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| 1.
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Nagano, China ; Yamamura, Tomohiko ; Horinouchi, Tomoko ; Aoto, Yuya ; Ishiko, Shinya ; Sakakibara, Nana ; Shima, Yuko ; Nakanishi, Koichi ; Nagase, Hiroaki ; Iijima, Kazumoto ; Nozu, Kandai
概要:
Numerous disease-causing gene mutations have been identified in proteinuric diseases, such as nephrotic syndrome and glo
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merulosclerosis. 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.
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| 2.
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Horinouchi, Tomoko ; Yamamura, Tomohiko ; Minamikawa, Shogo ; Nagano, China ; Sakakibara, Nana ; Nakanishi, Koichi ; Shima, Yuko ; Morisada, Naoya ; Ishiko, Shinya ; Aoto, Yuya ; Nagase, Hiroaki ; Takeda, Hiroki ; Rossanti, Rini ; Ishimori, Shingo ; Kaito, Hiroshi ; Matsuo, Masafumi ; Iijima, Kazumoto ; Nozu, Kandai
概要:
Background: X-linked Alport syndrome (XLAS) is a progressive, hereditary glomerular nephritis of variable severity cause
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d 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.
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| 3.
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Horinouchi, Tomoko ; Nozu, Kandai ; Yamamura, Tomohiko ; Minamikawa, Shogo ; Nagano, China ; Sakakibara, Nana ; Nakanishi, Koichi ; Shima, Yuko ; Morisada, Naoya ; Ishiko, Shinya ; Aoto, Yuya ; Nagase, Hiroaki ; Takeda, Hiroki ; Rossanti, Rini ; Kaito, Hiroshi ; Matsuo, Masafumi ; Iijima, Kazumoto
概要:
X-linked Alport syndrome (XLAS) is a congenital renal disease caused by mutations in COL4A5. In XLAS cases suspected of
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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.
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| 4.
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Fujimura, Junya ; Nozu, Kandai ; Yamamura, Tomohiko ; Minamikawa, Shogo ; Nakanishi, Keita ; Horinouchi, Tomoko ; Nagano, China ; Sakakibara, Nana ; Nakanishi, Koichi ; Shima, Yuko ; Miyako, Kenichi ; Nozu, Yoshimi ; Morisada, Naoya ; Nagase, Hiroaki ; Ninchoji, Takeshi ; Kaito, Hiroshi ; Iijima, Kazumoto
概要:
Introduction:Gitelman syndrome (GS) is a tubulopathy exhibited by salt loss. GS cases are most oftendiagnosed by chance
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blood test. Aside from that, some cases are also diagnosed from tetanic symptomsassociated with hypokalemia and/or hypomagnesemia or short stature. As for complications, thyroiddysfunction and short stature are known, but the incidence rates for these complications have not yet beenelucidated. In addition, no genotype–phenotype correlation has been identified in GS. Methods:We examined the clinical characteristics and genotype–phenotype correlation in geneticallyproven GS cases with homozygous or compound heterozygous variants inSLC12A3(n¼185). Results:In our cohort, diagnostic opportunities were by chance blood tests (54.7%), tetany (32.6%), orshort stature (7.2%). Regarding complications, 16.3% had short stature, 13.7% had experienced febrileconvulsion, 4.3% had thyroid dysfunction, and 2.5% were diagnosed with epilepsy. In one case, QT pro-longation 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 serummagnesium 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 thefirst time, clinical characteristics in genetically proven GScases in the Japanese population, including prevalence of complications. Patients with hypokalemiadetected by chance blood test should have gene tests performed. Patients with GS need attention fordeveloping extrarenal complications, such as short stature, febrile convulsion, thyroid dysfunction, epi-lepsy, or QT prolongation. It was also revealed for thefirst time that hypomagnesemia was not severe insome variants in SLC12A3.
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| 5.
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Yamamura, Tomohiko ; Nozu, Kandai ; Minamikawa, Shogo ; Horinouchi, Tomoko ; Sakakibara, Nana ; Nagano, China ; Aoto, Yuya ; Ishiko, Shinya ; Nakanishi, Koichi ; Shima, Yuko ; Nagase, Hiroaki ; Rossanti, Rini ; Ye, Ming J. ; Nozu, Yoshimi ; Ishimori, Shingo ; Morisada, Naoya ; Kaito, Hiroshi ; Iijima, Kazumoto
概要:
Background: Alport syndrome (AS) is a hereditary disease caused by mutations in COL4A3‐5 genes. Recently, comprehensive
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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.
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| 6.
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Hama, Taketsugu ; Nakanishi, Koichi ; Ishikura, Kenji ; Ito, Shuichi ; Nakamura, Hidefumi ; Sako, Mayumi ; Saito-Oba, Mari ; Nozu, Kandai ; Shima, Yuko ; Iijima, Kazumoto ; Yoshikawa, Norishige
概要:
Background: Eighty percent of children with steroid-sensitive nephrotic syndrome (SSNS) relapse within 2 years and 40-50
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% patients show frequently-relapsing nephrotic syndrome (FRNS). Patients showing a relapse within 6 months after initial remission are at high risk of FRNS. Since frequent prednisolone treatment for FRNS induces severe prednisolone side effects, development of a treatment to prevent patients from shifting to FRNS is desirable. Mizoribine is an immunosuppressive drug with fewer side effects than prednisolone. Recent studies reported the efficacy of high-dose mizoribine in children with FRNS. Methods/design: We conduct a multicenter, open, randomized controlled trial to investigate the efficacy and safety of standard prednisolone plus high-dose mizoribine therapy in children with SSNS showing a relapse within 6 months after an initial remission. Patients are allocated to either standard prednisolone alone treatment group, or standard prednisolone plus high-dose mizoribine group. For the former group, mizoribine is administered at a dose of 10 mg/kg/day once daily and continued for 2 years. The primary endpoint is the duration to frequent relapse. Discussion: The results provide important data on use of high-dose mizoribine to prevent SSNS patients from shifting to FRNS. Since blood concentrations of mizoribine have not been investigated in detail until now, there is a possibility that mizoribine is underestimated in favor of other immunosuppressive drugs. In future, high-dose mizoribine therapy may lead to prevention of relapse in children at high risk of FRNS, and to decreased total dose of prednisolone.
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