中华肾脏病杂志
中華腎髒病雜誌
중화신장병잡지
2008年
8期
538-543
,共6页
房秋园%章友康%侯平%王素霞%张宏%郑欣
房鞦園%章友康%侯平%王素霞%張宏%鄭訢
방추완%장우강%후평%왕소하%장굉%정흔
薄基底膜肾病%肾小球硬化症,局灶性%突变%筛查
薄基底膜腎病%腎小毬硬化癥,跼竈性%突變%篩查
박기저막신병%신소구경화증,국조성%돌변%사사
Thin basement membrane nephropathy%Glomerulosclerosis,Focal%Mutation%Screening
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.
目的 探討薄基底膜腎病(TBMN)閤併跼竈節段性腎小毬硬化癥(FSGS)的遺傳學機製.方法 對一病理學診斷為TBMN閤併FSGS患者及其傢繫的COL4A3和COL4A4基因突變,應用與COL4A3和COL4A4基因連鎖的微衛星標記連鎖分析方法進行分析.PCR擴增COIAA3和COL4A4全部98箇外顯子後,直接測序篩查突變.同時測序排除已為公認的FSGS相關基因NPHS1、NPHS2、WT1、TRPC6、ACTN4、CD2AP突變導緻FSGS的可能.結果 微衛星標記連鎖分析顯示此傢繫與COL4A3和COL4A4基因連鎖.直接測序在此傢繫中髮現疾病患者COL4A4基因1214位的鳥嘌呤突變為腺嘌呤,導緻Ⅳ型膠原α4鏈第405位甘氨痠突變為穀氨痠,併且髮現COL4A3基因一多態性IVS1-4C>T.此多態性隨疾病分佈,可能與緻病相關.未髮現FSGS相關基因的突變.結論 此傢繫是在TBMN的基礎上髮生FSGS.Ⅳ型膠原α4鏈突變及隨疾病分佈的基因多態性是否導緻TBMN閤併FSGS或使其易感性增加尚待更多傢繫進一步研究.
목적 탐토박기저막신병(TBMN)합병국조절단성신소구경화증(FSGS)적유전학궤제.방법 대일병이학진단위TBMN합병FSGS환자급기가계적COL4A3화COL4A4기인돌변,응용여COL4A3화COL4A4기인련쇄적미위성표기련쇄분석방법진행분석.PCR확증COIAA3화COL4A4전부98개외현자후,직접측서사사돌변.동시측서배제이위공인적FSGS상관기인NPHS1、NPHS2、WT1、TRPC6、ACTN4、CD2AP돌변도치FSGS적가능.결과 미위성표기련쇄분석현시차가계여COL4A3화COL4A4기인련쇄.직접측서재차가계중발현질병환자COL4A4기인1214위적조표령돌변위선표령,도치Ⅳ형효원α4련제405위감안산돌변위곡안산,병차발현COL4A3기인일다태성IVS1-4C>T.차다태성수질병분포,가능여치병상관.미발현FSGS상관기인적돌변.결론 차가계시재TBMN적기출상발생FSGS.Ⅳ형효원α4련돌변급수질병분포적기인다태성시부도치TBMN합병FSGS혹사기역감성증가상대경다가계진일보연구.
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.