Abstract
Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the COL4A5 gene. This study explored novel deletion and missense mutations in COL4A5 responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs∗11) in exon 7 of COL4A5. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 μmol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the COL4A5 gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried COL4A5 deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%, P = 0.041). This study identified two novel COL4A5 mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the COL4A5 gene, and presented findings that are significant for the screening and genetic diagnosis of AS.
Highlights
Encoded by the collagen type IV alpha-3 (COL4A3), alpha-4 (COL4A4), and alpha-5 (COL4A5) genes, Alport syndrome (AS) is a rare inherited renal disease caused by abnormalities of the α3, α4, or α5 chains in type IV collagen [1]
The proband (III-4) in pedigree 1 had severely impaired renal function, with serum urea of 49.9 mmol/L, serum creatinine (Scr) of 1793 μmol/L, hemoglobin counts of 48.1 g/L, serum potassium of 4.95 mmol/L, and serum calcium concentrations of 1.16 mmol/L and received emergency hemodialysis
A novel deletion mutation (c.422_428del) was identified in exon 7 of COL4A5 using Whole Exome Sequencing (WES) in a Chinese family with X-linked AS, a finding which was validated by Sanger sequencing
Summary
Encoded by the collagen type IV alpha-3 (COL4A3), alpha-4 (COL4A4), and alpha-5 (COL4A5) genes, Alport syndrome (AS) is a rare inherited renal disease caused by abnormalities of the α3, α4, or α5 chains in type IV collagen [1]. These genetic defects lead to inadequate structure and function of basement membranes in glomeruli, the cochlea, ocular lenses, and other organs. The autosomal recessive inheritance pathway accounts for approximately 15% of cases and is characterized by COL4A3 and/or COL4A4 allele mutations. Autosomal dominant AS is rare (only 5% cases), with the pathological phenotype being caused by heterozygous mutations in COL4A3 or COL4A4 [3,4,5]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.