Five novel mutations identified in the COL4A3, COL4A4 and COL4A5 genes in 10 families with Alport syndrome

Abstract

Abstract Background Alport syndrome (AS) is an inherited nephropathy caused by mutations in the type IV collagen genes. It is clinically characterized by damage to the eyes, ears and kidneys. Diagnosis of AS is hampered by its atypical clinical picture, particularly when the typical features, include persistent hematuria and microscopic changes in the glomerular basement membrane (GBM), are the only clinical manifestations in the patient. Methods We screened nine families with suspected AS using whole exome sequencing (WES) and analyzed the harmfulness, conservation, and protein structure changes of mutated genes. In further, we performed in vitro functional analysis of two missense mutations in the COL4A5 gene (c.2359G > C, p.G787R and c.2605G > A, p.G869R). Results We identified 11 pathogenic variants in the type IV collagen genes (COL4A3, COL4A4 and COL4A5). These pathogenic variants include eight missense mutations, two nonsense mutations and one frameshift mutation. Notably, Family 2 had degenic mutations in the COL4A3 (p.G1170A) and UMOD genes (p.M229K). Family 3 had a degenic missense mutation (p.G997E) in COL4A3 and a frameshift mutation (p.P502L fs*151) in COL4A4. To our knowledge, five of the 11 mutations are novel mutations. In addition, We found that COL4A5 mutation relation mRNA levels were significantly decreased compared to control, while the cellular localization remained the same. Conclusions Our research expands the spectrum of COL4A3-5 pathogenic variants, which is helpful for clinical and scientific research.