Effects of a Novel COL4A3 Homozygous/Heterozygous Splicing Mutation on the Mild Phenotype in a Family With Autosomal Recessive Alport Syndrome and a Literature Review

Alport syndrome involves chronic progressive kidney failure and extrarenal organ damage caused by COL4A3, COL4A4, and COL4A5 mutations.

We present a novel finding of a previously unreported c.687 + 1G > T mutation in COL4A3 that disrupts transcription and translation, impairing α3α4α5 (IV) chain formation, altering the integrity of the glomerular basement membrane, causing hereditary Alport syndrome. This discovery enriches the genetic map of Alport syndrome, aiding in clinical genetic guidance, and enhancing the efficacy of prenatal testing.

We initially discerned a COL4A3 splicing mutation via next-generation sequencing. Next, we used bioinformatics, renal biopsy pathology, and an in vitro minigene experiment. Complementary analysis of clinical data was carried out, and we explored the expression and function of the variants to verify their pathogenicity.

A splicing mutation (c.687 + 1G > T) in COL4A3 was found in a Chinese family. Bioinformatics analysis revealed its impact on splicing, causing a translational frameshift, which was confirmed by an in vitro minigene assay. The proband's glomerular basement membrane displayed reduced type IV collagen α3, α4, and α5 chains, with some absent, suggesting disruption of collagen IV trimers in the glomerular basement membrane, potentially damaging the glomerular filtration barrier.