A novel heterozygous COL4A4 missense mutation in a Chinese family with focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular histological lesion associated with high‐grade proteinuria and end‐stage renal disease. Histologically, FSGS is characterized by focal segmental sclerosis with foot process effacement. The aim of this study was to identify the disease‐causing mutation in a four‐generation Chinese family with FSGS. A novel missense mutation, c.1856G>A (p.Gly619Asp), in the collagen type IV alpha‐4 gene (COL4A4) was identified in six patients and it co‐segregated with the disease in this family. The variant is predicted to be disease‐causing and results in collagen IV abnormalities. Our finding broadens mutation spectrum of the COL4A4 gene and extends the phenotypic spectrum of collagen IV nephropathies. Our study suggests that exome sequencing is a cost‐effective and efficient approach for identification of disease‐causing mutations in phenotypically complex or equivocal disorders. Timely screening for COL4A3/COL4A4 mutations in patients with familial FSGS may help both accurately diagnose and treat these patients.

Three Novel Heterozygous<b><i> COL4A4</i></b> Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

“…Analyzing correlations between genotype and phenotype, we found that the clinical phenotypes of the 3 probands manifested in mild phenotypes of microhematuria, proteinuria without higher serum creatinine levels, and progressive renal injury. Published data showed that most of the heterozygous mutations found in COL4A4 are glycine at different positions [Kamiyoshi et al, 2016;Wu et al, 2016]. Compared to other reports, except for the clinical phenotype caused by heterozygous COL4A4 , the glycine substitution reported here is similar to that found in the literature [Jefferson et al, 1997;Kamiyoshi et al, 2016;Wu et al, 2016].…”

“…Published data showed that most of the heterozygous mutations found in COL4A4 are glycine at different positions [Kamiyoshi et al, 2016;Wu et al, 2016]. Compared to other reports, except for the clinical phenotype caused by heterozygous COL4A4 , the glycine substitution reported here is similar to that found in the literature [Jefferson et al, 1997;Kamiyoshi et al, 2016;Wu et al, 2016]. We also reported 2 nonsense heterozygous mutations in 2 probands, manifesting in mild phenotypes.…”

“…We excluded other inherited nephropathies such as ADAS, TBMN, and Fabry disease. Wu et al [2016] reported that heterozygous COL4A4 mutations can cause primary familial FSGS, but whether collagen mutations associated with FSGS are the primary cause of FSGS or are secondary to the GBM defect remains controversial [Nogueira et al, 2000;van Paassen et al, 2004;Haas, 2006]. Our findings suggest that COL4A4 gene mutations play a direct role in the development of segmental thinning of GBM and that FSGS may be secondary to the GBM defect.…”

“…As a pathological phenotype, the causative genes of FSGS have been consistently investigated [Barua et al, 2014;Huynh Cong et al, 2014]. Recently, it has been shown that familial FSGS can also be explained by heterozygous mutations in the COL4A3 or COL4A4 genes [Gast et al, 2016;Wu et al, 2016]. While some cases of ADAS, TBMN, and FSGS can be attributed to heterozygous COL4A4 mutations, COL4A4 -associated collagen type IV kidney diseases are heterogeneous.…”

“…While some cases of ADAS, TBMN, and FSGS can be attributed to heterozygous COL4A4 mutations, COL4A4 -associated collagen type IV kidney diseases are heterogeneous. Furthermore, the pathological backgrounds and clinical phenotypes of this disease remain unclear [Tazón Vega et al, 2003;Wu et al, 2016]. We investigated the relationship between different collagen type IV kidney disease subtypes and COL4A4 heterozygous mutation genotype-phenotype correlations in associated collagen type IV kidney disease.…”