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山村 智彦大学院医学研究科 医科学専攻助教
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■ 受賞- 2021年07月 第56回日本小児腎臓病学会学術集会, 森田賞（臨床研究部門）
- 2021年07月 第56回日本小児腎臓病学会学術集会, 森田賞（基礎研究部門）
- 2019年09月 The 2019 International workshop on Alpot Syndrome, The Cecil Alport Award for the best young investigator
- 2019年06月 第54回日本小児腎臓病学会学術集会, 優秀演題奨励賞
- 2019年06月 第62回日本腎臓学会学術集会, 会長賞
- 2018年06月 第61回日本腎臓学会学術集会, 優秀演題賞
- 2016年09月 第17回国際小児腎臓病学会学術集会, Travel grant
- 2016年07月 第51回日本小児腎臓病学会学術集会, 優秀演題奨励賞
- 2016年06月 第59回日本腎臓学会学術集会, 優秀演題賞
- 2016年 兵庫県健康財団研究奨励賞
- 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.2025年04月, Clinical and experimental nephrology, 英語, 国内誌研究論文（学術雑誌）
- 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.2025年04月, Pediatric nephrology (Berlin, Germany), 40(4) (4), 1033 - 1040, 英語, 国際誌研究論文（学術雑誌）
- 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.2025年03月, Pediatric nephrology (Berlin, Germany), 英語, 国際誌研究論文（学術雑誌）
- 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.2025年02月, Clinical and experimental nephrology, 英語, 国内誌研究論文（学術雑誌）
- 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.2025年02月, Kidney international reports, 10(2) (2), 516 - 521, 英語, 国際誌研究論文（学術雑誌）
- 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.2024年12月, Genes to cells : devoted to molecular & cellular mechanisms, 29(12) (12), 1118 - 1130, 英語, 国際誌研究論文（学術雑誌）
- 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.2024年10月, Kidney360, 5(10) (10), 1510 - 1517, 英語, 国際誌研究論文（学術雑誌）
- 2024年08月, Nephrology Dialysis Transplantation, 英語[査読有り]研究論文（学術雑誌）
- 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.2024年04月, Pediatric nephrology (Berlin, Germany), 英語, 国際誌研究論文（学術雑誌）
- Springer Science and Business Media LLC, 2024年04月, Clinical and Experimental Nephrology研究論文（学術雑誌）
- BACKGROUND: The kidney contains distinct glomerular and tubulointerstitial compartments with diverse cell types and extracellular matrix components. The role of immune cells in glomerular environment is crucial for dampening inflammation and maintaining homeostasis. Macrophages are innate immune cells that are influenced by their tissue microenvironment. However, the multifunctional role of kidney macrophages remains unclear. METHODS: Flow and imaging cytometry were used to determine the relative expression of CD81 and CX3CR1 (C-X3-C motif chemokine receptor 1) in kidney macrophages. Monocyte replenishment was assessed in Cx3cr1CreER X R26-yfp-reporter and shielded chimeric mice. Bulk RNA-sequencing and mass spectrometry-based proteomics were performed on isolated kidney macrophages from wild type and Col4a5-/- (Alport) mice. RNAscope was used to visualize transcripts and macrophage purity in bulk RNA assessed by CIBERSORTx analyses. RESULTS: In wild type mice we identified three distinct kidney macrophage subsets using CD81 and CX3CR1 and these subsets showed dependence on monocyte replenishment. In addition to their immune function, bulk RNA-sequencing of macrophages showed enrichment of biological processes associated with extracellular matrix. Proteomics identified collagen IV and laminins in kidney macrophages from wild type mice whilst other extracellular matrix proteins including cathepsins, ANXA2 and LAMP2 were enriched in Col4a5-/- (Alport) mice. A subset of kidney macrophages co-expressed matrix and macrophage transcripts. CONCLUSIONS: We identified CD81 and CX3CR1 positive kidney macrophage subsets with distinct dependence for monocyte replenishment. Multiomic analysis demonstrated that these cells have diverse functions that underscore the importance of macrophages in kidney health and disease.2024年03月, Matrix biology : journal of the International Society for Matrix Biology, 127, 23 - 37, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE OF REVIEW: Matrikines are cell-signalling extracellular matrix fragments and they have attracted recent attention from basic and translational scientists, due to their diverse roles in age-related disease and their potential as therapeutic agents. In kidney, the matrix undergoes remodelling by proteolytic fragmentation, so matrikines are likely to play a substantial, yet understudied, role in ageing and pathogenesis of age-related diseases. RECENT FINDINGS: This review presents an up-to-date description of known matrikines with either a confirmed or highly anticipated role in kidney ageing and disease, including their point of origin, mechanism of cleavage, a summary of known biological actions and the current knowledge which links them to kidney health. We also highlight areas of interest, such as the prospect of matrikine cross-tissue communication, and gaps in knowledge, such as the unexplored signalling potential of many kidney disease-specific matrix fragments. SUMMARY: We anticipate that knowledge of specific matrikines, and their roles in controlling processes of kidney pathology, could be leveraged for the development of exciting new future therapies through inhibition or even with their supplementation.2023年11月, Current opinion in nephrology and hypertension, 32(6) (6), 551 - 558, 英語, 国際誌研究論文（学術雑誌）
- 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, 2023年09月, Communications Biology, 6(1) (1)研究論文（学術雑誌）
- Elsevier {BV}, 2023年07月, Kidney International Reports, 英語[査読有り]研究論文（学術雑誌）
- 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.2023年05月, Clinical and experimental nephrology, 英語, 国内誌研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2023年05月, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 124 - 124, 日本語
- [This corrects the article DOI: 10.1016/j.ekir.2021.12.037.].2023年05月, Kidney international reports, 8(5) (5), 1127 - 1129, 英語, 国際誌
- (一社)日本小児腎臓病学会, 2023年05月, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 94 - 94, 日本語
- (一社)日本小児腎臓病学会, 2023年05月, 日本小児腎臓病学会雑誌, 36(Suppl.) (Suppl.), 94 - 94, 日本語
- 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.2023年03月, Clinical and experimental nephrology, 27(3) (3), 218 - 226, 英語, 国内誌研究論文（学術雑誌）
- 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.2022年11月, Pediatric nephrology (Berlin, Germany), 38(7) (7), 1 - 10, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2022年11月, 日本小児腎臓病学会雑誌, 35(2) (2), 159 - 159, 日本語
- 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.2022年09月, American journal of medical genetics. Part A, 188(9) (9), 2576 - 2583, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. METHODS: This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. RESULTS: The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). CONCLUSIONS: We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.2022年08月, Kidney360, 3(8) (8), 1384 - 1393, 英語, 国際誌研究論文（学術雑誌）
- 日本小児腎不全学会, 2022年08月, 日本小児腎不全学会雑誌, 42, 97 - 100, 日本語
- 日本小児腎不全学会, 2022年08月, 日本小児腎不全学会雑誌, 42, 97 - 100, 日本語早期の遺伝学的検査が治療方針選択に有用であったステロイド抵抗性ネフローゼ症候群の1例
- 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.2022年06月, Clinical and experimental nephrology, 26(6) (6), 561 - 570, 英語, 国内誌研究論文（学術雑誌）
- (一社)日本腎臓学会, 2022年05月, 日本腎臓学会誌, 64(3) (3), 231 - 231, 日本語Alport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)日本小児腎臓病学会, 2022年04月, 日本小児腎臓病学会雑誌, 35(1Suppl.) (1Suppl.), 109 - 109, 日本語
- (一社)日本小児腎臓病学会, 2022年04月, 日本小児腎臓病学会雑誌, 35(1Suppl.) (1Suppl.), 105 - 105, 日本語
- 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.2022年03月, Kidney360, 3(3) (3), 497 - 505, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本小児科学会, 2022年03月, 日本小児科学会雑誌, 126(3) (3), 545 - 546, 日本語肉眼的血尿をきたした膜性増殖性糸球体腎炎(MPGN)(C3腎症)の1例
- 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.2022年02月, Journal of human genetics, 67(7) (7), 427 - 440, 英語, 国際誌研究論文（学術雑誌）
- (公社)日本小児科学会, 2022年02月, 日本小児科学会雑誌, 126(2) (2), 230 - 230, 日本語Alport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
- 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.2022年02月, Clinical and experimental nephrology, 26(2) (2), 140 - 153, 英語, 国内誌研究論文（学術雑誌）
- 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.2022年01月, Pediatric nephrology (Berlin, Germany), 37(8) (8), 1845 - 1853, 英語, 国際誌研究論文（学術雑誌）
- 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年, Frontiers in medicine, 9, 841391 - 841391, 英語, 国際誌研究論文（学術雑誌）
- Introduction: COL4A5 is a causative gene of X-linked Alport syndrome (XLAS). Male patients with XLAS with nonsense variants have the most severe phenotypes of early onset end-stage kidney disease (ESKD); those with splicing variants have middle phenotypes and those with missense variants have the mildest phenotypes. Therefore, genotyping for male patients with XLAS can be used to predict kidney prognosis. Single-base substitutions at the last nucleotide position in each exon are known to affect splicing patterns and could be splicing variants. Nevertheless, in XLAS, these variants are generally considered to be missense variants, without conducting a transcript analysis, which underestimates some patients as having mild phenotypes. This study aimed to investigate whether single-base substitutions at the last nucleotide position of COL4A5 exons cause aberrant splicing. Methods: In total, 20 variants were found in the Human Gene Mutation Database (n = 14) and our cohort (n = 6). We performed functional splicing assays using a hybrid minigene analysis and in vivo transcript analyses of patients' samples when available. Then, we investigated genotype-phenotype correlations for patients with splicing variants detected in this study by comparing data from our previous studies. Results: Among the 20 variants, 17 (85%) caused aberrant splicing. Male patients with splicing variants had more severe phenotypes when compared with those with missense variants. Findings from the in vivo analyses for 3 variants were identical to those from the minigene assay. Conclusion: Our study revealed that most single-base substitutions at the last nucleotide position of COL4A5 exons result in splicing variants, rather than missense variants, thereby leading to more severe phenotypes.2022年01月, Kidney international reports, 7(1) (1), 108 - 116, 英語, 国際誌研究論文（学術雑誌）
- 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.2021年12月, Journal of the American Society of Nephrology : JASN, 33(2) (2), 401 - 419, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Alport syndrome (AS), which is a rare hereditary disease caused by mutations of genes including COL4A3, COL4A4 and COL4A5, has a wide spectrum of phenotypes. Most disease-causing variants of AS are located in the exons or the conservative splicing sites of these genes, while little is known about the intronic disease-causing variants. METHODS: A Chinese AS family was recruited in this study. All the clinical data of AS patient were collected from medical records. After pedigree analysis, the pathogenic variants were studied by the whole exome sequencing (WES). Minigene assay and in vivo RT-PCR analysis were performed to validate the functions of the variants. RESULTS: Renal biopsy showed a typical histopathology changes of AS. WES revealed compound heterozygous substitution, NM_033380 c.991-14(IVS17) A > G, in the intron 17 of the COL4A5 gene, which were confirmed by Sanger sequencing. Moreover, the variant was co-segregated with the phenotype in this family. Minigene assay in cultured cell lines showed that a splicing error was induced by this intronic variant, which further confirmed by in vivo RT-PCR analysis. CONCLUSION: A novel intronic disease-causing variant in COL4A5 gene was identified by WES, which was the molecular pathogenic basis of AS.2021年11月, BMC nephrology, 22(1) (1), 380 - 380, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2021年11月, 日本小児腎臓病学会雑誌, 34(2) (2), 177 - 177, 日本語
- (一社)日本小児腎臓病学会, 2021年11月, 日本小児腎臓病学会雑誌, 34(2) (2), 204 - 205, 日本語
- (一社)日本小児腎臓病学会, 2021年11月, 日本小児腎臓病学会雑誌, 34(2) (2), 204 - 205, 日本語
- (株)診断と治療社, 2021年11月, 小児科診療, 84(11) (11), 1436 - 1440, 日本語
- 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), 2021年10月, Kidney360, 10.34067/KID.0004952021 - 10.34067/KID.0004952021研究論文（学術雑誌）
- 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.2021年10月, Journal of human genetics, 67(3) (3), 143 - 148, 英語, 国際誌研究論文（学術雑誌）
- 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.2021年10月, Kidney international reports, 6(10) (10), 2585 - 2593, 英語, 国際誌研究論文（学術雑誌）
- 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.2021年09月, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 37(2) (2), 262 - 270, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Only a few studies have investigated epidemiological and clinicopathological information regarding pediatric and adolescent and young adult (AYA) patients with renal disease. The purpose of this study was to clarify the differences and relationship of clinicopathological findings between pediatric and AYA patients using the Japan Renal Biopsy Registry (J-RBR). METHODS: This cross-sectional study analyzed data from patients registered in the J-RBR between 2007 and 2017. Clinicopathological findings at diagnosis were analyzed for 3,463 pediatric (age < 15 years) and 6,532 AYA (age 15-30 years) patients. RESULTS: Although chronic nephritic syndrome was the most common clinical diagnosis at age > 5 years, nephrotic syndrome was the most frequent diagnosis at age < 4 years. The most common pathological diagnosis as classified by pathogenesis in pediatric patients was primary glomerular disease (except IgA nephropathy), whereas IgA nephropathy was increased in AYA patients. Mesangial proliferative glomerulonephritis was the most common pathological diagnosis as classified by histopathology in both pediatric and AYA patients. Minor glomerular abnormalities were the most frequent histopathologic diagnoses of nephrotic syndrome in childhood, but their frequency decreased with age. CONCLUSION: To the best of our knowledge, this is the first report of clinicopathological features of pediatric and AYA patients in a large nationwide registry of renal biopsy. There were differences of clinical, pathological and histopathologic findings between pediatric and AYA patients.2021年09月, Clinical and experimental nephrology, 25(9) (9), 1018 - 1026, 英語, 国内誌研究論文（学術雑誌）
- Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM_001022.4]. Nearly 180 RPS19 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in vitro functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four RPS19 deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.2021年09月, Pediatric hematology and oncology, 38(6) (6), 515 - 527, 英語, 国際誌研究論文（学術雑誌）
- 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.2021年08月, Scientific reports, 11(1) (1), 16099 - 16099, 英語, 国際誌研究論文（学術雑誌）
- (株)東京医学社, 2021年08月, 腎と透析, 91(増刊) (増刊), 808 - 811, 日本語
- (株)東京医学社, 2021年07月, 腎と透析, 91(1) (1), 89 - 93, 日本語
- 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.2021年07月, Clinical and experimental nephrology, 25(7) (7), 779 - 787, 英語, 国内誌研究論文（学術雑誌）
- 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.2021年06月, Clinical and experimental nephrology, 25(11) (11), 1224 - 1230, 英語, 国内誌研究論文（学術雑誌）
- 日本小児泌尿器科学会, 2021年06月, 日本小児泌尿器科学会雑誌, 30(2) (2), 202 - 202, 日本語
- (一社)日本小児腎臓病学会, 2021年05月, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 92 - 92, 日本語
- (一社)日本小児腎臓病学会, 2021年05月, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 92 - 92, 日本語
- (一社)日本小児腎臓病学会, 2021年05月, 日本小児腎臓病学会雑誌, 34(1Suppl.) (1Suppl.), 126 - 126, 日本語
- 2021年05月, Clinical and experimental nephrology, 25(5) (5), 564 - 564, 英語, 国内誌
- Introduction: WT1 missense mutation in exon 8 or 9 causes infantile nephrotic syndrome with early progression to end-stage kidney disease (ESKD), Wilms tumor, and 46,XY female. However, some patients with missense mutations in exon 8 or 9 progress to ESKD in their teens or later. Therefore, we conducted a systematic review and functional analysis of WT1 transcriptional activity. Methods: We conducted a systematic review of 174 cases with WT1 exon 8 or 9 missense variants from our cohort (n=13) and previous reports (n=161). Of these cases, mild and severe genotypes were selected for further in vitro functional analysis using luciferase assay. Results: The median age of developing ESKD was 1.17 years. A comparative study was conducted among three WT1 genotype classes: mutations of the DNA-binding site (DBS group), mutations outside the DNA-binding site but at sites important for zinc finger structure formation by 2 cysteines and 2 histidines (C2H2 group), and mutations leading to other amino acid changes (Others group). The DBS group showed the severest phenotype and the C2H2 group was intermediate, whereas the Others group showed the mildest phenotype (developing ESKD at 0.90, 2.00, and 3.92 years, respectively, with significant differences). In vitro functional analysis showed dominant-negative effects for all variants; in addition, the DBS and C2H2 mutations were associated with significantly lower WT1 transcriptional activity than the other mutations. Conclusion: Not only the DNA-binding site but also C2H2 zinc finger structure sites are important for maintaining WT1 transcriptional activity, and their mutation causes severe clinical symptoms.Elsevier BV, 2021年05月, Kidney International Reports, 6(8) (8), 2114 - 2121, 英語, 国際誌研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2021年04月, 日本小児腎臓病学会雑誌, 34(1) (1), 87 - 87, 日本語
- (一社)日本小児腎臓病学会, 2021年04月, 日本小児腎臓病学会雑誌, 34(1) (1), 91 - 91, 日本語
- (一社)日本小児腎臓病学会, 2021年04月, 日本小児腎臓病学会雑誌, 34(1) (1), 93 - 93, 日本語
- 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.2021年02月, CEN case reports, 10(1) (1), 100 - 105, 英語, 国内誌研究論文（学術雑誌）
- (有)科学評論社, 2021年01月, 腎臓内科, 13(1) (1), 105 - 112, 日本語遺伝性腎疾患における遺伝学的検査方法の進歩
- 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.2020年12月, Kidney research and clinical practice, 39(4) (4), 402 - 413, 英語, 国際誌研究論文（学術雑誌）
- (有)科学評論社, 2020年11月, 腎臓内科, 12(5) (5), 467 - 473, 日本語【腎臓内科医が知っておくべき遺伝性腎疾患】Alport症候群
- 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.2020年09月, Kidney360, 1(9) (9), 936 - 942, 英語, 国際誌研究論文（学術雑誌）
- 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.2020年08月, Scientific reports, 10(1) (1), 14026 - 14026, 英語, 国際誌研究論文（学術雑誌）
- 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.2020年07月, Kidney international, 98(6) (6), 1605 - 1614, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2020年07月, Pediatric nephrology (Berlin, Germany), 35(12) (12), 2319 - 2326, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2020年07月, CEN case reports, 9(4) (4), 431 - 436, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- (一社)日本腎臓学会, 2020年07月, 日本腎臓学会誌, 62(4) (4), 362 - 362, 日本語Alport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
- (一社)日本腎臓学会, 2020年07月, 日本腎臓学会誌, 62(4) (4), 255 - 255, 日本語小児における糖鎖不全IgA1免疫染色
- (一社)日本腎臓学会, 2020年07月, 日本腎臓学会誌, 62(4) (4), 257 - 257, 日本語スプライシング異常が疑われるCLCN5遺伝子変異のDent病発症メカニズムの解明
- (一社)日本腎臓学会, 2020年07月, 日本腎臓学会誌, 62(4) (4), 293 - 293, 日本語WT1遺伝子exon8-9ミスセンス変異における遺伝子型-臨床型の相関に関する検討
- 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.2020年07月, Clinical and experimental nephrology, 24(7) (7), 606 - 612, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2020年06月, CEN case reports, 9(4) (4), 418 - 422, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2020年06月, Molecular genetics & genomic medicine, 8(8) (8), e1342, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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).2020年06月, Kidney international, 98(5) (5), 1308 - 1322, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2020年06月, Nature communications, 11(1) (1), 2777 - 2777, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公社)日本小児科学会, 2020年06月, 日本小児科学会雑誌, 124(6) (6), 1036 - 1036, 日本語母児間輸血症候群後に慢性腎臓病(CKD)に至った3例
- (公社)日本小児科学会, 2020年06月, 日本小児科学会雑誌, 124(6) (6), 1044 - 1044, 日本語小児期に腎低形成と診断された新生児高β2ミクログロブリン尿症の1例
- 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.2020年06月, Journal of human genetics, 65(6) (6), 541 - 549, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2020年05月, Kidney International Reports, 5(5) (5), 718 - 726[査読有り]研究論文（学術雑誌）
- 発達腎研究会, 2020年04月, 発達腎研究会誌, 28(1) (1), 29 - 32, 日本語WT1遺伝子異常症
- Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.2020年04月, Journal of human genetics, 65(4) (4), 355 - 362, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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".2020年04月, Pediatrics international : official journal of the Japan Pediatric Society, 62(4) (4), 428 - 437, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 237 - 237, 日本語X染色体連鎖型Alport症候群患者におけるサイレント変異の病的意義の検討
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 238 - 238, 日本語Dent disease-1とDent disease-2の臨床像の差異に関する検討
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 305 - 305, 日本語日本人における遺伝性ネフローゼ症候群の網羅的遺伝子診断体制
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 305 - 305, 日本語糖鎖不全IgA1免疫染色が診断に有用であったステロイド抵抗性ネフローゼ症候群の1例
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 303 - 303, 日本語小児IgA腎症の組織学的軽症例と重症例における多剤併用療法の効果に関する比較
- (公社)日本小児科学会, 2020年02月, 日本小児科学会雑誌, 124(2) (2), 418 - 418, 日本語小児期に腎低形成と診断された新生児高β2ミクログロブリン尿症の1例
- 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.2020年01月, Scientific reports, 10(1) (1), 270 - 270, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2019年11月, 日本小児腎臓病学会雑誌, 32(2) (2), 139 - 139, 日本語
- 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.2019年09月, Scientific reports, 9(1) (1), 12696 - 12696, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.2019年09月, Clinical and experimental nephrology, 23(9) (9), 1119 - 1129, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2019年09月, Molecular genetics & genomic medicine, 7(9) (9), e883, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 日本小児高血圧研究会, 2019年07月, 日本小児高血圧研究会誌, 16(1) (1), 14 - 21, 日本語当科における24時間自由行動下血圧測定(ABPM)の使用経験
- 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.2019年07月, Journal of human genetics, 64(7) (7), 673 - 679, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本腎臓学会, 2019年05月, 日本腎臓学会誌, 61(3) (3), 298 - 298, 日本語NPHS1は小児ステロイド感受性ネフローゼ症候群の疾患感受性遺伝子である
- (一社)日本腎臓学会, 2019年05月, 日本腎臓学会誌, 61(3) (3), 318 - 318, 日本語常染色体劣性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, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 100 - 100, 日本語
- (一社)日本腎臓学会, 2019年05月, 日本腎臓学会誌, 61(3) (3), 303 - 303, 日本語遺伝性ネフローゼ症候群における臨床的特徴の検討
- (一社)日本腎臓学会, 2019年05月, 日本腎臓学会誌, 61(3) (3), 355 - 355, 日本語Dent病およびLowe症候群の臨床遺伝学的検討
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 91 - 91, 日本語
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 92 - 92, 日本語
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 180 - 180, 日本語
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 119 - 119, 日本語
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 120 - 120, 日本語
- (一社)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 56 - 56, 日本語
- 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.2019年05月, Clinical and experimental nephrology, 23(5) (5), 669 - 675, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2019年04月, 日本小児腎臓病学会雑誌, 32(1) (1), 31 - 36, 日本語
- 発達腎研究会, 2019年04月, 発達腎研究会誌, 27(1) (1), 7 - 8, 日本語オリゴメガネフロニアと角膜ジストロフィ[査読有り]
- (公社)日本小児科学会, 2019年03月, 日本小児科学会雑誌, 123(3) (3), 621 - 621, 日本語無症候性血尿にて長期経過の後に蛋白尿が出現し常染色体劣性Alport症候群の診断に至った1例
- (公社)日本小児科学会, 2019年03月, 日本小児科学会雑誌, 123(3) (3), 628 - 628, 日本語クラリスロマイシンによりカルシニューリン阻害薬血中濃度の異常上昇をきたした2例
- (公社)日本小児科学会, 2019年02月, 日本小児科学会雑誌, 123(2) (2), 217 - 217, 日本語腎生検後のADH上昇と生理食塩水輸液の安全性に関する検討
- (公社)日本小児科学会, 2019年02月, 日本小児科学会雑誌, 123(2) (2), 217 - 217, 日本語先天性/乳児およびステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制
- 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.2019年02月, CEN case reports, 8(1) (1), 14 - 17, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2019年02月, Clinical and experimental nephrology, 23(2) (2), 158 - 168, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 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.2019年01月, Journal of human genetics, 64(1) (1), 3 - 9, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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 SLC12A3.2019年01月, Kidney international reports, 4(1) (1), 119 - 125, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 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.2018年11月, Scientific reports, 8(1) (1), 17322 - 17322, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2018年11月, 日本小児腎臓病学会雑誌, 31(2) (2), 175 - 175, 日本語
- (一社)日本小児腎臓病学会, 2018年11月, 日本小児腎臓病学会雑誌, 31(2) (2), 176 - 176, 日本語
- 2018年11月, J Hum Genet.Clinical spectrum of male patients with OFD1 mutations.[査読有り]
- 2018年09月, Case Rep Nephrol Dial., 8(3) (3), 198 - 206[査読有り]
- 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.2018年08月, Journal of the American Society of Nephrology : JASN, 29(8) (8), 2244 - 2254, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2018年08月, Clin Exp Nephrol.A review of clinical characteristics and genetic backgrounds in Alport syndrome.[査読有り]
- 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.2018年08月, Clinical and experimental nephrology, 22(4) (4), 881 - 888, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- 2018年07月, 日本小児腎不全学会雑誌, 38, 148 - 151, 日本語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[査読有り]研究論文（学術雑誌）
- 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.2018年07月, Journal of human genetics, 63(8) (8), 887 - 892, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2018年06月, 日本小児高血圧研究会誌, 15(1) (1), 21 - 25, 日本語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[査読有り]研究論文（学術雑誌）
- Pathogenic variants in specific complement-related genes lead to atypical hemolytic uremic syndrome (aHUS). Some reports have indicated that patients with digenic variants in these genes might present severer phenotypes. Upon detecting novel intronic variants, transcriptional analysis is necessary to prove pathogenicity; however, when intronic variants are located in intron 1 and, as a result, no transcript is produced, no appropriate method had been established to reveal the pathogenicity. Recently, the minigene assay was used to assess the pathogenicity of intronic variants. Here, we report an infantile case of aHUS caused by digenic mutations in two different complement-related genes, C3 and MCP. Targeted sequencing detected a known variant in C3 and a novel variant in the intron 1 splicing donor site of MCP. To assess the pathogenicity of this intronic variant, we conducted functional splicing assay using a minigene construct and quantitative PCR analysis of the MCP transcript, revealing the pathogenicity of the intronic variant. In conclusion, the minigene assay revealed the pathogenicity of the intron 1 splicing donor site variant for the first time. This case showed a severe phenotype of infantile-onset aHUS associated with digenic variants in two complement-related genes.2018年06月, Journal of human genetics, 63(6) (6), 755 - 759, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 99 - 99, 日本語
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 100 - 100, 日本語
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 101 - 101, 日本語
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 147 - 147, 日本語
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 156 - 156, 日本語
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 200 - 200, 日本語
- 2018年05月, 日本小児体液研究会誌, 10, 67 - 72, 日本語低身長を契機に診断に至ったGitelman症候群の2例[査読有り]研究論文（学術雑誌）
- 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.2018年05月, Journal of human genetics, 63(5) (5), 589 - 595, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 発達腎研究会, 2018年04月, 発達腎研究会誌, 26(1) (1), 8 - 10, 日本語X染色体不活化とDent病
- (一社)日本腎臓学会, 2018年04月, 日本腎臓学会誌, 60(3) (3), 336 - 336, 日本語X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
- (一社)日本腎臓学会, 2018年04月, 日本腎臓学会誌, 60(3) (3), 337 - 337, 日本語Gitelman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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 337 - 337, 日本語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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 338 - 338, 日本語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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 344 - 344, 日本語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
- 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年, Nephron, 138(2) (2), 166 - 171, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2017年12月, Environmental Health and Preventive Medicine (Web), 22(1) (1), 22:15 (WEB ONLY), 英語日本の小児一次救急医療センターにおいてロタウイルスワクチンの任意導入後の急性胃腸炎患者数変化[査読有り]研究論文（学術雑誌）
- 2017年12月, CLINICAL AND EXPERIMENTAL NEPHROLOGY, 21(6) (6), 1003 - 1010, 英語[査読有り]研究論文（学術雑誌）
- 2017年12月, EUROPEAN JOURNAL OF MEDICAL GENETICS, 60(12) (12), 631 - 634, 英語[査読有り]研究論文（学術雑誌）
- 2017年12月, BMC NEPHROLOGY, 18(1) (1), 353, 英語[査読有り]研究論文（学術雑誌）
- 2017年10月, CLINICAL AND EXPERIMENTAL NEPHROLOGY, 21(5) (5), 877 - 883, 英語[査読有り]研究論文（学術雑誌）
- 2017年10月, CLINICAL AND EXPERIMENTAL NEPHROLOGY, 21(5) (5), 889 - 894, 英語[査読有り]研究論文（学術雑誌）
- Elsevier Inc, 2017年09月, Kidney International Reports, 2(5) (5), 850 - 855, 英語[査読有り]研究論文（学術雑誌）
- 2017年07月, JOURNAL OF HUMAN GENETICS, 62(7) (7), 733 - 735, 英語[査読有り]研究論文（学術雑誌）
- 2017年06月, 日本小児高血圧研究会誌, 14(1号) (1号), 32 - 36, 日本語蛋白尿、高血圧を認め24時間自由行動下血圧測定を施行した極低出生体重の1例[査読有り]研究論文（学術雑誌）
- 2017年05月, MOLECULAR GENETICS & GENOMIC MEDICINE, 5(3) (3), 287 - 294, 英語[査読有り]研究論文（学術雑誌）
- 2017年02月, JOURNAL OF HUMAN GENETICS, 62(2) (2), 335 - 337, 英語[査読有り]研究論文（学術雑誌）
- 2017年02月, CLINICAL AND EXPERIMENTAL NEPHROLOGY, 21(1) (1), 136 - 142, 英語[査読有り]研究論文（学術雑誌）
- 2017年, ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE, 22(1) (1), 15, 英語[査読有り]研究論文（学術雑誌）
- 2016年08月, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 11(8) (8), 1441 - 1449, 英語[査読有り]研究論文（学術雑誌）
- 2016年07月, 日本小児腎不全学会雑誌, 36, 175 - 178, 日本語異なる経過をたどった腸管出血性大腸菌による溶血性尿毒症症候群の姉妹例[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2016年06月, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 93 - 93, 日本語
- (一社)日本小児腎臓病学会, 2016年06月, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 118 - 118, 日本語
- (一社)日本小児腎臓病学会, 2016年06月, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 91 - 91, 日本語
- (一社)日本小児腎臓病学会, 2016年06月, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 92 - 92, 日本語
- (一社)日本小児腎臓病学会, 2016年06月, 日本小児腎臓病学会雑誌, 29(1Suppl.) (1Suppl.), 206 - 206, 日本語
- 2016年06月, 日本小児高血圧研究会誌, 13(1号) (1号), 3 - 6, 日本語24時間自由行動下血圧測定が有用であった本態性高血圧の一例[査読有り]研究論文（学術雑誌）
- 2016年04月, CLINICAL AND EXPERIMENTAL NEPHROLOGY, 20(2) (2), 253 - 257, 英語[査読有り]研究論文（学術雑誌）
- (公社)日本小児科学会, 2016年02月, 日本小児科学会雑誌, 120(2) (2), 240 - 240, 日本語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, 2016年02月, 日本小児科学会雑誌, 120(2) (2), 242 - 242, 日本語腎移植後にウイルス関連の重症合併症を呈した4症例
- 2016年02月, GENETICS IN MEDICINE, 18(2) (2), 180 - 188, 英語[査読有り]研究論文（学術雑誌）
- 2016年, INTERNAL MEDICINE, 55(19) (19), 2843 - 2847, 英語[査読有り]研究論文（学術雑誌）
- (一社)日本小児腎臓病学会, 2015年06月, 日本小児腎臓病学会雑誌, 28(1Suppl.) (1Suppl.), 146 - 146, 日本語びまん性メサンギウム細胞増殖を呈した特発性ネフローゼ症候群の臨床病理学的検討
- 要旨 ステロイド依存性頻回再発型ネフローゼ症候群(FRSDNS)におけるシクロスポリン(CsA)とミゾリビン(MZR)の併用療法の安全性・有効性について後方視的検討を行ったので報告する。FR-SDNS に対してCsA・MZR 併用療法を行った20 症例を対象とした。有害事象は軽度の高尿酸血症1 例のみであった。有効性に対する検討では20 例中CsA 単独期間，CsA・MZR 併用療法期間がそれぞれ半年以上の9 症例を対象とし総プレドニゾロン(PSL)投与量，再発回数について前後比較検討した。総PSL 投与量は併用前0.37±0.28 mg/kg/day から0.15±0.15 mg/kg/day へ(p=0.016)，再発回数は併用前1.7±0.9回/6 か月から0.8±0.7 回/6 か月(p<0.01)といずれも有意に減少した。CsA 投与下でも再発を繰り返す症例に対してMZR 併用療法は試みてもよい治療法だと考えられた。The Japanese Society for Pediatric Nephrology, 2015年, 日本小児腎臓病学会雑誌, 28(1) (1), 12 - 17, 日本語
- 高度蛋白尿を呈するも，ステロイド剤やACEI，ARBを含む多剤併用療法に良好な反応を示した紫斑病性腎炎の小児10例について検討した。8例は1.0g/day/m2以上の蛋白尿もしくは早朝尿蛋白/尿クレアチニン比1.0 g/g以上が少なくとも1～2か月程度続き，残りの2例は発症時すでに低アルブミン血症(血清アルブミン3.0g/dL未満)に陥っていた。いずれの症例も治療開始後は比較的すみやかに蛋白尿が消失した。再評価の腎生検では病理組織の改善も確認され，ステロイド剤を中止してから少なくとも18か月間以上の経過観察を続けたが，尿所見が再増悪する例はなかった。高度蛋白尿を呈する紫斑病性腎炎症例でも，ステロイド剤やACEI，ARBを含む多剤併用療法により改善を期待しうると思われた。The Japanese Society for Pediatric Nephrology, 2012年, 日本小児腎臓病学会雑誌, 25(2) (2), 110 - 113, 日本語
- 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年, 英語
- 東京医学社, 2024年12月15日, 腎と透析, 97(7) (7), 151 - 154
- 東京医学社, 2023年11月30日, 小児内科, 55(13) (13), 673 - 676
- 診断と治療社, 2023年04月15日, 小児科診療, 86(13) (13), 61 - 63
- 東京医学社, 2023年03月25日, 腎と透析, 94(3) (3), 419 - 423
- 東京 : 診断と治療社, 2023年02月, 小児科診療 = The Journal of pediatric practice, 86(2) (2), 135 - 137, 日本語
- 2023年, 日本小児腎臓病学会雑誌(Web), 36Alport症候群原因遺伝子COL4A5の各種exon欠損がIV型コラーゲン三量体分泌に与える影響
- 2021年, 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
- (株)診断と治療社, 2020年04月01日, 診断と治療, 108(4) (4), 513 - 517
- 2020年, 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, 2019年11月, 日本小児腎臓病学会雑誌, 32(2) (2), 138 - 138, 日本語Alport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)日本小児腎臓病学会, 2019年05月, 日本小児腎臓病学会雑誌, 32(1Suppl.) (1Suppl.), 90 - 90, 日本語Alport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)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 99 - 99, 日本語In 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, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 100 - 100, 日本語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, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 101 - 101, 日本語Copy Number Variations解析により遺伝学的診断が臨床診断と異なる結果を得た4症例の検討
- (一社)日本小児腎臓病学会, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 147 - 147, 日本語In 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, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 156 - 156, 日本語尿中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, 2018年05月, 日本小児腎臓病学会雑誌, 31(1Suppl.) (1Suppl.), 200 - 200, 日本語Gitelman症候群185例における臨床的特徴に関する検討
- (公社)日本小児科学会, 2018年04月, 日本小児科学会雑誌, 122(4) (4), 814 - 815, 日本語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
- (株)診断と治療社, 2018年04月, 小児科診療, 81(増刊) (増刊), 777 - 779, 日本語【小児の治療指針】 腎・尿路 Alport症候群
- (一社)日本腎臓学会, 2018年04月, 日本腎臓学会誌, 60(3) (3), 285 - 285, 日本語腎臓病領域における希少疾患と指定難病 小児希少疾患の遺伝子解析の意義
- (一社)日本腎臓学会, 2018年04月, 日本腎臓学会誌, 60(3) (3), 336 - 336, 日本語X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
- (一社)日本腎臓学会, 2018年04月, 日本腎臓学会誌, 60(3) (3), 337 - 337, 日本語Gitelman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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 337 - 337, 日本語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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 338 - 338, 日本語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, 2018年04月, 日本腎臓学会誌, 60(3) (3), 344 - 344, 日本語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
- 発達腎研究会, 2018年04月, 発達腎研究会誌, 26(1) (1), 8 - 10, 日本語X染色体不活化とDent病
- (公社)日本小児科学会, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 256 - 256, 日本語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, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 257 - 257, 日本語Gitelman症候群の臨床的特徴に関する検討
- (公社)日本小児科学会, 2018年02月, 日本小児科学会雑誌, 122(2) (2), 285 - 285, 日本語尿中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, 2017年11月, 日本小児腎臓病学会雑誌, 30(2) (2), 179 - 179, 日本語エクソンスキッピング療法によるアルポート症候群特異的治療法の開発
- 2017年09月, PEDIATRIC NEPHROLOGY, 32(9) (9), 1756 - 1756, 英語A VARIETY OF PHENOTYPES REFLECTED BY GENOTYPES AND LAMININ beta 2 EXPRESSION ON GLOMERULUS IN PIERSON SYNDROME研究発表ペーパー・要旨（国際会議）
- 2017年09月, PEDIATRIC NEPHROLOGY, 32(9) (9), 1754 - 1754, 英語IN VITRO SPLICING ASSAYS TO DETECT INTRONIC PATHOGENIC VARIANTS IN INHERITED KIDNEY DISEASES研究発表ペーパー・要旨（国際会議）
- (公社)日本小児科学会, 2017年05月, 日本小児科学会雑誌, 121(5) (5), 903 - 903, 日本語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, 2017年05月, 日本小児科学会雑誌, 121(5) (5), 908 - 908, 日本語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
- (公社)日本小児科学会, 2017年05月, 日本小児科学会雑誌, 121(5) (5), 913 - 913, 日本語24時間自由行動下血圧測定が高血圧診療に有用であった1例
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 102 - 102, 日本語エクソンスキッピング療法によるアルポート症候群特異的治療法の開発
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 153 - 153, 日本語
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 174 - 174, 日本語Lowe症候群およびDent2の分子生物学的検討
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 181 - 181, 日本語先天性ネフローゼ症候群/乳児ネフローゼ症候群およびステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制の構築
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 186 - 186, 日本語In vivoおよびin vitroの解析によりsplicing異常による疾患発症を証明したフィブロネクチン腎症の一例
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 187 - 187, 日本語無症候性蛋白尿を呈し次世代シークエンサーにてNPHS1遺伝子異常を同定した女児例
- (一社)日本小児腎臓病学会, 2017年05月, 日本小児腎臓病学会雑誌, 30(1Suppl.) (1Suppl.), 211 - 211, 日本語minigeneを用いた遺伝性腎疾患におけるpathogenic splicing variantの同定
- (一社)日本腎臓学会, 2017年04月, 日本腎臓学会誌, 59(3) (3), 257 - 257, 日本語女性Dent病における遺伝学的背景
- (一社)日本腎臓学会, 2017年04月, 日本腎臓学会誌, 59(3) (3), 314 - 314, 日本語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, 2017年02月, 日本小児科学会雑誌, 121(2) (2), 235 - 235, 日本語下痢関連溶血性尿毒症症候群(D+HUS)の急性期経過と予後
- (株)文光堂, 2016年12月, 病理と臨床, 34(12号) (12号), 1317 - 1325, 日本語【腎生検病理診断の実際と新たな展開】 遺伝性腎疾患の最近の進歩[査読有り]記事・総説・解説・論説等（学術雑誌）
- (一社)日本小児腎臓病学会, 2016年11月, 日本小児腎臓病学会雑誌, 29(2) (2), 180 - 180, 日本語
- (一社)日本小児腎臓病学会, 2016年11月, 日本小児腎臓病学会雑誌, 29(2) (2), 182 - 182, 日本語女性のDent病患者2例における発症機序に関する考察
- 2016年10月, PEDIATRIC NEPHROLOGY, 31(10) (10), 1751 - 1751, 英語Genetic and clinical characteristics of female X-linked Alport syndrome: 267 cases study研究発表ペーパー・要旨（国際会議）
- 2016年10月, PEDIATRIC NEPHROLOGY, 31(10) (10), 1870 - 1870, 英語Clinical characteristics and long term outcome of diarrhea associated hemolytic uremic syndrome研究発表ペーパー・要旨（国際会議）
- 2016年10月, PEDIATRIC NEPHROLOGY, 31(10) (10), 1831 - 1832, 英語Genetic approach to the siblings with congenital/infantile nephrotic syndrome by targeted resequencing研究発表ペーパー・要旨（国際会議）
- 2016年, 日本小児血液・がん学会雑誌(Web), 53(1) (1)化学療法後の好中球減少期に血栓性静脈炎によりメチシリン耐性表皮ブドウ球菌の持続菌血症を呈した急性骨髄性白血病の1例
- 2015年09月, PEDIATRIC NEPHROLOGY, 30(9) (9), 1669 - 1669, 英語GENETIC, PATHOLOGICAL AND CLINICAL BACKGROUNDS IN AUTOSOMAL DOMINANT ALPORT SYNDROME研究発表ペーパー・要旨（国際会議）
- 日本小児医事出版社, 2015年02月, 小児科臨床, 68(2) (2), 239 - 244, 日本語臨床研究・症例報告 結節性病変などの膜性増殖性糸球体腎炎様病変を伴ったIgA腎症の5歳男児例
■ 講演・口頭発表等
- The 18th congress of Asian society of pediatric research, 2023年11月, 英語Gene therapy for Alport syndrome[招待有り]シンポジウム・ワークショップパネル（指名）
- American society of Nephrology Kidney week 2023, 2023年11月, 英語Exploring the molecular basis of Ramipril-induced nephroprotection in Alport syndrome
- European society of pediatric nephrology (ESPN) 55th annual meeting, 2023年09月, 英語Emerging therapy in Alport syndrome[招待有り]シンポジウム・ワークショップパネル（指名）
- ASN Kidney week 2019, 2019年11月, 英語Exon skipping therapy for COL4A5 gene truncating variant rescued progression of kidney failure in X-linked Alport syndrome口頭発表（一般）
- 2019 International Workshop on Alport Syndrome, 2019年09月, 英語Exon skipping therapy for COL4A5 gene truncating variant rescued progression of kidney failure in X-linked Alport syndrome口頭発表（一般）
- 第54回日本小児腎臓病学会学術集会, 2019年06月, 日本語Alport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口頭発表（一般）
- 第62回日本腎臓学会学術集会, 2019年06月, 日本語遺伝性尿細管機能異常症のEBM[招待有り]シンポジウム・ワークショップパネル（指名）
- 第62回日本腎臓学会学術集会, 2019年06月, 日本語NPHS1は小児ステロイド感受性ネフローゼ症候群の疾患感受性遺伝子である口頭発表（一般）
- ASN Kidney Week 2018, 2018年10月, 英語, 国際会議Factors regulating the severity in male X-linked Alport syndrome: study of 367 cases
- 第53回日本小児腎臓病学会学術集会, 2018年06月, 英語, 国内会議Genotype-phenotype correlation in male X-linked Alport syndrome: 341 cases study
- 第61回日本腎臓学会学術集会, 2018年06月, 日本語, 国内会議X染色体連鎖型Alport症候群男性患者341名の臨床遺伝学的検討
- 第121回日本小児科学会学術集会, 2018年04月, 日本語, 国内会議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
- 13th Asian Congress of Pediatric Nephrology, 2017年10月, 英語, 国際会議A comprehensive diagnosis by targeted sequencing for clinically suspected Alport syndrome patients in Japanポスター発表
- ASN Kidney Week 2017, 2017年10月, 英語, American Society of Nephrology, New Orleans, USA, 国際会議The comprehensive gene screening for congenital, infantile, and steroid resistant nephrotic syndrome in Japanポスター発表
- ASN Kidney Week 2017, 2017年09月, 英語, 国際会議Functional splicing analysis in an infantile case of atypical hemolytic uremic syndrome caused by digenic mutations in C3 and MCP genes.ポスター発表
- ・第38回日本小児腎不全学会, 2017年09月, 日本語, 日本小児腎不全学会, 淡路, 国内会議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例口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議先天性ネフローゼ症候群/乳児ネフローゼ症候群およびステロイド抵抗性ネフローゼ症候群における網羅的遺伝子診断体制の構築口頭発表（一般）
- 第31回日本小児救急医学会, 2017年06月, 日本語, 日本小児救急医学会, 東京, 国内会議神戸こども初期急病センターにおける水痘・おたふく風邪での受診状況－水痘ワクチン定期接種後の変化も踏まえて－口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議エクソンスキッピング療法によるアルポート症候群特異的療法治療法の開発口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議minigeneを用いた遺伝性腎疾患におけるpathogenic splicing variantの同定口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議Lowe症候群およびDent2の分子生物学的検討口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議lgA腎症候群における降圧薬治療不応例に関する臨床病理学的検討口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議In vivoおよび in vitroの解析によりsplicing異常による疾患発症を証明したフィブロネクチン腎症の一例口頭発表（一般）
- 第52回日本小児腎臓病学会, 2017年06月, 日本語, 日本小児腎臓病学会, 東京, 国内会議Establishment of a comprehensive diagnostic method using next generation sequencer for the Alport syndrome口頭発表（一般）
- 第120回 日本小児科学会学術集会, 2017年05月, 日本語, 日本小児科学会, 東京, 国内会議迅速検査を行った咽頭炎患児におけるA群溶連菌感染症の陽性率とその陽性予測因子口頭発表（一般）
- 第60回日本腎臓学会, 2017年05月, 日本語, 日本腎臓学会, 仙台, 国内会議女性Dent病における遺伝学的背景口頭発表（一般）
- 日本小児科学会兵庫県地方会, 2017年05月, 日本語, 日本小児科学会, 神戸, 国内会議治療方針決定の一助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例口頭発表（一般）
- 第60回日本腎臓学会, 2017年05月, 日本語, 日本腎臓学会, 仙台, 国内会議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口頭発表（一般）
- 第120回 日本小児科学会学術集会, 2017年05月, 日本語, 日本小児科学会, 東京, 国内会議下痢関連溶血性尿毒症症候群(D+HUS)の急性期経過と予後[招待有り]口頭発表（招待・特別）
- Asian Congress of Pediatric Nephrology 2017 & 39th Malaysian Pediatric Association Annual Congress,, 2017年05月, 英語, Kuala Lumpur, Malaysia., 国際会議The utility of urinary CD80 as a diagnostic maker in patients with renal disease口頭発表（一般）
- 50th Anniversary Meeting of the European Society for Pediatric Nephrology, 2017年05月, 英語, The International Pediatric Nephrology Association, Glasgou, Scotland, 国際会議In vitro splicing assays to detecy intronic pathogenic variants in inherited kidney diseaseポスター発表
- ASN Kidney Week 2017 Annual Meeting, 2017年05月, 英語, American Society of Nephrology, New Orleans, USA, 国際会議Functional splicing analysis in an infantile case of atypical hemolytic uremic syndrome caused by digenic mutations in C3 and MCP genes.ポスター発表
- 50th Anniversary Meeting of the European Society for Pediatric Nephrology, 2017年05月, 英語, The International Pediatric Nephrology Association, Glasgou, Scotland, 国際会議A variety of phenotypes reflected by genotypes and laminin β2 sxpression on glomerulus in Pierson syndromeポスター発表
- Asian Congress of Pediatric Nephrology 2017 & 39th Malaysian Pediatric Association Annual Congress,, 2017年05月, 英語, Kuala Lumpur, Malaysia., 国際会議A comprehensive diagnosis by targeted sequencing for clinically suspectsd alport syndrome patients in Japanポスター発表
- The15th Japan-Korea-China Pediatrics Nephrology Seminar 2017, 2017年04月, 英語, International Pediatric Nephrology Association, Tokyo, Japan, 国際会議Diagnostic strategy for inherited hypomagnesemia口頭発表（一般）
- ISN Frontiers Meeting 2018, 2017年02月, 英語, 国際腎臓学会, 東京, 国際会議Clinical characteristics in Gitelman syndromeポスター発表
- ISN Frontiers Meetings 2018, 2017年01月, 英語, 国際腎臓学会, 東京, 国際会議The comprehensive gene screening for congenital, infantile, and steroid resistant nephrotic syndrome in Japanポスター発表
- Kidney Week of the American Society of Nephrology 2016, 2016年11月, 英語, Kidney Week of the American Society of Nephrology, Chicago, USA, 国際会議Characteristics of genetic and biomolecular backgrounds in patients with LAMB2 related nephropathy口頭発表（一般）
- 12nd Congress for Asian Society for Pediatric Research 2016, 2016年11月, 英語, Congress for Asian Society for Pediatric Research, Bangkok, Thailand, 国際会議Changes In Patients With Acute Gastroenteritis After Voluntary Introduction Of Rotavirus Vaccine In A Japanese Children’s Primary Emergency Medical Centerポスター発表
- 第38回日本小児腎不全学会学術集会, 2016年10月, 日本語, 日本小児腎不全学会, 岐阜, 国内会議当院における小児腎移植の現状と課題口頭発表（一般）
- 17thCongress of the International Pediatric Nephrology Association, 2016年09月, 英語, Congress of the International Pediatric Nephrology Association, Iguazu, Brazil, 国際会議Genetic and clinical characteristics of female X-linked Alport Syndrome: 267case study口頭発表（一般）
- 第 269 回 日本小児科学会兵庫県地方会, 2016年09月, 日本語, 日本小児科学会兵庫県地方会, 姫路, 国内会議24時間自由行動下血圧測定が高血圧診療に有用であった1例口頭発表（一般）
- 第51回日本小児腎臓病学会学術集会, 2016年07月, 日本語, 日本小児腎臓病学会, 愛知, 国内会議女性のDent病患者者2例における発症機序に関する考察口頭発表（一般）
- 第51回日本小児腎臓病学会学術集会, 2016年07月, 日本語, 日本小児腎臓病学会, 愛知, 国内会議次世代シークエンサーにて診断に至ったSDCCAG8変異によるネフロン癆の女児例口頭発表（一般）
- 第51回日本小児腎臓病学会学術集会, 2016年07月, 日本語, 日本小児腎臓病学会, 愛知, 国内会議下痢関連溶血性尿毒症症候群（D+HUS）の急性期経過と予後口頭発表（一般）
- 第51回日本小児腎臓病学会学術集会, 2016年07月, 日本語, 日本小児腎臓病学会, 愛知, 国内会議ターゲットシークエンス法による常染色体優性Alport症候群診断法の確立および遺伝学的背景、臨床的、病理学的検討口頭発表（一般）
- 第51回日本小児腎臓病学会学術集会, 2016年07月, 日本語, 日本小児腎臓病学会, 愛知, 国内会議X染色体連鎖型Alport症候群女性267例の遺伝学的・臨床的検討口頭発表（一般）
- 第59回日本腎臓学会学術総会, 2016年06月, 日本語, 日本腎臓学会, 横浜, 国内会議次世代シークエンサー（NGS）による染色体優性Alport症候群診断法の確立および臨床的、病理学的検討口頭発表（一般）
- 第268回日本小児科学会兵庫県地方会, 2016年05月, 日本語, 日本小児科学会兵庫県地方会, 神戸, 国内会議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例口頭発表（一般）
- 第119回日本小児科学会学術集会, 2016年05月, 日本語, 日本小児科学会, 札幌, 国内会議腎移植後にウイルス関連の重症合併症を呈した4症例口頭発表（一般）
- 第119回日本小児科学会学術集会, 2016年05月, 日本語, 日本小児科学会, 札幌, 国内会議次世代シークエンサーによる染色体優性Alport症候群診断法の確立口頭発表（一般）
- The 14th China-Japan-Korea Pediatric Nephrology Seminar 2016, 2016年05月, 英語, China-Japan-Korea Pediatric Nephrology Seminar, Beijing,, China, 国際会議Pathological and genetic aspects of the siblings with congenital/infantile nephrotic syndrome口頭発表（一般）
- 日本小児科学会
- 日本小児腎不全学会
- 日本腎臓学会
- 日本小児腎臓病学会
- American Society of Nephrology
- International Pediatric Nephrology Association
- 日本学術振興会, 海外特別研究員派遣制度, 2022年04月 - 2024年03月, 研究代表者免疫系の関与に着目したAlport症候群の疾患進展機序解明と新規治療標的の探索
- 日本学術振興会, 科学研究費助成事業 若手研究, 若手研究, 神戸大学, 2019年04月 - 2021年03月X染色体連鎖型アルポート症候群女性患者の重症化メカニズム解明に関する研究まず、すでに保有するX染色体連鎖型アルポート症候群女性患者の血液から抽出したゲノムDNAを用いてX染色体不活化解析を施行した。先行研究から日本人女性患者の末期腎不全到達年齢中央値である65歳よりも早い段階で末期腎不全に至った症例を13例抽出し解析を行った結果、明らかなX染色体不活化の偏りを認めた症例は1例のみであった。結果として、少なくとも血液のX染色体不活化が疾患重症度と関与する可能性は極めて低いと判断された。 次に、腎生検により得られた切片から抽出したDNAおよびRNAにおける不活化解析を行う準備として、自施設にて過去に腎生検を行い保存されている検体(パラフィン切片)を用いて薄切切片からのDNAおよびRNA抽出量の確認を施行した。レーザーキャプチャーマイクロダイセクション(LMD)による糸球体の単離を行わない状態で10um厚の切片全体(1×15mm程度)からのRNAおよびDNAの抽出量はそれぞれ200ng/切片および100ng/切片と解析に耐えうる量であることが判明した。一方で、パラフィン切片中の糸球体の面積比率からはLMDを行うと解析に十分な量のDNAおよびRNAが回収できない可能性が考えられた。そこでパラフィン切片ではなく凍結切片を用いてRNAの抽出を行ったところ、単位面積あたり約6倍のRNAが回収できることを確認した。 今後はまず切片全体から抽出したDNAおよびRNAで不活化解析を行い、解析系ができることを確認した上で、LMDを用いて糸球体のみを単離し不活化解析を行う予定としている。また、平行して免疫染色による不活化解析も施行予定である。
- 日本学術振興会, 学術研究助成基金助成金／若手研究(B), 若手研究(B), 神戸大学, 2016年04月 - 2018年03月, 研究代表者我々は、次世代シークエンサー（NGS）を用いたtargeted sequencingにより既知のポドサイト関連45遺伝子を網羅的に解析できる診断体制を確率し、研究期間内にAlport症候群（AS）が疑われた185家系に対して解析を施行、147家系で原因遺伝子変異を同定した。多数の症例の解析を行った結果、X染色体連鎖型ASの女性患者における臨床像と遺伝子型の関係を解析することが可能となり報告を行った。また、AS疑い患者の中に含まれる他の遺伝性腎疾患の患者の診断や、コピー数異常や体細胞モザイクを有するAS患者の診断もNGSを用いて行うことが可能であることを明らかとし、報告を行った。競争的資金