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薄基底膜肾病并发局灶节段性肾小球硬化症一家系的COL4A3和COL4A4基因突变分析
其他题名Mutation analysis of COL4A3/COL4A4 genes in a family with thin basement membrane nephropathy and focal segmental glomerulosclerosis
房秋园; 章友康; 侯平; 王素霞; 张宏; 郑欣
关键词薄基底膜肾病 突变 肾小球硬化症 筛查 局灶性 Thin Basement Membrane Nephropathy Mutation Glomerulosclerosis Screening Focal
刊名中华肾脏病杂志
2008
DOI10.3321/j.issn:1001-7097.2008.08.011
24期:8页:538-543
收录类别中国科技核心期刊 ; 中文核心期刊 ; CSCD
文章类型Journal Article
摘要目的 探讨薄基底膜肾病(TBMN)合并局灶节段性肾小球硬化症(FSGS)的遗传学机制.方法 对一病理学诊断为TBMN合并FSGS患者及其家系的COL4A3和COL4A4基因突变,应用与COL4A3和COL4A4基因连锁的微卫星标记连锁分析方法进行分析.PCR扩增COIAA3和COL4A4全部98个外显子后,直接测序筛查突变.同时测序排除已为公认的FSGS相关基因NPHS1、NPHS2、WT1、TRPC6、ACTN4、CD2AP突变导致FSGS的可能.结果 微卫星标记连锁分析显示此家系与COL4A3和COL4A4基因连锁.直接测序在此家系中发现疾病患者COL4A4基因1214位的鸟嘌呤突变为腺嘌呤,导致Ⅳ型胶原α4链第405位甘氨酸突变为谷氨酸,并且发现COL4A3基因一多态性IVS1-4C>T.此多态性随疾病分布,可能与致病相关.未发现FSGS相关基因的突变.结论 此家系是在TBMN的基础上发生FSGS.Ⅳ型胶原α4链突变及随疾病分布的基因多态性是否导致TBMN合并FSGS或使其易感性增加尚待更多家系进一步研究. Objective To elucidate whether focal segmental glomerulosclerosis (FSGS) is a secondary development of the COL4-linked thin basement membrane nephropathy (TBMN) or the primary FSGS produces thin glomerular basement membrane (GBM). Methods The family members presented microscopic hematuria,increasing proteinuria with the years and a dual pathological diagnosis of FSGS and TBMN was made in the proband.DNA linkage analysis at locus 2q36-37 that contains the COL4A3/COL4A4 genes was performed with polymorphic micmsateilite markers D2S434,D2S279,D2S1370,D2S256 and D2S427.Haplotypes were constructed at the COL4A3/COL4A4 loci for affected and unaffected family members.All exons of COL4A3 and COL4A4 genes were screened for mutations in the proband.Mutation screening was also performed for NPHS1,NPHS2,CD2AP,WTI,TRPC6 and ACTN4 to exclude familial FSGS.Mutation or polymorphism found in the family were examined in 50 healthy controls. Results In this family hematuria segregated with the 55224 haplotype at the COL4A3/COL4A4 locus.G to A substitution at nucleotide 1214 resulting in an glycine being replaced by glutamate (G405E) was demonstrated for the first time in cxon 20 of COL4A4 gene.G4OSE was present in all four members of the family with hematuria but not in the seven unaffected family members nor in 50 healthy controls.A novel polymorphism segregating with hematuria (IVS1-4C>T in exon 2 ofCOL4A3) was also found which was only present in all four affected family members but not in the seven unaffected family members. No mutations were demonstrated in FSGS associated genes,however,a novel SNP (R268Q),which distributed with the disease ineompletely,was described in the NPHS1 gene coding nephrin,the podocyte slit diaphragm protein. Conclusions In this family,FSGS occurres on the basis of TBMN.Maybe the particular COL4A3/COL4A4 mutation and polymorphism work together to develop proteinuria and eventually leading to FSGS.But whether the mutation and the polymorphism segregating with the disease predispose to develop FSGS in TBMN patients is required further study.
语种中文
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文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/45828
专题北京大学第一临床医学院_肾脏内科
作者单位北京大学第一医院肾内科北京大学肾脏病研究所,100034
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房秋园,章友康,侯平,等. 薄基底膜肾病并发局灶节段性肾小球硬化症一家系的COL4A3和COL4A4基因突变分析[J]. 中华肾脏病杂志,2008,24(8):538-543.
APA 房秋园,章友康,侯平,王素霞,张宏,&郑欣.(2008).薄基底膜肾病并发局灶节段性肾小球硬化症一家系的COL4A3和COL4A4基因突变分析.中华肾脏病杂志,24(8),538-543.
MLA 房秋园,et al."薄基底膜肾病并发局灶节段性肾小球硬化症一家系的COL4A3和COL4A4基因突变分析".中华肾脏病杂志 24.8(2008):538-543.
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