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HORINOUCHI TomokoUniversity Hospital / Center for Perinatal CareAssociate Professor
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■ Award- Oct. 2024 IPNA, Renee Habib Young Investigator Award
- Jun. 2024 日本腎臓学会, Clinical Scientist Award
- Jun. 2023 神戸大学, 令和5年度優秀若手研究者賞
- May 2022 2021年度神戸大学医学部附属病院下半期研修医ミーティングベストレクチャー賞
- Mar. 2022 2021年度神戸大学医学部附属病院ベストティーチャー賞
- Jul. 2021 第56回日本小児腎臓病学会学術集会 優秀演題奨励賞
- Jun. 2021 第64回日本腎臓学会学術総会優秀演題賞
- Jan. 2021 第55回日本小児腎臓病学会学術集会 優秀演題奨励賞
- May 2020 日本小児腎臓病学会, 森田賞（基礎医学部門）
- May 2020 令和2年度田中千賀子学術奨励賞
- Aug. 2019 第5回腎臓セミナー NEXUS Japan YIA
- Jun. 2019 第54回日本小児腎臓病学会学術集会 奨励賞臨床部門
- Jun. 2018 第61回日本腎臓学会学術総会 会長賞
- 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[Refereed]Scientific journal
- 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.Corresponding, Apr. 2025, Pediatric nephrology (Berlin, Germany), 40(4) (4), 1033 - 1040, English, International magazine[Refereed]Scientific journal
- 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.Corresponding, Mar. 2025, Pediatric nephrology (Berlin, Germany), English, International magazine[Refereed]Scientific journal
- Nephrotic syndrome is the most common glomerular disease in children, and various hypotheses regarding its etiology have been proposed, primarily focusing on immune-related mechanisms. Nephrotic syndrome can manifest as a monogenic disease caused by deleterious variants in genes such as NPHS1, which encodes nephrin. In steroid-sensitive nephrotic syndrome, HLA class II and immune-related genes have been identified as susceptibility genes. Moreover, NPHS1 is a susceptibility gene for steroid-sensitive nephrotic syndrome in patients from East Asian populations. Anti-nephrin antibodies have been identified as a significant factor in the pathogenesis of nephrotic syndrome. These discoveries have substantially advanced our understanding of nephrotic syndrome. However, the mechanisms underlying the production of anti-nephrin antibodies and their association with genetic backgrounds have remained unclear and warrant further investigation.Mar. 2025, Clinical and experimental nephrology, English, Domestic magazine[Refereed][Invited]Scientific journal
- 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[Refereed]Scientific journal
- 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.Corresponding, Feb. 2025, Modern rheumatology case reports, English, International magazine[Refereed]Scientific journal
- 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.Corresponding, Feb. 2025, Kidney international reports, 10(2) (2), 516 - 521, English, International magazine[Refereed]Scientific journal
- OBJECTIVE: To compare the number and incidence of Kawasaki disease (KD) patients in years 2 through 4 of the coronavirus disease 2019 pandemic, and determine the impact of 3 years of implementation of infection control measures and their subsequent relaxation on the epidemiology of KD in Japan. STUDY DESIGN: We conducted a population-based, cohort study including consecutive KD patients in Kobe City between 2021 and 2023. We compared the incidence of KD cases, in relation to timing of infection control measures, as well as infectious disease cases based on a regional surveillance system. Data from a previous 2016 through 2020 study were used for comparison. RESULTS: A total of 566 children with KD were identified during the study period. During the infection control period in 2021 to 2022, the incidence of KD remained low compared with the prepandemic level (281.3 and 327.5/100 000 children aged 0-4 years in 2021 to 2022 and 2016 through 2019, respectively), but a recovery trend began in the 0-1-year age group. During the relaxation period in 2023, the incidence of KD increased across a wide-age range, reaching the highest recorded in Japan (426.7/100 000 children aged 0-4 years), and the median age of onset increased to age 30 months. The resurgence of KD coincided with the epidemic patterns for multiple infectious diseases in 2023. The seasonality of KD observed before the pandemic was altered. CONCLUSIONS: KD resurged in 2023 after relaxation of the prolonged coronavirus disease 2019 pandemic restrictions in Japan. This phenomenon coincided with the rise of multiple infectious diseases, and supports the pathogenesis of KD being triggered by infectious agents.Dec. 2024, The Journal of pediatrics, 275, 114251 - 114251, English, International magazine[Refereed]Scientific journal
- Alport syndrome (AS) is a hereditary disease caused by mutations in the COL4A5 gene and leads to chronic kidney disease. Currently, no specific treatment has been developed. However, a recent study using AS-model mice demonstrated that the exon skipping method could partially rescue the symptoms. In this study, we evaluated the effects of the exon skipping method using kidney organoids generated from AS-patient-derived induced pluripotent stem cells (AS-iPSCs). We generated kidney organoids from AS-iPSCs, which exhibited nephron structures. As expected, the C-terminus of COL4A5 was not expressed in AS-organoids. Interestingly, anti-sense oligonucleotides restored the expression of the C-terminus of COL4A5 in vitro. Next, we transplanted AS-organoids into mice and evaluated glomerular basement membrane formation in vivo. We found that AS-organoids formed a lower slit diaphragm ratio compared to control organoids. Finally, we assessed the effects of exon skipping on transplanted organoids but observed minimum effects. These studies suggest that AS-iPSCs can generate kidney organoids lacking the C-terminus of COL4A5, and that exon skipping can induce its expression in vitro.Dec. 2024, Genes to cells : devoted to molecular & cellular mechanisms, 29(12) (12), 1118 - 1130, English, International magazine[Refereed]Scientific journal
- 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.Corresponding, Oct. 2024, Kidney360, 5(10) (10), 1510 - 1517, English, International magazine[Refereed]Scientific journal
- 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
- 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.Corresponding, Apr. 2024, Pediatric nephrology (Berlin, Germany), English, International magazine[Refereed]Scientific journal
- Springer Science and Business Media LLC, Apr. 2024, Clinical and Experimental Nephrology[Refereed]Scientific journal
- 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.Corresponding, Apr. 2024, CEN case reports, English, Domestic magazine[Refereed]Scientific journal
- PURPOSE: Tubulointerstitial nephritis (TIN) has various etiologies, including IgG4-related disease (IgG4-RD), autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and others. IgG4-positive plasma cell infiltration can occasionally be found in TIN unrelated to IgG4-RD. Therefore, there may be problems with usage of IgG4 immunostaining to differentiate between TIN with and TIN without IgG4-RD. This study aimed to compare the proportion of plasma cells that are positive for each IgG subclass and to clarify the predominant IgG subclass trends and clinical characteristics associated with IgG4-RD and non-IgG4-related interstitial nephritis. METHODS: The study enrolled 44 cases of TIN: 6 of IgG4-RD, 8 of autoimmune disease, 9 of AAV, and 21 of unknown disease group. In addition to clinical characteristics, IgG subclass composition of interstitial plasma cells was evaluated among 4 groups by immunohistochemistry. RESULTS: IgG1 was the predominant IgG subclass in TIN unrelated to IgG4-RD. In the IgG4-RD group, the IgG subclass rate was high in both IgG1 and IgG4. The rate of average IgG4-positive cells was significantly lower in the autoimmune disease group and unknown disease group compared with the IgG4-RD group. CONCLUSION: The present study revealed IgG1-dominant immune profiles of TIN unrelated to IgG4-RD. Further investigation is required to elucidate the clinicopathological differences between IgG1-dominant and IgG4-dominant groups in IgG4-RD.Feb. 2024, International urology and nephrology, English, International magazine[Refereed]Scientific journal
- Serum leucine-rich alpha-2 glycoprotein (LRG) has been utilized for adult inflammatory bowel disease (IBD); however, its efficacy in pediatric IBD remains unknown. The aim of this study was to compare the diagnostic accuracy of serum LRG for pediatric IBD with that of current inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This retrospective case-control study included pediatric patients, aged <16 years, who underwent colonoscopy and/or esophagogastroduodenoscopy between April 2017 and March 2022. All eligible patients were divided into two groups: patients with IBD, diagnosed with ulcerative colitis and Crohn's disease, and non-IBD controls. The optimal cut-off value of serum LRG for IBD diagnosis was determined from receiver operating characteristic analysis, and diagnostic accuracy of serum LRG was compared to serum ESR and CRP. A total of 53 patients (24 with IBD and 29 non-IBD controls) met the inclusion criteria. The cut-off value of serum LRG for IBD diagnosis was determined to be 19.5 μg/ml. At this cut-off value, serum LRG had a positive predictive value (PPV) of 0.80 and negative predictive value (NPV) of 0.88. In contrast, PPV and NPV were 0.78 and 0.70 for serum ESR and 0.82 and 0.72 for serum CRP, respectively. Serum LRG can be a potential diagnostic marker for pediatric IBD, with higher diagnostic accuracy than that of the conventional serum markers ESR and CRP.Jan. 2024, The Kobe journal of medical sciences, 69(4) (4), E122-E128, English, Domestic magazineScientific journal
- BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.Nov. 2023, Clinical and experimental nephrology, English, Domestic magazine[Refereed]Scientific journal
- Abstract Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3, COL4A4 or COL4A5 gene mutations and characterized by abnormalities of glomerular basement membranes (GBMs). Due to a lack of curative treatments, the condition proceeds to end-stage renal disease even in adolescents. Hampering drug discovery is the absence of effective in vitro methods for testing the restoration of normal GBMs. Here, we aimed to develop kidney organoid models from AS patient iPSCs for this purpose. We established iPSC-derived collagen α5(IV)-expressing kidney organoids and confirmed that kidney organoids from COL4A5 mutation-corrected iPSCs restore collagen α5(IV) protein expression. Importantly, our model recapitulates the differences in collagen composition between iPSC-derived kidney organoids from mild and severe AS cases. Furthermore, we demonstrate that a chemical chaperone, 4-phenyl butyric acid, has the potential to correct GBM abnormalities in kidney organoids showing mild AS phenotypes. This iPSC-derived kidney organoid model will contribute to drug discovery for AS.Springer Science and Business Media LLC, Sep. 2023, Communications Biology, 6(1) (1)[Refereed]Scientific journal
- Elsevier {BV}, Jul. 2023, Kidney International Reports, English[Refereed]Scientific journal
- BACKGROUND: Patients with severe IgA vasculitis with nephritis (IgAVN) typically receive aggressive therapy as an initial approach. We have consistently performed combination therapy including corticosteroids and immunosuppressants as initial therapy for severe IgAVN over a 20-year-plus period, with only minor changes to the treatment protocol. This study seeks to reveal the efficacy of combination therapy for severe IgAVN. METHODS: We retrospectively studied 50 Japanese children diagnosed between 1996 and 2019 with clinicopathologically severe IgAVN who were defined as ISKDC classification grade IIIb-V and/or serum albumin < 2.5 g/dL. RESULTS: The median age at the onset of IgAVN was 8.0 years (IQR: 6.0-10.0). At biopsy, 44% of patients had nephrotic syndrome and 14% had kidney dysfunction. All patients were treated with combination therapy after biopsy. Abnormal proteinuria resolved after initial therapy in all 50 patients. However, eight patients (16%) had recurrence of proteinuria. Abnormal proteinuria was again resolved in three of these patients with additional treatment. At the last follow-up (median 59.5 months; IQR, 26.2-84.2), the median urine protein-to-creatine ratio was 0.08 g/gCr (IQR, 0.05-0.15), and only one patient had kidney dysfunction. CONCLUSIONS: Combination therapy provided good kidney outcomes for Japanese children with severe IgAVN. Even including recurrent cases, the degree of proteinuria was slight, and kidney function was good at the last follow-up. A higher resolution version of the Graphical abstract is available as Supplementary information.Corresponding, Jun. 2023, Pediatric nephrology (Berlin, Germany), English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- [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[Refereed]
- 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[Refereed]Scientific journal
- A Japanese boy developed nephrotic syndrome (NS) and had microscopic hematuria at 8 years old. Renal biopsy was performed. Light microscopy study revealed mesangial proliferation and all immunofluorescent stains (including IgA) were negative, so he was diagnosed with non-IgA diffuse mesangial proliferation (DMP). Complete remission was achieved at 13 days after the initiation of oral prednisolone, and hematuria also disappeared 3 days later, but the patient developed frequently relapsing nephrotic syndrome. Cyclosporine A (CyA) was introduced at 10 years old, and there were no relapses between then and when it was discontinued at 12 years old. A second renal biopsy revealed minimal change without CyA nephrotoxicity. However, there was repeated relapse of NS after discontinuation, so CyA was reintroduced 8 months later, and NS remained in remission thereafter. Microscopic hematuria appeared at 13 years old, however, with gross hematuria appearing at the time of infection. A third renal biopsy revealed mesangial proliferation with IgA-dominant deposition, so the patient was diagnosed with IgA nephropathy. Currently (14 years old), CyA treatment has been discontinued and the patient is undergoing lisinopril therapy for IgA nephropathy, but there are still relapses of NS. To the best of our knowledge, there have been no previous reports of a patient with non-IgA DMP at the onset of NS who had later development of IgA nephropathy. The patient showed non-IgA DMP at the onset, suggesting that NS with non-IgA DMP and IgA nephropathy has some common pathophysiology. Treatment for NS, such as PSL and/or CyA treatment, may suppress the clinical manifestation of late IgA nephropathy.Corresponding, Apr. 2023, CEN case reports, English, Domestic magazine[Refereed]Scientific journal
- BACKGROUND AND OBJECTIVES: The evident genotype-phenotype correlation shown by the X-linked Alport syndrome warrants the assessment of the impact of identified gene variants on aberrant splicing. We previously reported that single nucleotide variants (SNVs) in the last nucleotide of exons in COL4A5 cause aberrant splicing. It is known that the nucleotides located 2nd and 3rd to the last nucleotides of exons can also play an essential role in the first step of the splicing process. In this study, we aimed to investigate whether SNVs positioned 2nd or 3rd to the last nucleotide of exons in COL4A5 resulted in aberrant splicing. METHODS: We selected eight candidate variants: six from the Human Gene Variant Database Professional and two from our cohort. We performed an in-vitro splicing assay and reverse transcription-polymerase chain reaction (RT-PCR) for messenger RNA obtained from patients, if available. RESULTS: The candidate variants were initially classified into the following groups: three nonsense, two missense, and three synonymous variants. Splicing assays and RT-PCR for messenger RNA revealed that six of the eight variants caused aberrant splicing. Four variants, initially classified as non-truncating variants, were found to be truncating ones, which usually show relatively more severe phenotypes. CONCLUSION: We revealed that exonic SNVs positioned 2nd or 3rd to the last nucleotide of exons in the COL4A5 were responsible for aberrant splicing. The results of our study suggest that attention should be paid when interpreting the pathogenicity of exonic SNVs near the 5' splice site.Mar. 2023, Clinical and experimental nephrology, 27(3) (3), 218 - 226, English, Domestic magazine[Refereed]Scientific journal
- Feb. 2023, Journal of nephrology, 1 - 4, English, International magazine[Refereed]Scientific journal
- We encountered a case with congenital iris coloboma, omphalocele, and developmental delay with a 2.5 Mb deletion on chromosome 4q25 encompassing PITX2, leading to Axenfeld-Rieger syndrome (ARS), NEUROG2, and ANK2. ARS is characterized by the aplasia of the anterior eye, odontogenesis, and abdominal wall aplasia. In our case, iris coloboma and omphalocele were thought to be caused by PITX2 haploinsufficiency. However, these symptoms are nonspecific, and clinical symptoms alone can make it difficult to make a correct diagnosis. In addition, the genes responsible for developmental delay, among others, are not well understood. Developmental delay, in this case, might be caused due to NEUROG2 haploinsufficiency. In spite of the partial deletion of ANK2, the causative gene of long QT syndrome type 4, the electrocardiogram was normal. Genetic testing can lead to a correct diagnosis, and it may be effective in detecting complications.Corresponding, 2023, Case reports in genetics, 2023, 4592114 - 4592114, English, International magazine[Refereed]
- BACKGROUND: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available. METHODS: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as - X to + Y (period from day - 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination. RESULTS: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01). CONCLUSIONS: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.Nov. 2022, Pediatric nephrology (Berlin, Germany), 38(7) (7), 1 - 10, English, International magazine[Refereed]Scientific journal
- 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.Corresponding, Sep. 2022, American journal of medical genetics. Part A, 188(9) (9), 2576 - 2583, English, International magazine[Refereed]Scientific journal
- BACKGROUND: Oligomeganephronia (OMN) is a rare congenital anomaly involving the kidney and urinary tract, characterized by decreased number and compensatory hypertrophy of the nephron. It is caused by abnormal kidney development during the embryonic period, especially in patients with low birth weight; however, the actual etiology and clinical features remain unknown. We aim to reveal the clinical and pathological characteristics, treatment, and outcome. METHODS: Ten patients diagnosed with OMN between 2013 and 2020 were retrospectively investigated. The data were presented as the median ± interquartile range, and statistical significance was set at p < 0.05. RESULTS: The age at diagnosis was 14.1 years, the male-to-female ratio was 6:4, and only four cases were born with low birth weight. The estimated glomerular filtration rate (eGFR) was 62.2 mL/min/1.73 m2. The glomerulus diameter of OMN patients was significantly larger (217 vs. 154 µm, p < 0.001) in OMN patients, and the number of glomeruli of OMN patients was lower (0.89 vs. 2.05/mm2, p < 0.001) than the control group. Eight of the ten cases were identified by urinary screening. Nine patients were treated with renin-angiotensin system (RAS) inhibitors, following which proteinuria successfully decreased or disappeared. Their median eGFR was also stable, 53.3 mL/min/1.73 m2. CONCLUSIONS: As few symptoms can lead to OMN discovery, most patients were found during urine screening at school. Kidney dysfunction was observed in all patients at the time of kidney biopsy. Proteinuria has been significantly reduced and the decline rate of eGFR might be improved by RAS inhibitors. "A higher resolution version of the Graphical abstract is available as Supplementary information".Corresponding, Jul. 2022, Pediatric nephrology (Berlin, Germany), 38(3) (3), 757 - 762, English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- American Society of Nephrology ({ASN}), May 2022, Kidney360, 3(8) (8), 1384 - 1393, English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- 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.Corresponding, Mar. 2022, Kidney360, 3(3) (3), 497 - 505, English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.Feb. 2022, Journal of the American Society of Nephrology : JASN, 33(2) (2), 401 - 419, English, International magazine[Refereed]Scientific journal
- Feb. 2022, CEN case reports, 11(1) (1), 159 - 160, English, Domestic magazine[Refereed]
- 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[Refereed]Scientific journal
- 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.Corresponding, Jan. 2022, Pediatric nephrology (Berlin, Germany), 37(8) (8), 1845 - 1853, English, International magazine[Refereed]Scientific journal
- Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.Lead, Jan. 2022, Pediatric nephrology (Berlin, Germany), English, International magazine[Refereed]Scientific journal
- X-linked Alport syndrome (XLAS) is caused by pathogenic variants in COL4A5 and is characterized by progressive kidney disease, hearing loss, and ocular abnormalities. Recent advances in genetic analysis and further understanding of genotype-phenotype correlations in affected male patients raises the importance of detecting splicing variants in COL4A5. Aberrant splicing of COL4A5 is caused not only by canonical splice site variants but also non-canonical splice site variants such as deep intronic changes or even substitutions in exons. Patients with splicing variants account for ~15% of all cases in XLAS. In addition, it has been shown that there is a significant difference in kidney survival depending on the aberrant splicing patterns of transcripts- in particular in-frame or out-of-frame nucleotide changes in transcripts. Therefore, cDNA analysis of patient mRNA is necessary to determine the impact of splice site variants and to confirm a diagnosis of XLAS and to predict the kidney prognosis. However, it is usually difficult to amplify COL4A5 transcripts extracted from peripheral blood leukocytes. For these cases, in vitro minigene assays or RNA sequence extracted from urine derived cells can confirm aberrant splicing patterns. Moreover, controlling aberrant splicing by nucleic acids or small molecular compounds in genetic diseases are attracting attention as a potential therapeutic strategy. Here, we review the frequency of splicing variants in COL4A5, the latest diagnostic strategies, and the prospects for new therapeutic approaches.2022, Frontiers in medicine, 9, 841391 - 841391, English, International magazine[Refereed]Scientific journal
- (株)診断と治療社, Nov. 2021, 小児科診療, 84(11) (11), 1436 - 1440, Japanese
- (株)東京医学社, Nov. 2021, 腎と透析, 91(5) (5), 837 - 843, Japanese
- 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, 2(12) (12), 10.34067/KID.0004952021 - 10.34067/KID.0004952021, English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- Elsevier BV, Oct. 2021, Kidney International Reports[Refereed]Scientific journal
- Oxford University Press (OUP), Sep. 2021, Nephrology Dialysis Transplantation, 37(2) (2), 262 - 270
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 > 50% enzyme activity, whereas the Lowe syndrome variants retained < 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.[Refereed]Scientific journal - ＜文献概要＞Point ◎遺伝性腎疾患は多岐にわたるが,臨床診断が困難な場合,臨床情報と遺伝学的検査を併せて検討することで正確な診断につながることがある.◎特に,疾患特異的な治療が存在する常染色体優性多発性嚢胞腎(ADPKD)やFabry病およびレニン・アンジオテンシン系(RAS)阻害薬が有効であるAlport症候群などではできるだけ早期の正確な診断が重要である.◎近年,次世代シークエンサーの進歩により,網羅的にさまざまな遺伝学的検査を行うことが可能となっている.◎遺伝学的検査に際しては,各種ガイドラインや指針の趣旨をよく理解しておく必要がある.Lead, (株)医学書院, Sep. 2021, Medicina, 58(10) (10), 1651 - 1654, Japanese
- 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[Refereed]Scientific journal
- (株)東京医学社, Aug. 2021, 腎と透析, 91(増刊) (増刊), 76 - 80, Japanese
- (株)東京医学社, Aug. 2021, 腎と透析, 91(増刊) (増刊), 808 - 811, Japanese
- Jul. 2021, Pediatric nephrology (Berlin, Germany), 36(7) (7), 1953 - 1954, English, International magazine[Refereed]Scientific journal
- Jul. 2021, Pediatric nephrology (Berlin, Germany), 36(7) (7), 1955 - 1958, English, International magazine[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- May 2021, Clinical and experimental nephrology, 25(5) (5), 564 - 564, English, Domestic magazine[Refereed]
- Elsevier BV, May 2021, Kidney International Reports[Refereed]Scientific journal
- Lead, (株)診断と治療社, Apr. 2021, 小児科診療, 84(増刊) (増刊), 306 - 309, Japanese
- Neonatal jaundice has been suggested as a perinatal risk factor for autism spectrum disorder (ASD). We examined UGT1A1 polymorphisms to assess the potential of neonatal jaundice as a risk factor for ASD in children by using DNA extracted from preserved umbilical cord. In total, 79 children with ASD were genotyped for UGT1A1*28 (c.-41-40dup), UGT1A1*6 (c.211 G > A), and UGT1A1*27 (c.686 C > A). The allele frequency of UGT1A1*6 (OR = 1.34, p = 0.26) and UGT1A1*28 (OR = 0.80, p = 0.54) and the prevalence of UGT1A1*28/*6 diplotypes did not differ significantly from those in the control population. No UGT1A1*27 allele was detected in the subjects. ASD symptom assessment scores were not associated with UGT1A1*28/*6/*27 genotypes or UGT1A1*28/*6 diplotypes. These results suggest that neonatal jaundice is not significantly associated with ASD.Lead, Mar. 2021, Journal of autism and developmental disorders, 52(2) (2), 483 - 489, English, International magazine[Refereed]Scientific journal
- ＜文献概要＞維持輸液療法は,かつては3号液(3分の1生食)を4-2-1ルールに基づく投与量で行うことが一般的であった.しかし,非浸透圧刺激性ADH分泌による医原性低Na血症発症の可能性を少しでも低下させるため,現在は等張液で開始のうえ,必要に応じて輸液内の電解質を調節することが推奨されている.一方で等張液を用いた維持輸液においては低K血症,高Na血症のリスクがある.一律にすべての患者において同じマニュアルで輸液製剤を決めるのではなく,インアウトバランスを中心に患者の状態を適切に判断し,輸液の組成および投与量を決定する.また,経口補水が可能となった際は速やかに輸液を中止する.Lead, 金原出版(株), Feb. 2021, 小児科, 62(2) (2), 130 - 135, Japanese
- 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[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- (有)科学評論社, Jan. 2021, 腎臓内科, 13(1) (1), 105 - 112, Japanese
- 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[Refereed]Scientific journal
- Lead, (株)東京医学社, Nov. 2020, 腎と透析, 89(5) (5), 846 - 849, Japanese
- 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[Refereed]Scientific journal
- 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[Refereed]Scientific journal
- 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.Jul. 2020, Kidney international, 98(6) (6), 1605 - 1614, English, International magazine[Refereed]Scientific journal
- 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.Jul. 2020, Pediatric nephrology (Berlin, Germany), 35(12) (12), 2319 - 2326, English, International magazine[Refereed]Scientific journal
- 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.Jul. 2020, CEN case reports, 9(4) (4), 431 - 436, English, Domestic magazine[Refereed]Scientific journal
- 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
- 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.Jun. 2020, CEN case reports, 9(4) (4), 418 - 422, English, Domestic magazine[Refereed]Scientific journal
- 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.Jun. 2020, Molecular genetics & genomic medicine, 8(8) (8), e1342, English, International magazine[Refereed]Scientific journal
- 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).Jun. 2020, Kidney international, 98(5) (5), 1308 - 1322, English, International magazine[Refereed]Scientific journal
- 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
- 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
- WT1遺伝子異常症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。腎臓の発生過程に発現し分化調節に働き、生後も糸球体上皮細胞に発現してポトサイト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呈する事が特徴である。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症候群患者の大部分はDNA結合ドメインをコードするエクソン8あるいは9のミスセンス変異が存在する。その結果生じる異常なWT1蛋白は、Dominant negative効果により正常WT1蛋白の機能を低下させるため重症になると考えられている。ここではWT1遺伝子の機能と疾患について簡単に説明する。(著者抄録)発達腎研究会, Apr. 2020, 発達腎研究会誌, 28(1) (1), 29 - 32, Japanese
- 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
- 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
- X染色体連鎖型Alport症候群におけるsplicing異常の同定と臨床遺伝学的検討X染色体連鎖型Alport症候群(XLAS)患者に対してトランスクリプト解析を行い、splicing異常により発症していた男性患者ではそのトランスクリプトレベルでtruncatingかnon-truncatingかを区別し、遺伝子型と臨床像の相関関係を比較した。当科で遺伝学的に診断を行った279家系のXLASのうち、71家系(25%)はtruncating変異、159家系(57%)はnon-truncating変異、49家系(18%)はsplicing異常をきたしており、splicing異常の41家系を検討対象とした。Human Splicing Finderを用いたin silico解析の結果から、19家系では完全にsplicingパターンを予測可能であり、17家系ではsplicing異常の可能性は予測できるものの、実際のsplicingパターンは予測不能であり、5家系ではsplicing異常の可能性が予測不能であった。29家系46例の男性患者の腎生存曲線を作成し求めたESRDに至った年齢の中央値はnon-truncating群で29歳、truncating群で20歳であり、統計学的有意差をもってnon-truncating群で腎予後が良好であった。Lead, (一社)日本腎臓学会, Nov. 2019, 日本腎臓学会誌, 61(8) (8), 1136 - 1138, Japanese
- 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.Lead, Sep. 2019, Scientific reports, 9(1) (1), 12696 - 12696, English, International magazine[Refereed]Scientific journal
- 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
- X-linked dominant chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome, CDPX2) caused by mutations in the emopamil-binding protein (EBP) gene and congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome caused by mutation in the NAD(P)H steroid dehydrogenase-like (NSDHL) gene are rare, typically male lethal disorders. CDPX2 skin lesions are characterized by transient severe congenital ichthyosis following the lines of Blaschko, whereas in CHILD syndrome, the lesions show striking lateralization. Here, we report a male CDPX2 patient with postzygotic mosaicism of the EBP gene presenting with lateralized skin lesions with strict midline demarcation as seen in CHILD syndrome (although this diagnosis was ruled out based on analysis of NSDHL), but also partly distributed along Blaschko's lines as seen in CDPX2. The lesions resolved within a few months, but the patient had other abnormalities, including shortening of the limbs, epiphyseal stippling, and forearm asymmetry; he also had problems with respiration and feeding in the first 4 years after birth. Kyphoscoliosis with dysplastic vertebral bodies progressed rapidly and required posterior spinal fusion surgery at 6 years old. These findings provide insights into the pathophysiology of CDPX2 and the mechanism of asymmetric lesion formation during development.Jul. 2019, American journal of medical genetics. Part A, 179(7) (7), 1315 - 1318, English, International magazine[Refereed]
- 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
- 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
- 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
- Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.SPRINGER, Feb. 2019, Clinical and experimental nephrology, 23(2) (2), 158 - 168, English, Domestic magazine[Refereed]Scientific journal
- 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
- 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
- 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
- BACKGROUND: Idiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80-90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10-20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome. METHODS: We conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000-1200 mg/m2/day (maximum 2 g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance). DISCUSSION: The results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in 'complicated' FRNS/SDNS cases. TRIAL REGISTRATION: This trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347 ).Lead, Nov. 2018, BMC nephrology, 19(1) (1), 302 - 302, English, International magazine[Refereed]Scientific journal
- Sep. 2018, Case reports in nephrology and dialysis, 8(3) (3), 198 - 206[Refereed]
- BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. METHODS: We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level. RESULTS: We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001). CONCLUSIONS: We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.Lead, Aug. 2018, Journal of the American Society of Nephrology : JASN, 29(8) (8), 2244 - 2254, English, International magazine[Refereed]Scientific journal
- Background Nephrotic syndrome is the most common cause of chronic glomerular disease in children. Most of these patients develop steroid-sensitive nephrotic syndrome (SSNS), but the loci conferring susceptibility to childhood SSNS are mainly unknown.Methods We conducted a genome-wide association study (GWAS) in the Japanese population; 224 patients with childhood SSNS and 419 adult healthy controls were genotyped using the Affymetrix Japonica Array in the discovery stage. Imputation for six HLA genes (HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1) was conducted on the basis of Japanese-specific references. We performed genotyping for HLA-DRB1/-DQB1 using a sequence-specific oligonucleotide-probing method on a Luminex platform. Whole-genome imputation was conducted using a phased reference panel of 2049 healthy Japanese individuals. Replication was performed in an independent Japanese sample set including 216 patients and 719 healthy controls. We genotyped candidate single-nucleotide polymorphisms using the DigiTag2 assay.Results The most significant association was detected in the HLA-DR/DQ region and replicated (rs4642516 [minor allele G], combined Pallelic=7.84×10-23; odds ratio [OR], 0.33; 95% confidence interval [95% CI], 0.26 to 0.41; rs3134996 [minor allele A], combined Pallelic=1.72×10-25; OR, 0.29; 95% CI, 0.23 to 0.37). HLA-DRB1*08:02 (Pc=1.82×10-9; OR, 2.62; 95% CI, 1.94 to 3.54) and HLA-DQB1*06:04 (Pc=2.09×10-12; OR, 0.10; 95% CI, 0.05 to 0.21) were considered primary HLA alleles associated with childhood SSNS. HLA-DRB1*08:02-DQB1*03:02 (Pc=7.01×10-11; OR, 3.60; 95% CI, 2.46 to 5.29) was identified as the most significant genetic susceptibility factor.Conclusions The most significant association with childhood SSNS was detected in the HLA-DR/DQ region. Further HLA allele/haplotype analyses should enhance our understanding of molecular mechanisms underlying SSNS.Lead, Aug. 2018, Journal of the American Society of Nephrology : JASN, 29(8) (8), 2189 - 2199, English, International magazine[Refereed]Scientific journal
- 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
- Pseudo-Bartter/Gitelman syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter syndrome (BS) or Gitelman syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.Jul. 2018, Journal of human genetics, 63(8) (8), 887 - 892, English, International magazine[Refereed]Scientific journal
- 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
- BACKGROUND/AIMS: Glomerulopathy with fibronectin deposits (GFND; OMIM: 601894) is a very rare inherited kidney disease caused by pathogenic variants in the FN1 gene. Only 9 exonic pathogenic variants in FN1, 9 at the heparin-binding site, and 1 at the integrin-binding site have been reported. No intronic variants in FN1 have been detected. METHODS: We found a pathogenic intronic variant in intron 36 (c.5888-2A>G) located at the heparin-binding site. To determine whether this mutation influences splicing processes, we conducted RT-PCR analysis and an in vitro splicing assay using minigene construction. RESULTS: RT-PCR using RNA extracted from leukocytes of the proband failed because of the low expression of FN1 mRNA in leukocytes. We conducted in vitro functional splicing analysis using minigenes and found that c.5888-2A>G caused a 12 bp deletion at exon 37 by the activation of a novel splicing acceptor site within exon 37. We were able to detect the same abnormal transcript in mRNA extracted from the patient's urinary sediment and confirmed the pathogenicity of c.5888-2A>G by both RT-PCR using the patient sample and an in vitro splicing assay. CONCLUSION: Intronic variants can cause GFND. Minigene analysis is useful for determining the pathogenicity of the intronic variants and could be used for all inherited kidney diseases.2018, Nephron, 138(2) (2), 166 - 171, English, International magazine[Refereed]Scientific journal
- BACKGROUND: Autosomal recessive distal renal tubular acidosis (dRTA) is a rare hereditary disease caused by pathogenic variants in the ATP6V0A4 gene or ATP6V1B1 gene, and characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia and nephrocalcinosis. Although several intronic nucleotide variants in these genes have been detected, all of them fell in the apparent splice consensus sequence. In general, transcriptional analysis is necessary to determine the effect on function of the novel intronic variants located out of splicing consensus sequences. In recent years, functional splicing analysis using minigene construction was used to assess the pathogenicity of novel intoronic variant in various field. METHODS: We investigated a sporadic case of dRTA with a compound heterozygous mutation in the ATP6V0A4 gene, revealed by next generation sequencing. One variant was already reported as pathogenic; however, the other was a novel variant in intron 11 (c.1029 + 5G > A) falling outside of the apparent splicing consensus sequence. Expression of ATP6V0A4 was not detected in peripheral leukocytes by RT-PCR analysis. Therefore, an in vitro functional splicing study using minigene construction was conducted to analyze the splicing pattern of the novel variant. RESULTS: A minigene assay revealed that the novel intronic variant leads to a 104 bp insertion immediately following exon 11. In addition, this result was confirmed using RNA extracted from the patient's cultured leukocytes. CONCLUSION: These results proved the pathogenicity of a novel intronic variant in our patient. We concluded that the minigene assay is a useful, non-invasive method for functional splicing analysis of inherited kidney disease, even if standard transcriptional analysis could not detect abnormal mRNA.BIOMED CENTRAL LTD, Dec. 2017, BMC nephrology, 18(1) (1), 353 - 353, English, International magazine[Refereed]Scientific journal
- BACKGROUND: Hereditary hypomagnesemia is difficult to diagnose accurately because of its rarity and the variety of causative genes. We established a flowchart for identifying responsible genes for hypomagnesemia, and we confirmed its diagnostic efficacy in patients with suspected inherited hypomagnesemia. METHODS: We established a flowchart and applied it to five index cases with suspected inherited hypomagnesemia. Direct sequence analysis was used to detect the causative gene variants in four cases, and targeted sequencing analysis using next-generation sequencing (NGS) of all causative genes for hypomagnesemia was used in one. RESULTS: Expected pathogenic variants were detected in the HNF1B, TRPM6, CLDN16, CASR, or SLC12A3 gene in all five cases. The results of all genetic analyses were consistent with the clinical diagnostic results using the flowchart. CONCLUSIONS: Accurate genetic diagnosis is crucial for estimating the prognosis, detecting complications in organs other than the kidneys, and for directing genetic counseling. The developed flowchart for identifying responsible genes for hypomagnesemia was useful for diagnosing inherited hypomagnesemia. In addition, NGS analysis will help to resolve clinical difficulties in making an accurate diagnosis and thus improve the diagnostic strategy for inherited hypomagnesemia.Lead, SPRINGER, Dec. 2017, Clinical and experimental nephrology, 21(6) (6), 1003 - 1010, English, Domestic magazine[Refereed]Scientific journal
- Lowe syndrome is an X-linked inherited disorder diagnosed by congenital cataracts, intellectual impairment, and renal tubular dysfunction. It is caused by pathogenic variants of the oculocerebrorenal syndrome of Lowe gene (OCRL), of which more than 250 have been reported so far. Around 30 of these variants are intronic nucleotide changes; however, to show the pathogenicity of these variants is usually laborious. In this report, we conducted genetic testing of a patient clinically diagnosed with Lowe syndrome to detect the presence of OCRL variants. We analyzed variant transcript expression in peripheral blood leukocytes and using a minigene construct in addition to in silico analysis. We detected a 9 base pair intronic insertion between OCRL exon 10 and exon 11 derived from the alteration of the splicing acceptor site in intron 10 caused by the intronic splicing variant NM_000276.3: c.940-11G>A (p.Lys313_Val314insAsnSer*). The findings obtained from transcript analysis of peripheral blood leukocytes and the minigene construct assay were identical to those of in silico analysis. All assays detected the same transcript abnormality and were reliable in revealing the pathogenicity of the intronic variant. The in vitro assay can also be used to clarify the complicated splicing mechanisms in inherited kidney diseases.ELSEVIER SCIENCE BV, Dec. 2017, European journal of medical genetics, 60(12) (12), 631 - 634, English, International magazine[Refereed]Scientific journal
- BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy. Although males with XLAS usually develop end-stage renal disease before 30 years of age, some men show a milder phenotype and possess somatic mosaic variants of the type IV collagen α5 gene (COL4A5), with severity depending on variant frequencies. In females, somatic mosaic variants are rarely reported in XLAS, and it is not clear what determines severity. METHODS: Two females with somatic mosaic mutations in COL4A5 with variant frequencies of 17.9 and 22.1% were detected using the next-generation sequencing. One patient only had hematuria. The other, however, had moderate proteinuria, which is a severe phenotype for a female XLAS patient of her age. The molecular mechanisms for the severe phenotype were investigated by examining variant frequencies in urinary sediment cells and X chromosome inactivation patterns, and by looking for modifier variants in podocyte-related genes using the next-generation sequencing. RESULTS: The severe phenotype patient had a variant frequency of 36.6% in urinary sediment cells, which is not markedly high, nor did she show skewed X chromosome inactivation. However, she did have the heterozygous variant in COL4A3, which can affect severity. CONCLUSION: Factors determining severity in female XLAS patients remain unclear. One studied patient with the somatic variant in COL4A5 showed a severe phenotype without skewed X chromosome inactivation, which might be derived from digenic variants in COL4A3 and COL4A5. Further studies are required to determine molecular mechanisms behind female XLAS resulting in the severe phenotype.Oct. 2017, Clinical and experimental nephrology, 21(5) (5), 877 - 883, English, Domestic magazine[Refereed]Scientific journal
- OBJECTIVES: To clarify the clinical characteristics and long-term outcomes of patients with diarrhea-associated hemolytic uremic syndrome (D + HUS) with a particular focus on time course. METHODS: We retrospectively analyzed the medical records of 61 patients with D + HUS who were admitted to Kobe University Hospital between 1995 and 2015. The onset of D + HUS was defined as day 1 of diarrhea. RESULTS: The age of onset was 4.1 (1.5-13.4) years, and the period between onset and diagnosis of D + HUS was 5 (3-18) days. The platelet count was lowest on day 7 (4-24), and the lactase dehydrogenase level was maximal on day 8 (4-25). Twenty-three patients required dialysis for 13 (2-37) days, starting at day 5-9. Seventeen patients showed central nervous system (CNS) symptoms at day 4-18. They were followed up for 3.7 (0-18.4) years. At the final follow-up, estimated glomerular filtration rate was 113.7 (57.9-159.9) ml/min/1.73 m2 with five patients having chronic kidney disease. Three patients developed CNS sequelae. The time to diagnosis was significantly shorter in the group of patients receiving dialysis than without dialysis (p = 0.018) and in the group with CNS complications than without (p = 0.013). CONCLUSION: CNS complications were often apparent after blood examination results improved. Moreover, a shorter period between the onset of diarrhea and a diagnosis of D + HUS indicated a more severe clinical course or long-term sequelae, and it should be considered as a risk factor for poor prognosis.Oct. 2017, Clinical and experimental nephrology, 21(5) (5), 889 - 894, English, Domestic magazine[Refereed]Scientific journal
- Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypocalciuria and hypomagnesemia. GS clinical symptoms range from mild weakness to muscular cramps, paralysis or even sudden death as a result of cardiac arrhythmia. GS is caused by loss-of-function mutations in the solute carrier family 12 member 3 (SLC12A3) gene, but molecular mechanisms underlying such a wide range of symptoms are poorly understood. Here we report cryptic exon activation in SLC12A3 intron 12 in a clinically asymptomatic GS, resulting from an intronic mutation c.1669+297 T>G that created a new acceptor splice site. The cryptic exon was sandwiched between the L3 transposon upstream and a mammalian interspersed repeat downstream, possibly contributing to inclusion of the cryptic exon in mature transcripts. The mutation was identified by targeted next-generation sequencing of candidate genes in GS patients with missing pathogenic SLC12A3 alleles. Taken together, this work illustrates the power of next-generation sequencing to identify causal mutations in intronic regions in asymptomatic individuals at risk of developing potentially fatal disease complications, improving clinical management of these cases.NATURE PUBLISHING GROUP, Feb. 2017, Journal of human genetics, 62(2) (2), 335 - 337, English, International magazine[Refereed]Scientific journal
- BACKGROUND: The etiology of Kawasaki disease (KD) is unknown. Reportedly, there is an association between KD and Yersinia pseudotuberculosis (YPT). Steroid therapy for KD patients with high risk of cardiac sequelae (CS) has been reported; however, the number of reports is limited. METHODS: We conducted a prospective study of 108 patients with newly diagnosed KD in one year to determine how many KD patients have positive anti-YPT antibody titers and/or positive anti-YPT-derived mitogen (YPM) antibody titers. In addition, we tried to identify clinical differences between KD patients in whom YPT infection was or not a contributing factor. We also compared clinical characteristics of patients treated with the protocol of the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease (RAISE) study (RAISE group) and with the conventional Intravenous immunoglobulin (IVIG) protocol (conventional group). RESULTS: Eleven patients (10%) were positive for anti-YPT and/or anti-YPM antibodies (positive group) and 97 (90%) were negative (negative group). Cardiac sequelae (CS) occurred significantly more frequently in the positive than the negative group (two patients, 18% vs one patient, 1%, p = 0.027). Forty patients were in the RAISE group. Two of 40 (5%) in the RAISE group and one of 68 (1.47%) in the conventional group had CS (p = 0.55). CONCLUSIONS: KD patients with YPT infection had CS significantly more frequently and treatment with RAISE protocol did not decrease the frequency of CS in our cohort, nor did YPT infection affect risk scores of no response to IVIG. However, our sample size was overly small to draw such conclusions. Further investigation in a larger cohort is necessary to confirm our findings. Additionally, further research is needed to determine whether early diagnosis of YPT can prevent KD from developing and reduce the incidence of CS.Lead, BIOMED CENTRAL LTD, Nov. 2015, BMC pediatrics, 15, 177 - 177, English, International magazine[Refereed]Scientific journal
- 小児の尿路感染症では抗生剤の採尿前投与などで起炎菌が同定されず、診断に苦慮することも多く、膀胱尿管逆流症の精査を受けずに後に逆流性腎症、末期腎不全として発見される例もある。今回、我々は尿路感染症が疑われる児や熱源が不明である児に対して腹部超音波検査で腎血流の低下を検出することにより尿路感染症と診断した症例もしくは尿培養陽性をもって尿路感染症と診断した症例を起炎菌検出の有無、腎血流低下の有無を基に3群に分け比較検討を行った。起炎菌同定かつ腎血流正常[UC(+)US(-)]群では他の2群と比較して有意に低月齢であった。起炎菌同定ができずかつ腎血流低下[UC(-)US(+)]群では抗生剤の前投与が有意に多かった。膀胱尿管逆流症は腎血流低下[UC(-)US(+)、UC(+)US(+)]群で50%、47.1%と腎血流正常[UC(+)US(-)]群での18.4%と比較して有意に高率であった。腹部超音波で腎血流を評価することは熱源の特定および膀胱尿管逆流症を予測するうえで有用であると考えられた。(著者抄録)(一社)日本小児腎臓病学会, Nov. 2013, 日本小児腎臓病学会雑誌, 26(2) (2), 182 - 186, Japanese
- Alport SyndromeCLINICAL CHARACTERISTICS: Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. DIAGNOSIS/TESTING: The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified by molecular genetic testing. Kidney biopsy, skin biopsy (in some individuals with XLAS), or clinical diagnostic criteria may be used to establish the diagnosis in those without access to genetic testing or those with uninformative results. MANAGEMENT: Treatment of manifestations: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESKD; standard treatment of hypertension; kidney transplantation for ESKD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Hearing aids as needed for SNHL; cataract removal as needed; in those with deletions of COL4A5 extending into intron 2 of COL4A6, surgical intervention for symptomatic leiomyomas as needed. Surveillance: Evaluation by a nephrologist including urinalysis, assessment of kidney function, and blood pressure every six to 12 months; monthly monitoring of at-risk transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis for the first year post transplant; audiologic evaluation every one to two years beginning at age six to seven years; ophthalmology evaluation for ocular abnormalities every one to two years beginning in adolescence in males with a COL4A5 truncating pathogenic variant and in persons with ARAS. Agents/circumstances to avoid: Drink adequate fluids as dehydration may accelerate the progression of nephropathy. Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise. Evaluation of relatives at risk: Evaluate at-risk family members in order to identify as early as possible those who would benefit from initiation of treatment either by molecular genetic testing if the pathogenic variant(s) in the family are known or urinalysis and blood pressure if the pathogenic variant(s) in the family are not known. GENETIC COUNSELING: COL4A5-related Alport syndrome is inherited in an X-linked manner (XLAS). COL4A3- and COL4A4-related Alport syndrome are inherited in an autosomal dominant (ADAS) or autosomal recessive (ARAS) manner. Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both COL4A3 and COL4A4 (in cis or in trans) or, more rarely, a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4. XLAS: The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has a COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. The risk to the sibs of a female proband depends on the genetic status of the parents: if the mother of the proband has a COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a COL4A5 pathogenic variant, he will transmit it to all of his daughters and none of his sons. Males and females who inherit the pathogenic variant will be affected. ARAS: If both parents are known to be heterozygous for a COL4A3 or COL4A4 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants (and having ARAS), a 50% chance of being heterozygous (and at risk for ADAS), and a 25% chance of inheriting neither of the familial pathogenic variants. ADAS: If a parent of the proband is affected and/or is known to have the COL4A3 or COL4A4 pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. The severity of clinical manifestations may vary greatly among heterozygous family members; some heterozygotes may be asymptomatic and some may develop ESKD. Digenic Alport syndrome: The risk to sibs depends on the involved genes, the location of the pathogenic variants (i.e., in cis or in trans) in families segregating pathogenic variants in COL4A3 and COL4A4, and the sex of the proband (in families segregating pathogenic variants in COL4A5 and COL4A3 or COL4A4). Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.University of Washington, Seattle, 1993, English
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- (一社)日本腎臓学会, Sep. 2023, 日本腎臓学会誌, 65(6-W) (6-W), 783 - 783, Japanese長期緩下剤内服により偽性Gitelman症候群を発症し末期腎不全に至った1例
- (一社)日本腎臓学会, Sep. 2023, 日本腎臓学会誌, 65(6-W) (6-W), 794 - 794, Japanese眼虚血症候群を合併した,維持腹膜透析の3歳男児例
- (公社)日本医師会, Jun. 2023, 日本医師会雑誌, 152(特別1) (特別1), S146 - S150, Japanese【遺伝を考える】(II章)遺伝学的診断 個別診療分野における遺伝学的診断の進歩 腎・泌尿器領域
- (公社)日本皮膚科学会, May 2023, 日本皮膚科学会雑誌, 133(5) (5), 1355 - 1355, Japanese母乳中に自己抗原反応性IgAが認められたNeonatal linear IgA bullous dermatosisの1例
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 95 - 95, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 96 - 96, JapaneseX染色体連鎖型Alport症候群女性における、X染色体不活化パターン・表現型相関
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 96 - 96, JapaneseLAMB2関連疾患における臨床的特徴と遺伝型・表現型相関
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 115 - 115, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 121 - 121, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 124 - 124, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 126 - 126, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 131 - 131, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 132 - 132, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 134 - 134, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 142 - 142, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 166 - 166, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 187 - 187, Japanese
- (一社)日本小児腎臓病学会, May 2023, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 198 - 198, Japanese
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 238 - 238, JapaneseCOL4A5遺伝子におけるsplicing異常をきたすvariantsの特徴と臨床型との相関に関する研究
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 239 - 239, Japanese本邦における2型Bartter症候群の臨床的特徴とGenotype/Phenotype Correlation
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 260 - 260, JapaneseCUBN異常症の遺伝学的特徴と臨床像
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 261 - 261, JapanesePodocalyxin異常に伴う腎炎発症機序の検討
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 261 - 261, Japanese当院で診断したMAFB異常4例と腎症に関する考察
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 262 - 262, JapaneseX染色体連鎖型Alport症候群女性における,X染色体不活化・表現型相関
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 323 - 323, Japanese小児C3腎炎の後方視的検討
- (一社)日本腎臓学会, May 2023, 日本腎臓学会誌, 65(3) (3), 335 - 335, Japanese小児IgA腎症の肉眼的血尿発作に伴う急性腎障害発症に鉄とマクロファージが関与する 多機関共同研究
- (公社)日本小児科学会, Apr. 2023, 日本小児科学会雑誌, 127(4) (4), 626 - 627, Japanese新型コロナワクチン接種後に血尿を伴うネフローゼ症候群を発症した1例
- (公社)日本小児科学会, Apr. 2023, 日本小児科学会雑誌, 127(4) (4), 633 - 633, JapaneseAcetazolamide内服と生活指導で発作予防可能であった低カリウム性周期性四肢麻痺の1例
- (一社)日本糖尿病学会, Apr. 2023, 糖尿病, 66(Suppl.1) (Suppl.1), S - 79, Japanese今だからこそ考える糖尿病地域連携～変容する時代や社会に対応する～ 鹿児島市域糖尿病医療連携体制9年の歩み
- ＜文献概要＞Alport症候群はCOL4A3/4/5遺伝子の異常により発症する進行性遺伝性腎症である.持続的血尿に加え,遺伝子変異や病理組織学的所見,家族歴や眼病変・難聴等に基づいて診断される.治療薬としてはRAS阻害薬が一般的だが,SGLT2阻害薬の効果も今後期待される.(株)診断と治療社, Apr. 2023, 小児科診療, 86(春増刊) (春増刊), 737 - 738, Japanese
- 発達腎研究会, Apr. 2023, 発達腎研究会誌, 30(1) (1), 15 - 16, Japanese当院で診断したMAFB異常4例のまとめと腎症に関する考察
- (株)メヂカルフレンド社, Mar. 2023, 看護展望, 48(4) (4), 0334 - 0339, Japanese
- ＜文献概要＞▼Alport症候群はCOL4A3/4/5遺伝子の異常により発症する進行性の遺伝性腎症である.▼腎外合併症としては眼病変と感音性難聴がよく知られている.▼まれな腎外合併症としてCOL4A5-COL4A6遺伝子座における連続した遺伝子欠失により生じるびまん性平滑筋腫症がある.▼治療薬としてはRAS阻害薬が一般的だが,SGLT2阻害薬の効果も今後期待される.(株)診断と治療社, Feb. 2023, 小児科診療, 86(2) (2), 171 - 174, Japanese
- (公社)日本小児科学会, Feb. 2023, 日本小児科学会雑誌, 127(2) (2), 204 - 204, JapaneseAVPR2ヘテロ接合体バリアントを持つ女性における,X染色体不活性化パターンと腎性尿崩症の発症との相関
- (公社)日本小児科学会, Feb. 2023, 日本小児科学会雑誌, 127(2) (2), 251 - 251, JapaneseCOL4A5遺伝子のイントロン+3から+5のバリアントにおける病原性の有無の検討
- (公社)日本小児科学会, Feb. 2023, 日本小児科学会雑誌, 127(2) (2), 305 - 305, Japanese非IgA型びまん性メサンギウム増殖発症の頻回再発型ネフローゼ症候群治療経過中にIgA腎症を発症した1例
- 2023, 日本小児栄養消化器肝臓学会雑誌, 37(1) (1)当院における小児炎症性腸疾患症例の総括と検討
- 2023, 日本小児科学会雑誌, 127(4) (4)一過性の細胞免疫不全所見を認めた超早期発症型炎症性腸疾患の1例
- (一社)日本糖尿病学会, Jan. 2023, 糖尿病, 66(1) (1), 110 - 111, Japanese応用カーボカウント導入が食事療法への興味に結びついた1型糖尿病患者の1例
- (一社)日本小児腎臓病学会, 2023, 日本小児腎臓病学会雑誌, 36, 50 - 51, Japanese
- (一社)日本小児腎臓病学会, 2023, 日本小児腎臓病学会雑誌, 36, 53 - 53, Japanese
- (一社)日本小児腎臓病学会, 2023, 日本小児腎臓病学会雑誌, 36, 53 - 54, Japanese
- (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), 167 - 167, Japanese
- (一社)日本腎臓学会, Oct. 2022, 日本腎臓学会誌, 64(6-W) (6-W), 714 - 714, Japanese活性型Rac1蛋白の定量解析により診断した新規ARHGAP24遺伝子変異による小児巣状分節性糸球体硬化症の1例
- (有)科学評論社, Jun. 2022, 腎臓内科, 15(6) (6), 633 - 643, 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
- 家族性中枢性尿崩症は緩徐進行性にバソプレシン(AVP)の分泌が低下し、多飲多尿を呈する常染色体顕性遺伝疾患である。AVP遺伝子の異常により変異蛋白が蓄積し、それによる小胞体ストレスが徐々にニューロン死を惹起すると考えられている。症例は14歳男児で、頭痛を主訴に来院した。家族歴として、母・母方祖母が中枢性尿崩症と診断されていた。児は弟と共に多飲多尿の症状を認めていたが、家族と同症状のため医療機関を受診していなかった。1日尿量6000mL、血清Na 139mEq/L、尿浸透圧58mOsm/kgで頭部MRIでは下垂体後葉の高信号が消失していた。デスモプレシン酢酸塩水和物投与後、尿浸透圧は493mOsm/kgまで上昇した。AVP遺伝子の検索を行ったところ、本人・母・弟にAVP遺伝子(NM_000490.5)の既報ヘテロ接合体変異(c.55G>A、p.Ala19Thr)を認め、AVP遺伝子異常に基づく中枢性尿崩症と確定診断した。家族性中枢性尿崩症家系では、家人も同様の症状を呈し、早期に医療機関の受診に至らないケースも多い。睡眠不足や日常生活のQOL改善、多飲多尿による水腎症・巨大膀胱の予防のためには早期診断・早期治療が有用で、その診断に遺伝学的検査が重要であった。(著者抄録)日本小児体液研究会, May 2022, 日本小児体液研究会誌, 14, 43 - 46, Japanese
- 我が国の高齢化率は2021年に29.1%と過去最高を更新した。高齢化率上昇に伴い要介護・要支援者も増加しており、介護予防はわが国にとって急務である。介護が必要となる原因の一つに転倒・骨折があり、今回千葉市A地区の一自治会において転倒経験を含む足のセルフケアに関する調査を行った。参加者は48名であり、介護認定を受けているのは4名であった。割合として基礎疾患に骨・関節疾患、高血圧症などを持つ者が多くいたが、殆どの者が運動習慣を持ち活動していた。足のセルフケアについては、観察は良く行っているが保湿や循環促進の為のケア実施率は低かった。靴選びにも注意していたが、爪先が上がる靴を意識していたのは1名だけであった。(著者抄録)東都大学ヒューマンケア学部看護学科研究・紀要委員会, May 2022, 東都大学紀要, 12(1) (1), 75 - 82, Japanese
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 180 - 180, Japanese遺伝子診断の臨床応用 Alport症候群
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 219 - 219, JapaneseOCRL遺伝子splicing異常による疾患発症メカニズムの検討
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 231 - 231, Japanese当院小児科の腎疾患患者の新型コロナウイルスワクチン接種状況
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 231 - 231, JapaneseCOL4A5遺伝子エクソン内3'末端から2・3番目の一塩基置換は高率にスプライシング異常を来す
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 231 - 231, JapaneseAlport症候群モデルマウスにおけるエクソンスキッピング療法の信頼性保証試験成績報告
- (一社)日本腎臓学会, May 2022, 日本腎臓学会誌, 64(3) (3), 242 - 242, Japaneseステロイド感受性ネフローゼ症候群初発時にはSwitched memory B細胞の増加を認める
- (株)東京医学社, Apr. 2022, 腎と透析, 92(4) (4), 690 - 697, Japanese
- 発達腎研究会, Apr. 2022, 発達腎研究会誌, 29(1) (1), 19 - 20, JapaneseIV型コラーゲンの三量体構造におけるプロリンの働き
- (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.), 65 - 65, Japanese
- (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.), 109 - 109, Japanese
- (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.), 110 - 110, Japanese
- (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.), 118 - 118, Japanese
- (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.), 154 - 154, Japanese
- (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.), 184 - 184, Japanese
- (株)メヂカルフレンド社, Mar. 2022, 看護展望, 47(4) (4), 0302 - 0305, Japanese
- (公社)日本小児科学会, Mar. 2022, 日本小児科学会雑誌, 126(3) (3), 552 - 552, Japanese神戸市東部療育センター診療所の開所後3年間のまとめ
- (公社)日本小児科学会, Mar. 2022, 日本小児科学会雑誌, 126(3) (3), 557 - 557, Japanese小児科医の意識調査 大事にする価値観は?兵庫県で次に取り組むべき課題は?
- (公社)日本小児科学会, Feb. 2022, 日本小児科学会雑誌, 126(2) (2), 230 - 230, JapaneseAlport症候群に対するアンチセンス核酸およびスプライシング調節蛋白による治療法の開発
- (公社)日本小児科学会, Feb. 2022, 日本小児科学会雑誌, 126(2) (2), 253 - 253, JapaneseOCRL異常におけるgenotype-phenotype correlationに関する検討
- (公社)日本小児科学会, Feb. 2022, 日本小児科学会雑誌, 126(2) (2), 255 - 255, Japanese中等度紫斑病性腎炎へのレニン・アンジオテンシン系阻害薬治療に関する検討
- (公社)日本小児科学会, Feb. 2022, 日本小児科学会雑誌, 126(2) (2), 375 - 375, Japanese遺伝子解析が早期診断の一助となった中枢性尿崩症の1家系
- (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
- (一社)日本胸部外科学会, Oct. 2021, 日本胸部外科学会定期学術集会, 74回, LTA3 - 1, Japanese
- (一社)日本腎臓学会, Sep. 2021, 日本腎臓学会誌, 63(6-E) (6-E), 658 - 658, Japanese腎臓研究の最前線 GWASを用いた腎疾患感受性遺伝子同定
- (一社)日本腎臓学会, Sep. 2021, 日本腎臓学会誌, 63(6-W) (6-W), 830 - 830, JapaneseCOL4A5遺伝子のエクソン3'末端に位置する一塩基置換はミスセンス変異ではなくスプライシング変異である
- (一社)日本腎臓学会, Sep. 2021, 日本腎臓学会誌, 63(6-W) (6-W), 833 - 833, Japanese早期の遺伝学的検査が治療方針の選択に有用であった小児ステロイド抵抗性ネフローゼの1例
- 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
- (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 396 - 396, 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
- (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 435 - 435, 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
- (一社)日本腎臓学会, Jun. 2021, 日本腎臓学会誌, 63(4) (4), 456 - 456, JapaneseCOL4A5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
- (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
- (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
- (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
- 2021, 日本腎臓学会誌(Web), 63(4) (4)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
- 2021, 日本人類遺伝学会大会プログラム・抄録集, 66th (CD-ROM)嚢胞性腎疾患の包括的遺伝子解析
- (一社)日本職業・災害医学会, Dec. 2020, 日本職業・災害医学会会誌, 68(臨増) (臨増), 別143 - 別143, Japanese羽ばたく管理栄養士-新しい診療報酬下における管理栄養士の役割- 情報通信機器を用いた外来栄養指導の検討
- (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.), 65 - 65, Japanese
- 福岡産科婦人科学会, Jul. 2020, 福岡産科婦人科学会雑誌, 44(1) (1), 23 - 23, Japanese
- (一社)日本腎臓学会, Jul. 2020, 日本腎臓学会誌, 62(4) (4), 362 - 362, JapaneseAlport症候群患者に対するエクソンスキッピング(ES)療法の開発
- (公社)日本小児科学会, Jun. 2020, 日本小児科学会雑誌, 124(6) (6), 1031 - 1031, Japanese紫斑病性腎炎の経過中に溶連菌感染後急性糸球体腎炎を発症した1例
- (一社)日本糖尿病学会, Apr. 2020, 糖尿病, 63(4) (4), 277 - 277, Japanese糖尿病療養指導の充実に向けた、管理栄養士の取り組み
- 2020, 日本小児腎臓病学会雑誌(Web), 33(1) (1)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
- (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), 138 - 138, JapaneseAlport症候群モデルマウスにおけるエクソンスキッピング療法の有効性の検討
- (一社)日本糖尿病学会, Sep. 2019, 糖尿病, 62(9) (9), 574 - 574, Japanese高糖度トマトが血糖上昇に及ぼす影響の検討
- 1歳6ヵ月男児。乳児期にPAX2遺伝子変異によるrenal-coloboma症候群と診断され、生後6ヵ月で経鼻経管栄養を導入した。嘔吐が遷延し、徐々に腎機能と代謝性アシドーシスも増悪した。嘔吐の精査で胃食道逆流を認め、1歳6ヵ月時に噴門形成に加え、同時に胃瘻造設とPDカテーテル留置を行った。術後21日目にMRSA腹膜炎を発症し、抗菌薬投与でも改善せずPDカテーテルを抜去した。胃瘻周囲の膿からもMRSAが検出され、腹膜炎との関連性が示唆された。小児の慢性腎不全では成長・発達のために経腸栄養が長期間必要となることがしばしばある。そのため、欧米では腹膜透析(PD)カテーテル留置と同時に胃瘻が造設されることも多い。胃瘻造設とPDカテーテル留置の同時手術の安全性、有効性が報告されているが、本症例のように同時手術後に腹膜炎を発症する例もあるため、手術適応、手術時期はおのおのの症例ごとに慎重に判断する必要がある。(著者抄録)日本小児腎不全学会, Jul. 2019, 日本小児腎不全学会雑誌, 39, 100 - 103, Japanese
- ネフローゼ症候群における全身性浮腫はNaと水貯留に起因するとされ、アルブミン(Alb)とフロセミドの投与により管理されることが多いが、それらを投与しても十分な効果が得られない症例も散見される。症例は1歳7ヵ月女児。高度蛋白尿、低アルブミン血症からネフローゼ症候群と診断し、プレドニゾロンを投与したが寛解せず、ステロイド抵抗性ネフローゼ症候群(SRNS)に至った。SRNSによる全身性浮腫に対して十分量のAlb補充と高用量のフロセミド投与を行ったが、遷延する尿量低下と浮腫増強を認め、それらに加え高血圧、胸水貯留、フロセミドによる低K血症、代謝性アルカローシスを認め治療に難渋した。利尿目的にカルペリチドを併用したところ、尿中へのNa排泄増加に伴って尿量は増加し、浮腫の改善が得られた。カルペリチドは種々の薬理作用により腎臓からのNa、水排泄を増加させ、利尿効果を発揮する。本症例のようにAlbとフロセミド投与でも改善せず、細胞外液量の増加をもたらす一次性のNa貯留を主因とする全身性浮腫に対しては低用量のカルペリチドは有効であり、Albやフロセミドとの併用を考慮してもよい。(著者抄録)日本小児体液研究会, May 2019, 日本小児体液研究会誌, 11, 51 - 54, Japanese
- (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 298 - 298, JapaneseNPHS1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
- (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 318 - 318, 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
- (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.), 100 - 100, Japanese
- (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
- Lead, (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
- (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
- (一社)日本腎臓学会, May 2019, 日本腎臓学会誌, 61(3) (3), 420 - 420, Japanese集学的治療を要した小児腎腫瘍患者の腎予後とその関連因子の検討[Refereed]
- (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.), 115 - 115, Japaneseネフローゼ症候群患児にみられた三次リンパ組織の形成機序
- (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.), 90 - 90, JapaneseAlport症候群モデルマウスにおけるエクソンスキッピング療法の有効性の検討
- (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重篤な消化器症状を呈したYersinia pseudotuberculosis感染症の14歳女児例[Refereed]
- (公社)日本小児科学会, Feb. 2019, 日本小児科学会雑誌, 123(2) (2), 253 - 253, Japanese多嚢胞性異形成腎患児の臨床的検討
- (公社)日本小児科学会, Feb. 2019, 日本小児科学会雑誌, 123(2) (2), 219 - 219, Japanese小児の腎腫瘍患者における片腎摘出後の腎予後と腎障害との関連因子の検討[Refereed]
- (株)東京医学社, Dec. 2018, 腎と透析, 85(6) (6), 777 - 781, Japanese[Refereed]Introduction scientific journal
- (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
- (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
- 【症例】11ヵ月女児。特発性ネフローゼ症候群と診断され、ステロイドが開始されたが尿蛋白の減少を認めず、内服24日目に当院へ転院となった。ステロイド抵抗性ネフローゼ症候群(SRNS)と診断し、腎生検と遺伝子解析を計画した。病理所見は巣状分節性糸球体硬化症であり、メチルプレドニゾロンパルス療法(MPT)とシクロスポリン、リシノプリル内服を開始し、遺伝子解析結果を待った。次世代シークエンサーを用いた遺伝性腎疾患のパネル解析により、既知のSRNS関連遺伝子に変異を認めなかった。免疫抑制剤による治療を継続し、MPT3クール後に尿蛋白は減少しはじめ、さらにリツキシマブを4回投与し、MPTを継続したところ、治療開始4ヵ月の時点で不完全寛解に至った。【結論】本症例では、遺伝子変異を認めないことが早期に判明したため免疫抑制剤による濃厚な治療を継続でき、結果として速やかに病勢の改善が得られた。疾患パネル解析は、SRNS患者の治療方針決定に有用である。(著者抄録)日本小児腎不全学会, Jul. 2018, 日本小児腎不全学会雑誌, 38, 148 - 151, 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例症例は8歳の女児で、肉眼的血尿を主訴に前医を受診した。1kg(+5%)の体重増加と上眼瞼の浮腫を認めたが、高血圧はなかった。肉眼的血尿と高度蛋白尿に加え、腎機能障害、低補体血症、低アルブミン血症を認めた。APSGNとして保存的加療が開始されたが、腎機能障害と乏尿が改善せず当院に転院となった。転院後もネフローゼレベルの蛋白尿と腎機能障害が遷延したため第14病日に腎生検を行った。光顕所見ではびまん性の管内細胞増殖と係蹄壁の二重化およびメサンギウム細胞増殖を認め、また40%の糸球体に線維細胞性半月体を認めた。免疫染色でC3の顆粒状沈着と電子顕微鏡所見でhumpを認めたことから、APSGNと確定診断した。メチルプレドニゾロンパルス療法を施行したところ発症後1ヵ月で腎機能は正常化し、また3ヵ月で尿蛋白は陰性化した。転院後も高血圧を呈することはなかった。APSGNにおける高血圧の発症機序は一般に、ナトリウム・水貯留によるhypervolemiaで説明される。本症例では経過を通じ溢水所見を呈したことはなく、これは血圧の推移と矛盾しない。しかしその一方で、腎機能の推移や腎病理所見からは腎性の要素で高血圧を呈する危険性も十分に考えられた。APSGNではまれとされる高度蛋白尿が病態を修飾した可能性も考えられた。溢水所見や血圧上昇を認めないAPSGNであっても体液量管理は慎重に行う必要がある。(著者抄録)日本小児高血圧研究会, Jun. 2018, 日本小児高血圧研究会誌, 15(1) (1), 21 - 25, Japanese[Refereed]
- (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
- (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
- (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
- (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
- (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
- (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
- (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, JapaneseIn vitro実験系を用いたCOL4A5 intron変異の病原性の検討
- (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
- (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, JapaneseCopy 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
- (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, JapaneseIn vitro splicing assayを用いたFrasier症候群の臨床遺伝学的検討
- (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.), 155 - 155, Japaneseゲノムワイド関連解析による小児特発性ネフローゼ症候群のrisk haplotype同定
- (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尿中CD80の腎疾患診断マーカーとしての有用性の検討
- (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, JapaneseGitelman症候群185例における臨床的特徴に関する検討
- (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.), 155 - 155, Japanese
- 症例1(6歳男児)、症例2(13歳男児)。両症例とも低身長を主訴に当院へ紹介となった。受診時、いずれの症例も血液検査では低K血症、代謝性アルカローシスを認めたが、血清Mgの低下は認めなかった。遺伝子検査の結果、SLC12A3遺伝子に複合ヘテロ接合体変異が確認され、Gitelman症候群と確定診断されたた。症例1はカリウム補充治療開始後1年が経過し、身長のcatch-up傾向を認めている。症例2はカリウム補充とGH補充療法を同時に開始し、catch-upを認めている。日本小児体液研究会, May 2018, 日本小児体液研究会誌, 10, 67 - 72, Japanese[Refereed]
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 336 - 336, JapaneseX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
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, JapaneseGitelman症候群185例における臨床的特徴に関する検討
- (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
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 338 - 338, Japanese多様な表現型を示したピアソン症候群における遺伝学的・分子生物学的検討
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, Japaneseゲノムワイド関連解析による小児特発性ネフローゼ症候群のrisk haplotype同定
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, 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
- (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
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 336 - 336, JapaneseX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
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 337 - 337, JapaneseGitelman症候群185例における臨床的特徴に関する検討
- (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
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 338 - 338, Japanese多様な表現型を示したピアソン症候群における遺伝学的・分子生物学的検討
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, Japaneseゲノムワイド関連解析による小児特発性ネフローゼ症候群のrisk haplotype同定
- (一社)日本腎臓学会, Apr. 2018, 日本腎臓学会誌, 60(3) (3), 344 - 344, 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
- X染色体不活化とDent病X染色体連鎖型腎疾患における女性症例の重症化には、X染色体不活化率の偏り(skewed X)が主な原因の一つと考えられている。X染色体不活化の解析法において、従来のHUMARA法では、i)変異遺伝子を直接測定しているものではなく、ii)ゲノムレベルの解析にとどまるという欠点があった。しかし、近年の次世代シークエンサー(NGS)の登場によりこれらの弱点を克服したRNA-Seq法による不活化解析が可能となった。Dent病は稀なX連鎖型遺伝性腎疾患であり、女性においては軽症となることが一般的であるが、一部重度の表現型を呈する症例も存在する。この原因についてはX染色体不活化の関連が疑われるが、未だそれを明確に示した報告は無く、HUMARA法やNGSを用いたX染色体不活化解析の報告が待たれる。(著者抄録)発達腎研究会, Apr. 2018, 発達腎研究会誌, 26(1) (1), 8 - 10, Japanese[Refereed]
- (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
- (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, JapaneseGitelman症候群の臨床的特徴に関する検討
- (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尿中CD80の腎疾患診断マーカーとしての有用性の検討
- 遺伝性リン代謝異常症や遺伝性マグネシウム代謝異常症は多岐にわたり,数々の原因遺伝子が同定されている.遺伝性高リン血症はFGF23の作用不全やPTHの作用不全を病態の首座とし,遺伝性低リン血症はFGF23の作用過剰や1,25(OH)2Dの作用不全,近位尿細管障害を病態の首座とする.また,遺伝性マグネシウム代謝異常症は尿細管におけるマグネシウムの再吸収調節機構異常が原因である.一般的に各疾患の頻度は低く,表現型にも多様性を認めることから,臨床診断が困難なことも多い.近年,次世代シークエンサーが各方面で応用されており,遺伝性リン代謝異常症や遺伝性マグネシウム代謝異常症においても遺伝子診断が比較的容易となる可能性が考えられる.(著者抄録)(株)日本メディカルセンター, Jan. 2018, 腎と骨代謝, 31(1) (1), 37 - 43, JapaneseIntroduction scientific journal
- 日本血液代替物学会, Nov. 2017, 人工血液, 25(1) (1), 19 - 19, Japanese
- 日本公衆衛生学会, Oct. 2017, 日本公衆衛生学会総会抄録集, 76回, 624 - 624, Japanese大隅地域における保健師人材育成の取り組みについて
- SPRINGER, Sep. 2017, PEDIATRIC NEPHROLOGY, 32(9) (9), 1756 - 1756, EnglishA VARIETY OF PHENOTYPES REFLECTED BY GENOTYPES AND LAMININ beta 2 EXPRESSION ON GLOMERULUS IN PIERSON SYNDROMESummary international conference
- SPRINGER, Sep. 2017, PEDIATRIC NEPHROLOGY, 32(9) (9), 1754 - 1754, EnglishIN VITRO SPLICING ASSAYS TO DETECT INTRONIC PATHOGENIC VARIANTS IN INHERITED KIDNEY DISEASESSummary international conference
- (有)科学評論社, Sep. 2017, 腎臓内科・泌尿器科, 6(3) (3), 245 - 248, Japanese各種疾患の移行医療 現状と課題 ネフローゼ症候群と移行医療
- (公社)日本小児科学会, May 2017, 日本小児科学会雑誌, 121(5) (5), 903 - 903, Japaneseナットクラッカー現象を合併した起立性蛋白尿の1例
- (公社)日本小児科学会, May 2017, 日本小児科学会雑誌, 121(5) (5), 908 - 908, Japanese成長障害の経過観察中に四肢麻痺をきたし診断に至った尿細管性アシドーシスの1例
- (一社)日本小児腎臓病学会, May 2017, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 153 - 153, Japanese
- (一社)日本小児腎臓病学会, May 2017, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 181 - 181, Japanese
- (一社)日本小児腎臓病学会, May 2017, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 186 - 186, Japanese
- (一社)日本小児腎臓病学会, May 2017, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 211 - 211, Japanese
- (一社)日本腎臓学会, Apr. 2017, 日本腎臓学会誌, 59(3) (3), 257 - 257, Japanese女性Dent病における遺伝学的背景
- (一社)日本腎臓学会, Apr. 2017, 日本腎臓学会誌, 59(3) (3), 314 - 314, 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
- (一社)日本がん看護学会, Jan. 2017, 日本がん看護学会誌, 31(Suppl.) (Suppl.), 269 - 269, Japaneseニボルマブ投与後の有害事象に関する実態調査
- (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), 180 - 180, Japanese
- (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), 182 - 182, Japanese
- 日本血液代替物学会, Oct. 2016, 人工血液, 24(1) (1), 16 - 16, Japanese
- (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.), 93 - 93, Japanese
- (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.), 118 - 118, Japanese
- (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.), 91 - 91, Japanese
- (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.), 92 - 92, Japanese
- (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.), 206 - 206, Japanese
- (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
- A Case of Long QT Syndrome with Ventricular Fibrillation Treated with Defibrillation Using an Automatic External Defibrillator1歳11ヵ月の女児。突然の意識消失と心肺停止を主訴に、母が救急要請した。救急隊到着時、モニター上、心室細動であったが、救急隊が実施した自動体外式除細動器(AED)により洞調律に復調し、救急要請から約30分でバギング下に著者らの施設へ搬送入院となった。搬送後は人工呼吸管理下に低体温療法を開始し、第2病日目の心電図でQT延長が判明した。その後も低体温療法を継続し、第3病日目に施行した脳波検査では異常所見を認めず、低体温療法終了した。以後、第4病日目に抜管したが、QT延長は持続し、臨床経過よりQT延長症候群の診断に至った。診断後、β遮断薬の内服を開始したところ、第30病日目に軽快退院となった。日本小児科学会, Mar. 2016, 日本小児科学会雑誌 = The journal of the Japan Pediatric Society, 120(3) (3), 623 - 628, Japanese
- (公社)日本小児科学会, Feb. 2016, 日本小児科学会雑誌, 120(2) (2), 240 - 240, Japanese次世代シークエンサーによる常染色体優性Alport症候群診断法の確立
- (公社)日本小児科学会, Feb. 2016, 日本小児科学会雑誌, 120(2) (2), 242 - 242, Japanese腎移植後にウイルス関連の重症合併症を呈した4症例
- (公社)日本小児科学会, Jan. 2016, 日本小児科学会雑誌, 120(1) (1), 80 - 80, Japanese当院における卵巣腫瘍の検討
- (公社)日本小児科学会, Jan. 2016, 日本小児科学会雑誌, 120(1) (1), 84 - 84, Japanese左鎖骨部腫瘤を呈した生後6ヵ月の乳児例[Refereed]
- (一社)日本小児血液・がん学会, Oct. 2015, 日本小児血液・がん学会雑誌, 52(4) (4), 342 - 342, Japanese外来化学療法中(ALL B12臨床試験)の中心静脈カテーテルの管理についての検討[Refereed]
- (一社)日本小児血液・がん学会, Oct. 2015, 日本小児血液・がん学会雑誌, 52(4) (4), 257 - 257, EnglishDENNドメイン蛋白質DENND2Aによる神経芽腫の制御機構(DENN domain protein DENND2A mediates the progression of neuroblastoma)[Refereed]
- 日本血液代替物学会, Sep. 2015, 人工血液, 23(1) (1), 17 - 17, Japanese
- 川崎病患者におけるエルシニア抗体・抗YPM抗体について検討した。川崎病患者108例を対象とした。抗Yp抗体もしくは抗YPM抗体の上昇を認めた群(陽性群)、抗YP抗体・抗YPM抗体いずれも上昇を認めなかった群(陰性群)の2群に分けた。陽性群11例(1O%)、陰性群97例であった。抗YPM抗体は3例/陽性群11例(27%)に認め、抗YPM抗体と抗Yp抗体どちらも上昇を認めた例は2例/11例(18%)であった。便培養・血液培養は多くの症例で施行したが、すべて陰性であった。陽性群で有意に消化管症状(陽性群8、陰性群33)、心後遺症(陽性群2、陰性群1)が多く、それ以外の項目には有意差を認めなかった。(株)ライフ・サイエンス, Jul. 2015, Progress in Medicine, 35(7) (7), 1125 - 1128, Japanese
- 姫路赤十字病院図書学術委員会, Jul. 2015, 姫路赤十字病院誌, 39, 80 - 80, Japanese難治性先天性乳糜腹水の1例
- (公社)日本小児科学会, Mar. 2015, 日本小児科学会雑誌, 119(3) (3), 632 - 632, Japanese当院で経験したBeckwith-Wiedemann症候群の2例
- (公社)日本小児科学会, Mar. 2015, 日本小児科学会雑誌, 119(3) (3), 636 - 636, Japanese潜在性菌血症を呈した先天性副腎過形成症(CAH)の1例
- (公社)日本小児科学会, Mar. 2015, 日本小児科学会雑誌, 119(3) (3), 636 - 636, Japanese咽後膿瘍様所見を呈する川崎病と咽後膿瘍との差異に関する検討
- 77歳の女性。夜間より腹痛と背部痛があり、翌朝に破裂性腹部大動脈瘤と診断された。CT検査で最大径9.7cmの腎動脈下腹部大動脈瘤と後腹膜腔の広範囲血腫を認め、緊急Yグラフト置換術を予定した。大動脈瘤切開後に血圧低下、徐脈から心停止となり、高カリウム血症(9.2mEq/L)を認めた。胸骨圧迫心マッサージなどを施行したが、蘇生できなかった。破裂性腹部大動脈瘤の麻酔管理では、出血への対応に加え、高カリウム血症に注意を要する。(著者抄録)(株)シービーアール, Nov. 2014, 臨床麻酔, 38(11) (11), 1551 - 1554, Japanese
- 症例 ロタウイルスによる可逆性脳梁膨大部病変を有する脳炎後に片側性小脳炎を合併した1例症例は7歳女児で、嘔吐、発熱に続き、意識障害、けいれんが出現し、紹介入院となった。入院時検査よりロタウイルスによる可逆性脳梁膨大部病変を有する脳炎/脳症(MERS)と診断し、輸液のみで経過観察したところ、第6病日より意識レベルは改善傾向を示し、第10病日の頭部MRIでは脳梁膨大部病変は改善傾向にあった。第12病日には意識清明となったが、左上下肢の運動失調・測定障害・構音障害など小脳症状が出現したため、メチルプレドニゾロン(mPSL)パルス療法を開始した。第18病日の頭部MRIにて左小脳皮質にDWI・FLAIR画像所見で高信号を認めたため、第19病日よりmPSLパルス2クール目・γグロブリンの5日間投与を開始した。その結果、第25病日の頭部MRIで高信号は改善傾向が示され、第26病日よりmPSLパルス3クール目を開始したところ、第29病日には退院となったが、発症10ヵ月時点では左上肢の軽度測定障害と巧緻運動障害、軽度の構音障害が残存し、頭部MRIでは左小脳萎縮が認められた。金原出版, Sep. 2014, 小児科, 55(10) (10), 1469 - 1473, Japanese
- 1歳6ヵ月女児。1週間持続する発熱を主訴とした。入院の約1ヵ月前より発熱を繰り返していた。入院時検査ではCRPが著明に高値で、入院後3日間の抗菌薬投与を行ったが、効果はなかった。不明熱として精査を行ったところ、胸腹部造影CTにて胸部大動脈の拡大および腹部大動脈の壁肥厚を認めたことより、高安動脈炎と診断した。入院7日目よりメチルプレドニゾロン(mPSL)・パルス療法を開始した結果、速やかに解熱し炎症反応は低下した。超音波、MRI所見では両側鎖骨下動脈・総頸動脈の壁の肥厚、腎動脈以下の腹部大動脈の狭小化を認めた。mPSLパルス療法後にPSL内服に変更し、解熱・炎症反応陰性の維持を確認して第28病日に退院となった。退院後、PSLを漸減したところ再燃したため、アザチオプリン、シクロフォスファミド・パルス、シクロスポリンを追加したが効果がなかった。現在、トシリズマブの投与を開始している。姫路赤十字病院図書学術委員会, Jun. 2014, 姫路赤十字病院誌, 38, 13 - 15, Japanese
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 961 - 961, Japanese新生児仮死における新生児発作
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 967 - 967, Japanese未診断の母体から出生した新生児Basedow病の1例
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 967 - 968, Japanese性別の異なる一絨毛膜二羊膜双胎の1例
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 961 - 961, Japanese著明な低体温をきたした新生児例
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 969 - 969, Japanese可逆性脳梁膨大部病変を伴う軽症脳炎/脳症(MERS)を発症したロタウイルス腸炎の3例
- (公社)日本小児科学会, Jun. 2014, 日本小児科学会雑誌, 118(6) (6), 970 - 970, Japanese不明熱精査により診断に至った幼児の高安動脈炎の1例
- (一社)日本小児感染症学会, Apr. 2014, 小児感染免疫, 26(1) (1), 106 - 106, JapaneseRSウイルス、黄色ブドウ球菌肺炎に肺出血を合併した1例
- 日本小児感染症学会, Apr. 2014, 小児感染免疫, 26(1) (1), 148 - 149, Japanese当院入院症例におけるロタウイルス関連中枢神経合併症の検討
- 千葉県内在住の高齢者40名を対象に口腔機能と体力を測定し、それらの測定値と年齢、性差との関係について検討した。その結果、高齢者における体力は年齢と有意な相関関係が示されたが、最大舌圧ならびに最大口唇圧と年齢との間には有意な相関はみられなかった。最大口唇圧には有意な性差が認められた。握力、タイムドアップゴーテストと、最大口唇圧、最大舌圧との間には有意な正の相関関係が認められた。全国大学歯科衛生士教育協議会編集委員会, Mar. 2014, 全国大学歯科衛生士教育協議会雑誌, (3) (3), 21 - 27, Japanese
- 千葉県立保健医療大学, Mar. 2014, 千葉県立保健医療大学紀要, 5(1) (1), 107 - 107, Japanese千葉県在住高齢者を対象とした健康教育プログラムの指導効果について いきいき100歳への挑戦(その2)
- (公社)日本小児科学会, Feb. 2014, 日本小児科学会雑誌, 118(2) (2), 338 - 338, Japanese心室細動発作で発症しAEDで救命しえた先天性QT延長症候群(LQT1)の1歳女児例
- (公社)日本小児科学会, Feb. 2014, 日本小児科学会雑誌, 118(2) (2), 378 - 378, JapaneseRestless legs syndromeの2小児例
- Dent病は低分子蛋白尿、高カルシウム尿症、腎石灰化/腎結石を特徴とし、成人期には腎不全に至る可能性があるX染色体性遺伝疾患であり、主たる原因はクロライドチャンネル5(ClC-5)遺伝子(CLCN5)の異常による。英国からの報告例ではくる病は多いとされるが、日本ではくる病を呈するものは少ないとされ、報告例も少ない。また治療・管理については確立されたものはない。症例は2歳4ヵ月の男児で、兄がDent病であったため、1歳時に尿検査を施行し、尿β2ミクログロブリンの異常高値、腎エコーにて両側腎に微細石灰化を認め、Dent病疑いとして経過観察していた。2歳4ヵ月時にO脚を認めたため、膝関節X線を撮影したところ、くる病変化を認めた。血液検査にてALPの高値、低リン血症を認めた。遺伝子検査にてCLCN5遺伝子のnonsense mutationを認めDent病に合併したくる病と診断、リン製剤の内服を開始したところ、骨変形は改善した。Dent病ではくる病の発症に注意して診療に当たる必要があり、我が国のDent病患者でのくる病合併の頻度の把握と管理指針の確立が必要であると考えられた。(著者抄録)(一社)日本小児腎臓病学会, Nov. 2013, 日本小児腎臓病学会雑誌, 26(2) (2), 297 - 303, Japanese
- (NPO)日本肺癌学会, Oct. 2013, 肺癌, 53(5) (5), 388 - 388, Japanese
- 姫路赤十字病院図書学術委員会, Jun. 2013, 姫路赤十字病院誌, 37, 103 - 103, Japanese超早産児の短期予後と今後の課題
- (一社)日本小児腎臓病学会, May 2013, 日本小児腎臓病学会雑誌, 26(1Suppl.) (1Suppl.), 205 - 205, Japanese
- Lead, (一社)日本小児腎臓病学会, May 2013, 日本小児腎臓病学会雑誌, 26(1Suppl.) (1Suppl.), 217 - 217, Japanese
- (一社)日本腎臓学会, Apr. 2013, 日本腎臓学会誌, 55(3) (3), 353 - 353, Japanese片側尿管結紮モデルラットに対する低血清培養脂肪由来間葉系幹細胞の効果
- (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 148 - 148, Japanese短腸症候群児の長期入院の問題点と在宅医療に向けての課題
- (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 149 - 149, Japanese深頸部に膿瘍を認めた20症例の検討
- (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 149 - 149, Japanese咽後膿瘍から環軸椎回旋位固定をきたした1例
- (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 143 - 143, JapaneseX連鎖性遺伝性水頭症が疑われた1例
- (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 146 - 146, Japanese血液型不適合によりビリルビン脳症をきたした2例
- Lead, (公社)日本小児科学会, Jan. 2013, 日本小児科学会雑誌, 117(1) (1), 147 - 147, JapaneseITP母体から出生した新生児の管理について 当院で経験した症例の検討
- (公社)日本新生児成育医学会, Oct. 2012, 日本未熟児新生児学会雑誌, 24(3) (3), 583 - 583, Japanese
- (公社)日本新生児成育医学会, Oct. 2012, 日本未熟児新生児学会雑誌, 24(3) (3), 584 - 584, Japanese
- (公社)日本新生児成育医学会, Oct. 2012, 日本未熟児新生児学会雑誌, 24(3) (3), 669 - 669, Japanese
- (公社)日本新生児成育医学会, Oct. 2012, 日本未熟児新生児学会雑誌, 24(3) (3), 691 - 691, Japanese
- (公社)日本新生児成育医学会, Oct. 2012, 日本未熟児新生児学会雑誌, 24(3) (3), 731 - 731, Japanese
- 第128回日本小児科学会学術集会, Apr. 2025小児特発性ネフローゼ症候群の病因論と抗ネフリン抗体[Invited]Nominated symposium
- The 21st JAPAN-KOREA-CHINA Prediatric Nephrology Seminar 2025, Apr. 2025, EnglishAnti-Nephrin Antibodies: Unveiling the Pathogenesis of Idiopathic Nephrotic Syndrome[Invited]Nominated symposium
- ISN World Congress of Nephrology 2025 (WCN’25), Feb. 2025, EnglishGenetic Variants in Kidney Diseases[Invited]Nominated symposium
- 第54回日本腎臓学会西部学術大会, Oct. 2024, Japanese小児期～成人期の腎代替療法提示:腎移植医療に内科医はどうかかわるのか, 小児期CKD対応の留意点[Invited]Nominated symposium
- Shining a light on Alport Syndrome: a one-day workshop for Asia, Aug. 2024, EnglishTypes of genetic tests in Alport syndrome[Invited]Public discourse
- 第67回日本腎臓病学会学術集会, Jun. 2024, EnglishMolecular Genetic Studies in Hereditary Kidney Diseases and Nephrotic Syndrome[Invited]Invited oral presentation
- 第67回日本腎臓病学会学術集会, Jun. 2024, JapaneseIV型コラーゲン関連腎症の理解を深める～浸透率と予後、そして治療～[Invited]Nominated symposium
- 第67回日本腎臓病学会学術集会, Jun. 2024, Japanese塩分再吸収に関わる遺伝子～日本人の塩分感受性を考える～[Invited]Nominated symposium
- 第59回日本小児腎臓病学会学術集会, Jun. 2024, Japaneseここまでわかったネフローゼ症候群ー小児特発性ネフローゼ症候群診療はどう変わる？ 小児特発性ネフローゼ症候群と抗ネフリン抗体[Invited]Nominated symposium
- the 22nd Asian Pacific Congress of Nephrology (APCN 2024) and the 44th Annual Meeng of the Korean Society of Nephrology (KSN 2024), Jun. 2024, EnglishPATHOGENESIS of Pediatric Nephrotic Syndrome[Invited]Nominated symposium
- Pediatric Academic Societies (PAS) Meeting 2024, May 2024, EnglishImpact of Anti-nephrin Antibody Detection on Treatment Strategies for Nephrotic Syndrome[Invited]Nominated symposium
- American Society of Nephrology Kidney week 2023, Nov. 2023, EnglishCommon Variants in Mendelian Disease Genes as Risk Factors for CKD[Invited]Nominated symposium
- Alport online workshops, Oct. 2023, EnglishFinding the missing variants in Alport syndrome: How to detect splicing variants[Invited]Public discourse
- 日本人類遺伝学会 2022, Dec. 2022, English小児急性期・新生児医療のゲノム医療 小児のnephrogenomics: Alport症候群における治療戦略[Invited]Nominated symposium
- 第65回日本腎臓病学会学術集会, Jun. 2022, Japanese遺伝子診断の臨床応用 「Alport症候群」[Invited]Nominated symposium
- 第57回日本小児腎臓病学会学術集会, May 2022, Japanese臨床試験とガイドライン ～これまでの成果と今後の課題～"「Alport症候群」[Invited]Nominated symposium
- 59th ERA congress, Paris & Virtual, May 2022, EnglishPathogenic evaluation of synonymous COL4A5 variants in X-linked Alport syndrome using a minigene assay[Invited]Invited oral presentation
- 第64回日本腎臓病学会学術集会, Jun. 2021, 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[Invited]Nominated symposium
- 第124回日本小児科学会学術集会, Apr. 2021, Japanese明日から使える輸液療法の考え方 小児の維持輸液は低張液? それとも等張液?[Invited]Nominated symposium
- The18th Japan-Korea-China Pediatrics Nephrology Seminar 2021, Apr. 2021, EnglishAlport syndrome UP TO DATE 2 Genetics and novel treatment[Invited]Nominated symposium
- American Society of Nephrology Kidney week 2018, Nov. 2019, EnglishCommon risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndromeOral presentation
- The15th Japan-Korea-China Pediatrics Nephrology Seminar, Apr. 2017, EnglishDiagnostic strategy for inherited hypomagnesemiaOral presentation
- AMED: 国立研究開発法人日本医療研究開発機構, 難治性疾患実用化研究事業, D-2. 希少難治性疾患の診療に直結するエビデンス創出研究（エビデンス創出・小児）, 国立大学法人神戸大学, Apr. 2024 - Mar. 2027, Principal investigatorAnti-Nephrin Antibody in Nephrotic Syndrome in children
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 社会医療法人愛仁会高槻病院(臨床研究センター), 01 Apr. 2023 - 31 Mar. 2026レニンアンギオテンシン系に着目した早産、低出生体重児の腎障害進展機序の解明研究
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 01 Apr. 2023 - 31 Mar. 2026RNA解析を用いた小児腎疾患と感染症の関連解明研究
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2023 - 31 Mar. 2026Elucidation of the mechanism of rituximab-induced long-term remission in childhood nephrotic syndrome
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2023 - 31 Mar. 2026Elucidation of the mechanism of rituximab-induced long-term remission in childhood nephrotic syndrome
- 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)), Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)), Kobe University, 07 Oct. 2021 - 31 Mar. 2024Joint international Research Project for International GWAS Meta-Analysis and Anti-Nephrin Autoantibodies in Childhood Nephrotic Syndrome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。
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Kobe University, 01 Apr. 2020 - 31 Mar. 2023Clarification of the pathogenesis of childhood nephrotic syndrome using iPS cell-derived kidney organoidsFrom 11 Japanese pediatric patients with nephrotic syndrome, we generated iPS cells with null (n = 5), hetero (n = 4) or homo (n = 2) risk haplotypes of the gene NPHS1 that encodes Nephrin, the most important slit-membrane major component protein as a urinary protein prevention mechanism. They also succeeded in producing kidney organoids from some of the iPS cells. In the future, all iPS cells will be induced to differentiate into kidney organoids or renal glomerular podocytes to clarify the relationship between NPHS1 risk haplotype and NPHS1 gene expression.
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists, Grant-in-Aid for Early-Career Scientists, Kobe University, 01 Apr. 2020 - 31 Mar. 2023Study to clarify the pathophysiology of childhood nephrotic syndrome and HLA class IIMany patients with childhood idiopathic nephrotic syndrome are steroid-sensitive (SSNS). Several genome-wide association studies have shown that HLA class II, which is related to immunity, and NPHS1, which encodes nephrin in glomeruli, are involved in pediatric SSNS. HLA class II genes are associated with susceptibility to many kinds of autoimmune diseases, one of the mechanisms being misfolded protein/HLA class II complexes, which is aberrantly transported to the cell surface in the affected tissues inducing immune responses. In this study, we investigated the relationship between each HLA allele and nephrin based on the hypothesis that nephrin protein/HLA class II complexes might be involved in the development of SSNS. We also searched for autoantibodies that respond to the nephrin complex (neo-self).
- 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)), Fund for the Promotion of Joint International Research (Fostering Joint International Research (B)), Kobe University, 09 Oct. 2018 - 31 Mar. 2021To 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).Competitive research funding
- 公益財団法人小児医学研究振興財団, Apr. 2020 - Mar. 2021, Principal investigatorスプライシング異常による遺伝性腎疾患発症メカニズムの解明と治療法開発研究
- Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists, Grant-in-Aid for Early-Career Scientists, Kobe University, 01 Apr. 2018 - 31 Mar. 2020, Principal investigatorThe purpose of this study is to discover autoantibodies that are involved in the development of pediatric steroid-sensitive nephrotic syndrome and molecules that can cause steroid-sensitive nephrotic syndrome due to single gene abnormalities. We have already identified several molecules that may be associated with the development of pediatric steroid-sensitive nephrotic syndrome. At present, the research which clarifies the function analysis and the interaction which these molecules bring is being advanced.Competitive research funding