A Nonsense Mutation in COL4A4 Gene Causing Isolated Hematuria in Either Heterozygous or Homozygous State.

Cheng Yang,Yang Guan,Zhaowei Chen,Yongqing Tong,Mary Mcgrath,Chunhua Song,Xiaohan Yuan,Guohua Ding,Huiming Wang,Yuan Song,Xinhua Chen

doi:10.3389/fgene.2019.00628

Abstract

Alport syndrome (AS) is a hereditary nephropathy characterized by glomerular basement membrane lesions. AS shows a relatively rare entity with autosomal dominant gene mutation (accounts for less than 5% of AS cases) and is widely believed to be a consequence of heterozygous variants in the COL4A3 and COL4A4 genes. Until now, there have been no reports of homozygous variants in genes in AS patients, and it is scarce to detect both homozygous and heterozygous variants in a single AS pedigree. We performed genetic analysis by exome sequencing (exome-seq) in a Chinese family with AS and found four individuals harboring the COL4A4 c.4599T > G variant, a novel COL4A4 nonsense mutation that gains stop codon and results in a truncated protein. The proband and her two siblings were determined to be heterozygous, whereas their mother was homozygous. The proband satisfied the criteria for the diagnosis of AS, which included clinical manifestations of microscopic hematuria and proteinuria, and pathological features of the glomerular basement membrane (GBM), including irregular thickening and splitting. However, the other three individuals who were homozygous or heterozygous for the variant exhibited mild clinical features with isolated microscopic hematuria. In summary, we identified a novel pathogenic variant in either the heterozygous or homozygous state of the COL4A4 gene in a Chinese family with AS. Our results also suggest that the severity of clinical manifestations may not be entirely attributed to by the COL4A4 genetic variant itself in patients.

Highlights

Alport syndrome (AS) is a genetic disorder characterized by glomerulonephritis, end-stage kidney disease, ocular abnormalities, and hearing loss
X-linked AS (XLAS) is associated with variants in the COL4A5 gene and accounts for 85% of patients with AS, while autosomal recessive AS (ARAS) is found with variants in the COL4A3 and COL4A4 genes and accounts for 15% of AS patients (Hudson et al, 2003; Nagel et al, 2005; Hertz et al, 2015), and autosomal dominant AS (ADAS) is seen with variants in the COL4A3 and COL4A4 genes, accounting for 5% of AS patients (Lemmink et al, 1996)
Collagen IV is the main component of the glomerular basement membrane (GBM) lamina densa (Laurie et al, 1984) and is encoded by six genes (COL4A1– COL4A6) (Harvey et al, 2006)

Summary

Introduction

Alport syndrome (AS) is a genetic disorder characterized by glomerulonephritis, end-stage kidney disease, ocular abnormalities, and hearing loss. It is caused by pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes, which encode the α3, α4, and α5 chains of collagen type IV (COL4) respectively. More than 1,700 unique variants have been identified in these genes and involve three inheritance patterns: X-linked AS (XLAS), autosomal recessive AS (ARAS), or autosomal dominant AS (ADAS). XLAS is associated with variants in the COL4A5 gene and accounts for 85% of patients with AS, while ARAS is found with variants in the COL4A3 and COL4A4 genes and accounts for 15% of AS patients (Hudson et al, 2003; Nagel et al, 2005; Hertz et al, 2015), and ADAS is seen with variants in the COL4A3 and COL4A4 genes, accounting for 5% of AS patients (Lemmink et al, 1996)

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