状分節性糸球体硬化症(FSGS1)はnon-truncating variantのみが発症する
    岩井義志, 榊原菜々, 木村裕香, 青山周平, 猪野木雄太, 田中悠, 北角英晶, 上田知佳, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • ADTKD-MUC1におけるショートリードシークエンス解析データを用いた病的バリアント検出方法
    長野智那, 森貞直哉, 青山周平, 木村裕香, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 堀之内智子, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • 全ゲノム解析によりその重症度の原因解明が可能となったAlport症候群の女児例
    上田知佳, 長野智那, 青山周平, 木村裕香, 猪野木雄太, 田中悠, 北角英晶, 榊原菜々, 堀之内智子, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • 早産や低出生体重既往児の,慢性腎臓病発症前の潜在的レニン・アンギオテンシン・アルドステロン系亢進の存在に関する組織学的検討
    石森真吾, 木村由香, 青山周平, 北角英晶, 上田知佳, 猪野木雄太, 田中悠, 石河慎也, 藤村順也, 堀之内智子, 山村智彦, 榊原菜々, 長野智那, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • 先天性ネフローゼ症候群と乳児ネフローゼ症候群における単一遺伝子異常の検出率,genotype-phenotype correlationに関する検討
    猪野木雄太, 堀之内智子, 木村裕香, 青山周平, 田中悠, 上田知佳, 北角英晶, 榊原奈々, 長野智那, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • 遺伝性尿細管機能異常症が疑われ,シェーグレン症候群の診断に至った1例
    上田知佳, 山村智彦, 青山周平, 木村裕香, 猪野木雄太, 田中悠, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 石森真吾, 野津寛大
    2025, 日本小児体液研究会誌, 17

  • Study on the development of focal segmental glomerulosclerosis in ACTN4 gene abnormality
    岩井義志, 榊原菜々, 木村裕香, 青山周平, 猪野木雄太, 田中悠, 北角英晶, 上田知佳, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児科学会雑誌, 129(2) (2)

  • 超早期発症型炎症性腸疾患に膜性腎症を合併した3歳男児
    青山周平, 山村智彦, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 長野智那, 堀之内智子, 石森慎吾, 野津寛大
    2025, 近畿小児科学会プログラム・抄録集, 38th

  • A case of Alport syndrome in which whole genome analysis was useful
    上田知佳, 長野智那, 青山周平, 木村裕香, 猪野木雄太, 田中悠, 北角英晶, 榊原菜々, 堀之内智子, 山村智彦, 石森真吾, 野津寛大
    2025, 日本小児科学会雑誌, 129(2) (2)

  • 間欠的跛行で発症した全身性エリテマトーデスの12歳女児例
    上地高志, 堀之内智子, 猪野木雄太, 田中悠, 北角英晶, 上田知佳, 長野智那, 山口雅人, 辻依子, 野津寛大
    2025, 日本小児科学会雑誌, 129(6) (6)

  • Molecular mechanisms of pathogenesis in mother-daughter cases with MED12 gene nonsense variant
    井上誠也, 大片祐一, 瀬戸俊之, 小崎健次郎, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 森貞直哉, 野津寛大
    2025, 日本小児科学会雑誌, 129(2) (2)

  • ネフロン癆関連シリオパチーの原因遺伝子と臨床像
    森貞直哉, 森貞直哉, 田中悠, 叶明娟, 花房宏昭, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2025, 日本小児遺伝学会学術集会プログラム・抄録集, 47th

  • ADTKD-MUC1診断における免疫蛍光染色の有用性
    青砥悠哉, 青砥悠哉, 長野智那, 藤井秀毅, 丸山順裕, 兵頭俊紀, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 堀之内智子, 山村智彦, 石森真吾, 森貞直哉, 原重雄, 野津寛大
    2025, 日本小児腎臓病学会雑誌(Web), 38

  • Alport症候群患者の診断における3歳児検尿の重要性の検討
    北角英晶, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 近藤淳, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • 腎生検時輸液における生理食塩水とリンゲル液の安全性の比較に関する検討
    田中悠, 堀之内智子, 猪野木雄太, 市川裕太, 上田知佳, 北角英晶, 近藤淳, 榊原菜々, 長野智那, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • ショートリードシークエンス解析データを用いたADTKD-MUC1における病的バリアント検出の試み
    長野智那, 森貞直哉, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 北角英晶, 近藤淳, 榊原菜々, 堀之内智子, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • 常染色体顕性アルポート症候群の表現型と遺伝型に関する検討
    田中悠, 榊原菜々, 猪野木雄太, 市川裕太, 北角英晶, 上田知佳, 近藤淳, 長野智那, 堀之内智子, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • COL4A5のイントロン深部に位置するバリアントによるスプライシング異常例の検討
    北角英晶, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 近藤淳, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • Digenic Alport syndromeの重症度に関する検討
    猪野木雄太, 堀之内智子, 田中悠, 市川裕太, 上田知佳, 北角英晶, 近藤淳, 榊原菜々, 長野智那, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • INF2関連腎症患者における臨床的検討
    上田知佳, 榊原菜々, 猪野木雄太, 市川裕太, 田中悠, 北角英晶, 近藤淳, 長野智那, 堀之内智子, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • Establishment of Quantitative Analysis of Active Rac1 Protein for Investigation of the Pathogenicity of Novel Variants in the Rho family small G protein-related Genes
    近藤淳, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 発達腎研究会誌(Web), 31(1) (1)

  • Alport症候群患者の診断における3歳児検尿の役割の検討
    北角英晶, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 近藤淳, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • 原因除去後長期にわたり持続する偽性Gitelman症候群の検討
    近藤淳, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • ネフリン/IgGカクテル抗体を用いた小児特発性ネフローゼ症候群腎組織の抗ネフリン抗体検出とその有用性
    市川裕太, 榊原菜々, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 近藤淳, 長野智那, 堀之内智子, 丸山順裕, 飯島一誠, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • 腎生検時輸液における生理食塩水とリンゲル液の安全性の比較に関する検討
    田中悠, 堀之内智子, 猪野木雄太, 市川裕太, 上田知佳, 北角英晶, 近藤淳, 榊原菜々, 長野智那, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • Digenic Alport syndromeの重症度に関する検討
    猪野木雄太, 堀之内智子, 田中悠, 市川裕太, 上田知佳, 北角英晶, 近藤淳, 榊原菜々, 長野智那, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • 若年で末期腎不全に至ったIgA腎症の移植後再発に対し,積極的にステロイドパルス療法を行うことで寛解導入した1例
    市川裕太, 近藤淳, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 野津寛大
    2024, 日本小児腎不全学会雑誌, 44

  • 検尿異常により発見された蛋白尿症と単一遺伝子異常との関連
    榊原菜々, 猪野木雄太, 市川裕太, 田中悠, 北角英晶, 上田知佳, 近藤淳, 長野智那, 堀之内智子, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • 腎組織の抗ネフリン抗体検出が治療方針決定に有用であったネフローゼ症候群2例
    市川裕太, 榊原菜々, 青山周平, 木村裕香, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 丸山順裕, 飯島一誠, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(6-W) (6-W)

  • 当院におけるステロイド抵抗性潰瘍性大腸炎症例の臨床的特徴と予後に関する検討
    近藤淳, 堀之内智子, 猪野木雄太, 市川裕太, 田中悠, 上田知佳, 北角英晶, 岡本典大, 宮崎はる香, 具潤亜, 鮫島由友, 長野智那, 渡邊大輔, 星奈美子, 大片祐一, 大井充, 尾藤祐子, 児玉裕三, 野津寛大
    2024, 日本小児栄養消化器肝臓学会雑誌(Web), 38(1) (1)

  • 蛋白尿及び腎機能低下の進行程度を指標に,至適なmedical nephrectomy管理をし得た先天性ネフローゼ症候群の1例
    上田知佳, 石森真吾, 石河慎也, 木村裕香, 猪野木雄太, 田中悠, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 山村智彦, 澤田真理子, 綾邦彦, 野津寛大
    2024, 日本小児腎不全学会学術集会プログラム・抄録集, 45th

  • 遺伝性尿細管機能異常症が疑われ,シェーグレン症候群の診断に至った1例
    上田知佳, 山村智彦, 木村裕香, 猪野木雄太, 田中悠, 北角英晶, 堀之内智子, 榊原菜々, 長野智那, 石森真吾, 野津寛大
    2024, 日本小児体液研究会プログラム・抄録集, 45th

  • 前部虚血性視神経症を合併した,維持腹膜透析の1例
    石森真吾, 木村裕香, 青山周平, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 堀之内智子, 山村智彦, 榊原菜々, 長野智那, 上田香織, 中西裕子, 野津寛大
    2024, 日本小児腎不全学会学術集会プログラム・抄録集, 45th

  • 視神経病変を合併した全身性エリテマトーデスの14歳女児例
    木村裕香, 山村智彦, 青山周平, 猪野木雄太, 田中悠, 上田知佳, 北角英晶, 榊原菜々, 長野智那, 堀之内智子, 石森真吾, 東田太一, 盛崇太郎, 中西裕子, 野津寛大
    2024, 日本小児リウマチ学会総会・学術集会プログラム・抄録集, 33rd (CD-ROM)

  • OCRL異常症の表現型は,phosphatidylinositol4,5-bisphosphate5-phosphatase活性と相関する
    鈴木諒太, 鈴木諒太, 榊原菜々, 市川裕太, 北角英晶, 上田知佳, 田中悠, 近藤淳, 長野智那, 堀之内智子, 岡本孝之, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • OCRL異常症の表現型は,phosphatidylinositol4,5-bisphosphate5-phosphatase活性と相関する
    鈴木諒太, 榊原菜々, 市川裕太, 北角英晶, 上田知佳, 田中悠, 岡田絵里, 近藤淳, 長野智那, 堀之内智子, 岡本孝之, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • 免疫蛍光染色によるADTKD-MUC1診断法の確立
    青砥悠哉, 青砥悠哉, 藤井秀毅, 丸山順裕, 兵頭俊紀, 市川裕太, 田中悠, 北角英晶, 近藤淳, 榊原菜々, 長野智那, 堀之内智子, 森貞直哉, 森貞直哉, 原重雄, 野津寛大
    2024, 日本小児腎臓病学会雑誌(Web), 37

  • 本邦のネフローゼ患者における抗ネフリン抗体の発現について
    長野智那, 市川裕太, 堀之内智子, 藤井秀毅, 飯島一誠, 野津寛大
    2024, 日本腎臓学会誌(Web), 66(4) (4)

  • Two cases of chronic active EB virus infection needed secondary HSCT
    植村優, 中谷尚子, 青砥悠哉, 二野菜々子, 長野智那, 山本暢之, 西村範行, 飯島一誠
    2021, 日本造血細胞移植学会総会プログラム・抄録集, 43rd

  • MSL3欠失を認めたBasilicata-Akhtar syndromeの日本人男児例
    花房宏昭, 森貞直哉, 長坂美和子, 叶明娟, 野口裕子, 長野智那, 野津寛大, 粟野宏之
    2021, 日本人類遺伝学会大会(CD-ROM), 66th

  • CLCN5遺伝子を含むX染色体微細欠失により発症したDent disease-1女性の2例
    榊原菜々, 野津寛大, 青砥悠哉, 長野智那, 堀之内智子, 忍頂寺毅史, 岡田絵里, 川口武彦, 今澤俊之, 稲垣徹史, 飯島一誠
    2021, 日本腎臓学会誌(Web), 63(4) (4)

  • 嚢胞性腎疾患の包括的遺伝子解析
    森貞直哉, 森貞直哉, 洪本加奈, 近藤淳, ROSSANTI Rini, 石河慎也, 青砥裕哉, 岡田絵里, 榊原奈々, 長野智那, 山村智彦, 堀之内智子, 貝藤裕史, 飯島一誠, 野津寛大
    2021, 日本人類遺伝学会大会プログラム・抄録集, 66th (CD-ROM)

  • 小児慢性腎炎における糖鎖不全IgA1(Gd-IgA1)免疫染色の有用性の検討
    石河慎也, 野津寛大, 近藤淳, 永井貞之, 青砥悠哉, 榊原菜々, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 貝藤裕史, 田中亮二郎, 島友子, 中西浩一, 吉川徳茂, 飯島一誠
    2020, 日本小児腎臓病学会雑誌(Web), 33(1) (1)

  • 小児における糖鎖不全IgA1免疫染色
    石河慎也, 野津寛大, 永井貞之, 青砥悠哉, 榊原菜々, 長野智那, 堀之内智子, 山村智彦, 石森真吾, 貝藤裕史, 田中亮二郎, 飯島一誠
    2020, 日本腎臓学会誌(Web), 62(4) (4)

  • 著明な羊水過多をきたし子宮内胎児死亡となったMAGED2変異による胎児期Bartter症候群の一例
    長坂美和子, 長坂美和子, 長坂美和子, 四本由郁, 四本由郁, 長野智那, 森貞直哉, 森貞直哉, 野津寛大, 飯島一誠, 玉置知子, 長坂美和子, 長坂美和子, 長坂美和子
    2020, 日本人類遺伝学会大会(CD-ROM), 65th

  • 小児ネフローゼの大規模ゲノムワイド関連解析と集団間メタ解析による新規遺伝要因の同定
    賈暁媛, 山村智彦, 長野智那, 人見祐基, KHOR Seik-Soon, 植野和子, 河合洋介, 長崎正朗, 野入英世, 堀之内智子, 野津寛大, 飯島一誠, 徳永勝士, 徳永勝士
    2020, 日本人類遺伝学会大会(CD-ROM), 65th

  • 幼児期に腎機能が悪化したTTC21B遺伝子による巣状分節性糸球体硬化症の同胞例
    釜江智佳子, 釜江智佳子, 小椋雅夫, 櫻井俊輔, 村越未希, 西健太朗, 金森透, 鈴木竜太郎, 佐藤舞, 長野智那, 野津寛大, 飯島一誠, 亀井宏一
    2020, 日本小児科学会雑誌, 124(2) (2)

  • INF2の遺伝子変異が判明した2名
    亀井宏一, 野津寛大, 長野智那, 釜江智佳子, 村越未希, 鈴木竜太郎, 金森透, 西健太朗, 佐藤舞, 小椋雅夫, 飯島一誠
    2020, 日本小児腎不全学会雑誌, 40

  • 当院で腎生検を施行した無症候性蛋白尿29名の臨床的検討
    村越未希, 小椋雅夫, 釜江智佳子, 西健太朗, 鈴木竜太郎, 金森透, 佐藤舞, 長野智那, 野津寛大, 飯島一誠, 亀井宏一
    2020, 日本小児腎臓病学会雑誌(Web), 33(1) (1)

  • Dent病に合併した薬剤性の急性尿細管間質性腎炎の1例
    財津 亜友子, 田中 征治, 江﨑 拓也, 長野 智那, 榊原 菜々, 野津 寛大, 飯島 一誠
    東京 : 日本小児腎不全学会, 2020, 日本小児腎不全学会雑誌 = Journal of Japanese Society for Pediatric Renal Failure, 40, 191 - 194, Japanese

  • Dent disease-2の女児例に関する初めての報告およびその発症機序の解明
    榊原菜々, 岡本孝之, 野津寛大, 佐藤泰征, 林麻子, 高橋俊行, 上田泰弘, 近藤淳, 永井貞之, 青砥悠哉, 石河慎也, ROSSANTI Rini, 長野智那, 堀之内智子, 山村智彦, 飯島一誠
    2020, 日本小児腎臓病学会雑誌(Web), 33(1) (1)

  • Genetic disease of the kidney and the urinary tract
    長野 智那, 野津 寛大, 飯島 一誠
    科学評論社, May 2019, 腎臓内科・泌尿器科 = Nephrology & urology, 9(5) (5), 425 - 429, Japanese

  • INF2の遺伝子変異が判明した2名
    亀井宏一, 野津寛大, 長野智那, 釜江智佳子, 釜江智佳子, 村越未希, 鈴木竜太郎, 金森透, 西健太朗, 佐藤舞, 小椋雅夫, 飯島一誠
    2019, 日本小児腎不全学会学術集会プログラム・抄録集, 41st

  • In vitro実験系を用いたCOL4A5 intron変異の病原性の検討
    堀之内 智子, 山村 智彦, 榊原 菜々, 長野 智那, 藤村 順也, 中西 啓太, 南川 将吾, 貝藤 裕史, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 99 - 99, Japanese

  • 次世代シークエンサーによるネフロン癆関連シリオパチーの包括的遺伝子解析
    榊原 菜々, 森貞 直哉, 長野 智那, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 山村 智彦, 貝藤 裕史, 野津 寛大, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 100 - 100, Japanese

  • Copy Number Variations解析により遺伝学的診断が臨床診断と異なる結果を得た4症例の検討
    長野 智那, 野津 寛大, 森貞 直哉, 松村 千恵子, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 101 - 101, Japanese

  • In vitro splicing assayを用いたFrasier症候群の臨床遺伝学的検討
    辻 ゆり佳, 山村 智彦, 野津 寛大, 榊原 菜々, 長野 智那, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 147 - 147, Japanese

  • 8歳でステロイド抵抗性ネフローゼ症候群を発症し後にNPHS1複合ヘテロ接合体変異が判明した女児例
    亀井 宏一, 野津 寛大, 中西 啓太, 長野 智那, 奥津 美夏, 石和 翔, 西 健太朗, 松村 壮史, 佐藤 舞, 小椋 雅夫, 佐古 まゆみ, 伊藤 秀一, 飯島 一誠, 石倉 健司
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 154 - 154, Japanese

  • 尿中CD80の腎疾患診断マーカーとしての有用性の検討
    南川 将吾, 野津 寛大, 前田 真吾, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 藤村 順也, 山村 智彦, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 156 - 156, Japanese

  • Gitelman症候群185例における臨床的特徴に関する検討
    藤村 順也, 野津 寛大, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本小児腎臓病学会, May 2018, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 200 - 200, Japanese

  • 治療方針の決定に疾患パネル解析を用いたステロイド抵抗性ネフローゼ症候群の1例
    長野 智那, 貝藤 裕史, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 山村 智彦, 野津 寛大, 神吉 直宙, 濱平 陽史, 飯島 一誠
    (公社)日本小児科学会, Apr. 2018, 日本小児科学会雑誌, 122(4) (4), 814 - 815, Japanese

  • X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
    山村 智彦, 野津 寛大, 長野 智那, 榊原 菜々, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 貝藤 裕史, 中西 浩一, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 336 - 336, Japanese

  • Gitelman症候群185例における臨床的特徴に関する検討
    藤村 順也, 野津 寛大, 長野 智那, 榊原 菜々, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, Japanese

  • 次世代シークエンサー解析データを用いたpair解析により診断に至った遺伝性腎疾患例に関する検討
    長野 智那, 野津 寛大, 森貞 直哉, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, Japanese

  • ステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制の構築
    中西 啓太, 野津 寛大, 榊原 菜々, 長野 智那, 藤村 順也, 堀之内 智子, 南川 将吾, 山村 智彦, 貝藤 裕史, 島 友子, 中西 浩一, 飯島 一誠
    (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, Japanese

  • 次世代シークエンサーを用いたAlport症候群の網羅的診断法の確立
    山村 智彦, 野津 寛大, 長野 智那, 榊原 菜々, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (公社)日本小児科学会, Feb. 2018, 日本小児科学会雑誌, 122(2) (2), 256 - 256, Japanese

  • Gitelman症候群の臨床的特徴に関する検討
    藤村 順也, 野津 寛大, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    (公社)日本小児科学会, Feb. 2018, 日本小児科学会雑誌, 122(2) (2), 257 - 257, Japanese

  • 尿中CD80の腎疾患診断マーカーとしての有用性の検討
    南川 将吾, 野津 寛大, 前田 真吾, 榊原 菜々, 長野 智那, 中西 啓太, 堀之内 智子, 藤村 順也, 山村 智彦, 貝藤 裕史, 飯島 一誠
    (公社)日本小児科学会, Feb. 2018, 日本小児科学会雑誌, 122(2) (2), 285 - 285, Japanese

  • 腎動脈ではなく腎末梢動脈狭窄による腎血管性高血圧症と診断し得たもやもや病の1例
    神田 杏子, 稲熊 洋祐, 中川 拓, 長野 智那, 貝藤 裕史, 野津 寛大, 飯島 一誠, 田中 亮二郎
    (公社)日本小児科学会, Feb. 2018, 日本小児科学会雑誌, 122(2) (2), 445 - 445, Japanese

  • 常染色体優性間質性腎疾患(ADTKD)の原因遺伝子と臨床像
    森貞直哉, 森貞直哉, 榊原菜々, 長野智那, 運崎愛, 運崎愛, 岡田絵里, 今澤俊之, 野津寛大, 飯島一誠
    2018, 日本人類遺伝学会大会プログラム・抄録集, 63rd

  • 症例報告 低身長を契機に診断に至ったGitelman症候群の2例
    藤村 順也, 野津 寛大, 長野 智那, 榊原 菜々, 中西 啓太, 堀之内 智子, 山村 智彦, 南川 将吾, 貝藤 裕史, 飯島 一誠
    日本小児体液研究会事務局, 2018, 日本小児体液研究会誌 = Japanese journal of pediatric body fluid and electrolyte, 10, 67 - 72, Japanese

  • A群溶連菌感染症,劇症型溶血性レンサ球菌感染症 (特集 夏場に流行る感染症 : 予防と早期発見,看護のポイント) -- (夏場に流行る感染症とは何だろう?)
    長野 智那
    へるす出版, Jul. 2016, 小児看護, 39(7) (7), 814 - 818, Japanese

  • 平滑筋腫を合併したアルポート症候群の臨床像と遺伝学的検討
    南川 将吾, 野津 寛大, 中西 啓太, 藤村 順也, 堀之内 智子, 神吉 直宙, 忍頂寺 毅史, 長野 智那, 後藤 芳充, 平野 大志, 藤永 周一郎, 高橋 英彦, 森下 高弘, 森貞 直哉, 田村 雅仁, 飯島 一誠
    (一社)日本小児腎臓病学会, Jun. 2016, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 95 - 95, Japanese

  • Clinical study of 77 pediatric and neonatal patients who were performed extracorporeal membrane oxygenation (ECMO) with CRRT(Continuous Renal Replacement Therapy)
    Hirotsugu Kitayama, Naohiro Wada, Masayoshi Yamada, Yuuichi Uno, China Nagano
    Aug. 2013, PEDIATRIC NEPHROLOGY, 28(8) (8), 1673 - 1673, English
    Summary international conference

  • Anaphylaxis and biphasic reaction in a children hospital
    China Nagano, Akira Ishiguro, Nobuyuki Yotani, Hirokazu Sakai, Takeo Fujiwara, Yukihiro Ohya
    Japanese Society of Allergology, 2013, Japanese Journal of Allergology, 62(2) (2), 163 - 170, Japanese

■ Lectures, oral presentations, etc.
  • OFD1に変異を有するシリオパチーの生存男児3例
    榊原 菜々, 森貞 直哉, 青砥 悠哉, 石河 慎也, NAGANO CHINA, MINAMIKAWA SHOGO, YAMAMURA TOMOHIKO, 清水 順也, 長谷 幸治, 和田 卓三, 島 友子, 中西 浩一, NOZU KANDAI, IIJIMA KAZUMOTO
    第40回日本小児腎不全学会学術集会, Nov. 2018, Japanese, 宮崎市, Domestic conference
    Oral presentation

  • The utility of urinary CD80 as a diagnostic maker in patients with renal diseases
    Shogo Minamikawa, Kandai Nozu, Shinya Ishiko, Yuya Aoto, Nana Sakakibara, China Nagano, Junya Fujimura, Tomohiko Yamamura, Shima Yuko, Keita Nakanishi, Kazumoto Iijima
    51th Annual Scientific Meeting of the European Society for Paediatric Nephrology, Oct. 2018, English, Antalya, International conference
    Oral presentation

  • Splicing assay with hybrid minigene: assessing pathogenicities in COL4A5 intronic mutations
    Tomoko Horinouchi, Kandai Nozu, Tomohiko Yamamura, Nana Sakakibara, China Nagano, Keita Nakanishi, Junya Fujimura, Shogo Minamikawa, Takeshi Ninchoji, Hiroshi Kaito, Yuko Shima, Kazumoto Iijima
    52st Annual Meeting of the American Society of Nephrology, Oct. 2018, English, San Diego, International conference
    Oral presentation

  • Factors regulating the severity in male X-linked Alport syndrome: study of 367 cases
    Tomohiko Yamamura, Kandai Nozu, Nana Sakakibara, China Nagano, Junya Fujimura, Tomoko Horinouchi, Keita Nakanishi, Shogo Minamikawa, Hiroshi Kaito, Yuko Shima, Kazumoto Iijima
    52st Annual Meeting of the American Society of Nephrology, Oct. 2018, English, San Diego, International conference
    Oral presentation

  • Comprehensive genetic analysis of nephronophthisis-related ciliopathies (NPHP-RC) using next generation sequencing
    Nana Sakakibara, Naoya Morisada, Shinya Ishiko, Yuya Aoto, China Nagano, Junya Fujimura, Shogo Minamikawa, Tomohiko Yamamura, Kandai Nozu, Kazumoto Iijima
    51th Annual Scientific Meeting of the European Society for Paediatric Nephrology, Oct. 2018, English, Antalya, International conference
    Oral presentation

  • Clinical characteristics of HNF1B related disorders in Japanese population
    China Nagano, Naoya Morisada, Nana Sakakibara, Tomohiko Yamamura, Shogo Minamikawa, Kandai Nozu, Kazumoto Iijima
    52st Annual Meeting of the American Society of Nephrology, Oct. 2018, English, San Diego, International conference
    Oral presentation

  • Clinical characteristics in Gitelman syndrome and correlation between genotype and phenotype
    Junya Fujimura, Kandai Nozu, Shinya Ishiko, Yuya Aoto, China Nagano, Nana Sakakibara, Shogo Minamikawa, Tomohiko Yamamura, Hiroshi Kaito, Kazumoto Iijima
    51th Annual Scientific Meeting of the European Society for Paediatric Nephrology, Oct. 2018, English, Antalya, International conference
    Oral presentation

  • An Infantile Nephrotic Syndrome Case Caused by COQ6 Gene Defects Revealed by Pair Analysis and Custom Array CGH
    Keita Nakanishi, Kandai Nozu, Takayuki Okamoto, Atsushi Hayashi, Tomoko Takahashi, Nana Sakakibara, China Nagano, Junya Fujimura, Tomoko Horinouchi, Shogo Minamikawa, Tomohiko Yamamura, Hiroshi Kaito, Yuko Shima, Koichi Nakanishi, Kazumoto Iijima
    52st Annual Meeting of the American Society of Nephrology, Oct. 2018, English, San Diego, International conference
    Oral presentation

  • 当科における24時間自由行動下血圧測定(ABPM)の使用経験
    榊原 菜々, 青砥 悠哉, 石河 慎也, NAGANO CHINA, MINAMIKAWA SHOGO, YAMAMURA TOMOHIKO, NOZU KANDAI, IIJIMA KAZUMOTO
    第25回日本小児高血圧研究会, Sep. 2018, Japanese, 名古屋市, Domestic conference
    Oral presentation

  • クラリスロマイシンによりカルシニューリン阻害薬血中濃度の異常上昇をきたした2例
    市川 裕太, MINAMIKAWA SHOGO, 青砥 悠哉, 石河 慎也, 榊原 菜々, NAGANO CHINA, YAMAMURA TOMOHIKO, NOZU KANDAI, IIJIMA KAZUMOTO
    第275回日本小児科学会近畿地方会, Sep. 2018, Japanese, 姫路市, Domestic conference
    Oral presentation

  • TGFBI関連角膜ジストロフィに腎症を合併した1例
    NAGANO CHINA, 青砥 悠哉, 石河 慎也, 榊原 菜々, MINAMIKAWA SHOGO, YAMAMURA TOMOHIKO, NOZU KANDAI, IIJIMA KAZUMOTO
    第27回発達腎研究会, Sep. 2018, Japanese, 名古屋市, Domestic conference
    Oral presentation

  • 尿中CD80の腎疾患診断マーカーとしての有用性の検討
    MINAMIKAWA SHOGO, NOZU KANDAI, 前田 真吾, 石河 慎也, 青砥 悠哉, NAGANO CHINA, 榊原 菜々, 藤村 順也, YAMAMURA TOMOHIKO, IIJIMA KAZUMOTO
    第53回小児腎臓病学会学術集会, Jun. 2018, Japanese, 福島市, Domestic conference
    Oral presentation

  • 多様な表現型を示したPierson症候群における遺伝学的・分子生物学的検討
    MINAMIKAWA SHOGO, NOZU KANDAI, 青砥 悠哉, 石河 慎也, 榊原 菜々, NAGANO CHINA, 藤村 順也, 堀之内 智子, 中西 啓太, 山村 智彦, 平野 大志, 原田 涼子, 濱田 陸, 西山 慶, 稲垣 徹史, IIJIMA KAZUMOTO
    第61回日本腎臓学会学術総会, Jun. 2018, Japanese, 新潟市, Domestic conference
    Oral presentation

  • 次世代シークエンサー解析データを用いたpair解析により診断に至った遺伝性腎疾患例に関する検討
    NAGANO CHINA, NOZU KANDAI, 森貞 直哉, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, 貝藤 裕史, IIJIMA KAZUMOTO
    第61回日本腎臓学会学術総会, Jun. 2018, Japanese, 新潟市, Domestic conference
    Oral presentation

  • 次世代シークエンサーによるネフロン癆関連シリオパチーの包括的遺伝子解析
    榊原 菜々, 森貞 直哉, NAGANO CHINA, 藤村 順也, 堀之内 智子, 中西 啓太, 南川 将吾, YAMAMURA TOMOHIKO, 貝藤 裕史, NOZU KANDAI, IIJIMA KAZUMOTO
    第53回小児腎臓病学会学術集会, Jun. 2018, Japanese, 福島市, Domestic conference
    Oral presentation

  • ステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制の構築
    中西 啓太, NOZU KANDAI, 榊原 菜々, NAGANO CHINA, 藤村 順也, 堀之内 智子, MINAMIKAWA SHOGO, YAMAMURA TOMOHIKO, 貝藤 裕史, 島 友子, 中西 浩一, IIJIMA KAZUMOTO
    第61回日本腎臓学会学術総会, Jun. 2018, Japanese, 新潟市, Domestic conference
    Oral presentation

  • X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
    YAMAMURA TOMOHIKO, NOZU KANDAI, 榊原 菜々, NAGANO CHINA, 藤村 順也, 堀之内 智子, 中西 啓太, MINAMIKAWA SHOGO, 貝藤 裕史, 中西 浩一, IIJIMA KAZUMOTO
    第61回日本腎臓学会学術総会, Jun. 2018, Japanese, 新潟市, Domestic conference
    Oral presentation

  • In vitro実験系を用いたCOL4A5 intron変異の病原性の検討
    堀之内 智子, YAMAMURA TOMOHIKO, 榊原 菜々, NAGANO CHINA, 藤村 順也, 中西 啓太, MINAMIKAWA SHOGO, 貝籐 裕史, NOZU KANDAI, IIJIMA KAZUMOTO
    第53回小児腎臓病学会学術集会, Jun. 2018, Japanese, 福島市, Domestic conference
    Oral presentation

  • Gitelman症候群185例における臨床的特徴に関する検討
    藤村 順也, NOZU KANDAI, 榊原 菜々, NAGANO CHINA, 中西 啓太, 堀之内 智子, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, 貝藤 裕史, IIJIMA KAZUMOTO
    第53回小児腎臓病学会学術集会, Jun. 2018, Japanese, 福島市, Domestic conference
    Oral presentation

  • Gitelman症候群185例における臨床的特徴に関する検討
    藤村 順也, NOZU KANDAI, 榊原 菜々, NAGANO CHINA, 中西 啓太, 堀之内 智子, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, 貝藤 裕史, IIJIMA KAZUMOTO
    第61回日本腎臓学会学術総会, Jun. 2018, Japanese, 新潟市, Domestic conference
    Oral presentation

  • Genotype-phenotype correlation in male X-linked Alport syndrome: 341 cases study
    Tomohiko Yamamura, Nana Sakakibara, China Nagano, Kandai Nozu, Junya Fujimura, Tomoko Horinouchi, Keita Nakanishi, Shogo Minamikawa, Hiroshi Kaito, Kazumoto Iijima
    第53回小児腎臓病学会学術集会, Jun. 2018, English, 福島市, Domestic conference
    Oral presentation

  • Copy Number Variations解析により遺伝学的診断が臨床診断と異なる結果を得た4症例の検討
    NAGANO CHINA, NOZU KANDAI, 森貞 直哉, 松村 千恵子, 榊原 菜々, 中西 啓太, 藤村 順也, 堀之内 智子, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, 貝藤 裕史, IIJIMA KAZUMOTO
    第53回小児腎臓病学会学術集会, Jun. 2018, Japanese, 福島市, Domestic conference
    Oral presentation

  • 無症候性血尿にて長期経過の後に蛋白尿が出現し常染色体劣性Alport症候群の診断に至った一例
    青砥 悠哉, MINAMIKAWA SHOGO, 石河 慎也, 榊原 菜々, NAGANO CHINA, FUJIMURA JUNYA, YAMAMURA TOMOHIKO, NOZU KANDAI, IIJIMA KAZUMOTO
    第274回日本小児科学会兵庫県地方会, May 2018, Japanese, 神戸市, Domestic conference
    Oral presentation

  • 尿中CD80の腎疾患診断マーカーとしての有用性の検討
    MINAMIKAWA SHOGO, NOZU KANDAI, 前田 真吾, 石河 慎也, 青砥 悠哉, NAGANO CHINA, 榊原 菜々, FUJIMURA JUNYA, YAMAMURA TOMOHIKO, IIJIMA KAZUMOTO
    第121回日本小児科学会学術集会, Apr. 2018, Japanese, 福岡市, Domestic conference
    Oral presentation

  • 次世代シークエンサーを用いたAlport症候群の網羅的診断法の確立
    YAMAMURA TOMOHIKO, NOZU KANDAI, NAGANO CHINA, 榊原 菜々, FUJIMURA JUNYA, 堀之内 智子, 中西 啓太, MINAMIKAWA SHOGO, 貝藤 裕史, IIJIMA KAZUMOTO
    第121回日本小児科学会学術集会, Apr. 2018, Japanese, 福岡市, Domestic conference
    Oral presentation

  • Gitelman症候群の臨床的特徴に関する検討
    FUJIMURA JUNYA, NOZU KANDAI, 榊原 菜々, NAGANO CHINA, 中西 啓太, 堀之内 智子, YAMAMURA TOMOHIKO, MINAMIKAWA SHOGO, KAITO HIROSHI, IIJIMA KAZUMOTO
    第121回日本小児科学会学術集会, Apr. 2018, Japanese, 福岡市, Domestic conference
    Oral presentation

  • A Case of infant nephrotic syndrome identifying compound heterozygous mutation of COQ6 gene
    China Nagano, Kandai Nozu, Takayuki Okamato, Naoya Morisada, Tomohiko Yamamura, Shogo Minamikawa, Tomoko Horinouchi, Keita Nakanishi, Junya Fujimura, Nana Sakakibara, Hiroshi Kaito, Kazumoto Iijima
    The 16th Korea-China-Yapan Pediatric Nephrology Seminar2018, Apr. 2018, English, Busan, International conference
    Oral presentation

■ Research Themes
  • Joint international Research Project for International GWAS Meta-Analysis and Anti-Nephrin Autoantibodies in Childhood Nephrotic Syndrome
    飯島 一誠, 賈 暁媛, 堀之内 智子, 長野 智那, 野津 寛大
    Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)), Kobe University, 07 Oct. 2021 - 31 Mar. 2024
    本研究は、Boston Children’s Hospital-HarvardのMatthew Sampson博士との国際共同研究であり、①国際GWASメタ解析で明らかになった7つの新たな疾患感受性遺伝子候補領域から疾患感受性遺伝子を同定すること、②日本人小児NS患者の病因として抗ネフリン自己抗体がどの程度関与しているのか、どのようなメカニズムでネフリンに対する自己免疫が生じるのかを疾患感受性遺伝子の側面から解明することを目的とする。 令和3年度は、日本人若手研究分担者である長野が、2021年6月より、Sampson博士の研究室で、研究を開始し、7つの疾患感受性遺伝子候補領域のfine-mappingを実施し、Nephrotic Syndrome Study Network (NEPTUNE)が保有する特発性ネフローゼ症候群患者の全ゲノム情報と腎生検検体（腎糸球体及び尿細管）のRNA-Seq情報を統合したデータベース（NephQTL）や、Harvard大学が保有する免疫細胞RNA-Seqデータベースとの統合解析を実施し、それぞれの遺伝子の発現パターンを明らかにした。一方、神戸大学を中心とした日本側の研究者は、小児特発性ネフローゼ症候群患者15例の活動期（高度蛋白尿出現時）と寛解期（蛋白尿消失期）のペア血漿を収集し、そのサンプルをBoston Children’s Hospitalに送った。現在、その結果を待っているところである。

  • iPS細胞由来腎臓オルガノイドを用いた小児ネフローゼ症候群の発症機序の解明
    飯島 一誠, 堀之内 智子, 高里 実, 野津 寛大, 長野 智那
    日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 01 Apr. 2020 - 31 Mar. 2023
    小児ネフローゼ症候群（NS）は小児慢性腎疾患で最も頻度が高い原因不明の指定難病である。我々は最近、日本人小児NS患者のゲノムワイド関連解析及び国際メタ解析を行い、腎糸球体ポドサイトに強発現し、尿蛋白防止機構として最も重要なスリット膜の主要構成蛋白であるNephrinをコードする遺伝子－NPHS1のvariantがNSの発症に関連する可能性を世界で初めて見出した。しかし、それらのvariantが、どのような機序でNSの発症に関与するのかは依然として明らかではなく、そのメカニズムを解明する必要がある。 本研究では、小児NS患者由来のiPS細胞を分化誘導し作成した腎臓オルガノイドを用いて、NPHS1のvariantがNSの発症に関与するメカニズムを解明することを目的とする。なお、先行研究から、NPHS1領域の主なvariantは、eQTLやsQTLとして作用するのではなく、minor alleleすべて（risk haplotype）をheteroで有する患者で、Allele-specific expression（ASE）という現象が生じていることが示唆されている。 令和3年度には、研究分担者である理研の高里研究室において、令和2年度に作成した8名のNS患者由来のiPS細胞の一部で、NPHS1領域のrisk haplotypeをhomo, heteroの状態で有する患者由来のiPS細胞をマルチステップ分化誘導し腎臓オルガノイドの作成に成功した。

  • WT1遺伝子異常症に対する病態解明と新規治療法の開発
    長野 智那
    日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 01 Apr. 2020 - 31 Mar. 2022
    WT1遺伝子はWilms腫瘍の原因遺伝子として単離された遺伝子である。WT1蛋白はC末端に4つのZnフィンガー構造(DNA結合ドメイン)を有し、DNA上の転写調節配列に結合し転写因子として働く。泌尿生殖器系の発生分化および、生後も腎糸球体の構造維持に関与している。WT1遺伝子異常症は常染色体優性遺伝形式を呈し、変異の部位により多彩な症状を来す。乳児期に発症する進行性の腎障害、Wilms腫瘍、性分化異常を呈するDenys-Drash症候群患者は主にエクソン8あるいは9のミスセンス変異を有し、緩徐に進行する腎障害、性分化異常やWilms腫瘍・性腺腫瘍を特徴とするFrasier症候群はイントロン9に変異を有するなど遺伝子型によりその臨床像が大きく異なることを特徴とする。しかし、WT1遺伝子異常症の日本人における正確な発症頻度は知られておらず、遺伝子診断体制も確立していない。また有効な治療法は存在しない。 本研究は日本人における両疾患の発症頻度を明らかにすると共に、Denys-Drash症候群については転写活性を測定する系を確立し、検出された新規変異の病原性の証明系の確立、発症メカニズム、転写活性と重症度との相関関係の解明を行う。またFrasier症候群においてはイントロン9のスプライスサイト変異により、9塩基に由来する3つのアミノ酸(リジン,スレオニン,セリン)が欠失することが特徴である。そのため、核酸医薬を用いたスプライシング制御により、これらの3つのアミノ酸の挿入をもたらす治療薬の開発により、同疾患に対する根本的治療法の確立を目指す。

  • 飯島 一誠
    学術研究助成基金助成金／国際共同研究加速基金(国際共同研究強化(B)), Oct. 2018 - Mar. 2021
    Competitive research funding

  • 長野 智那
    科学研究費補助金／若手研究, Apr. 2018 - Mar. 2020, Principal investigator
    Competitive research funding

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