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Analysis of NPHS1, NPHS2, ACTN4 and WT1 in Japanese patients with congenital nephrotic syndrome

日本先天性肾病综合征患者NPHS1、NPHS2、ACTN4、WT1分析

基本信息

批准号：
14570763
负责人：
NAKANISHI Koichi
金额：
$ 2.18万
依托单位：
Wakayama Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570763/
关键词：
Congenital nephrotic syndrome NPHS1 NPHS2 ACTN4 WT1 nephrin podocin α-Actinin-4 糸球体上皮細胞遺伝子変異

项目摘要

Background. Congenital nephrotic syndrome(CNS) causes significant renal failure, and is classified into two types : (i)Finnish type; and (ii)other, including diffuse mesangial sclerosis. Mutations of NPHS1 and NPHS2, which encode the slit diaphragm components nephrin and podocin, cause CNS and autosomal recessive familial steroid-resistant nephrotic syndrome, respectively. Most patients with Finnish-type CNS in Europe and the United States have NPHS1 mutations. However, NPHS2 mutations have been detected in some cases. Mutations in ACTN4, encoding α-actinin-4, cause an autosomal dominant focal segmental glomerulosclerosis. α-Actinin-4 stabilizes the podocyte cytoskeleton structure, connecting with actin filaments. WT1 mutations, causing Wilm's tumor, have been demonstrated in some CNS patients with diffuse mesangial sclerosis. Systematic investigation of genes for CNS in Japan has never been performed.Methods. To clarify the role of mutations in these four genes, we used PCR and direct sequencing to investigate all exons and exon-intron boundaries for these genes in 13 unrelated CNS patients from regional pediatric kidney disease centers in Japan.Results. A novel homozygous nonsense mutation of NPHS1, E246X in exon 7, and a novel homozygous deletion mutation of NPHS1, nt2156(del8) in exon 16 were detected in one patient each. A novel homozygous nonsense mutation of NPHS2, R196X in exon 5, was found in one patient, and the same heterozygous nonsense mutation was detected in another. No ACTN4 or WT1 mutations were detected.Conclusions. These studies demonstrate that mutation of NPHS1 is not a major cause of CNS in Japanese patients, and that mutation of NPHS2 can be responsible for CNS in this population.

背景先天性肾病综合征（CNS）引起显著的肾衰竭，并分为两种类型：（i）芬兰型;和（ii）其他，包括弥漫性系膜硬化。NPHS 1和NPHS 2的突变编码裂孔隔膜组分nephrin和podocin，分别引起CNS和常染色体隐性遗传家族性类固醇耐药肾病综合征。在欧洲和美国，大多数芬兰型CNS患者都有NPHS 1突变。然而，在某些情况下已经检测到NPHS 2突变。编码α-辅肌动蛋白-4的ACTN 4突变可引起常染色体显性局灶节段性肾小球硬化。α-肌动蛋白-4稳定足细胞骨架结构，与肌动蛋白丝连接。WT 1突变，导致肾母细胞瘤，已被证明在一些中枢神经系统患者弥漫性系膜硬化。在日本的中枢神经系统的基因的系统研究从来没有进行过。为了阐明这四个基因突变的作用，我们使用PCR和直接测序技术对来自日本地区儿童肾脏疾病中心的13名无关CNS患者的所有外显子和外显子-内含子边界进行了研究。在1例患者中检测到NPHS 1基因第7外显子E246 X纯合无义突变和第16外显子nt 2156（del 8）纯合缺失突变。在1例患者中发现了NPHS 2基因第5外显子R196 X纯合无义突变，在另1例患者中发现了相同的杂合无义突变。未检测到ACTN 4或WT 1突变。这些研究表明，NPHS 1突变不是日本患者CNS的主要原因，而NPHS 2突变可能是该人群CNS的原因。