Mutation analysis of COL4A3/COL4A4 genes in a family with thin basement membrane nephropathy and focal segmental glomerulosclerosis / 中华肾脏病杂志

ABSTRACT

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.