Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome

Mutations in either the COL4A3 or the COL4A4 genes, encoding the alpha3 and alpha4 chains of type IV collagen, are responsible for the autosomal-reces sive form of Alport syndrome, a progressive hematuric nephropathy character ized by glomerular basement membrane abnormalities. Reported here are the c omplete COL4A3 exon-intron structure and a comprehensive screen for mutatio ns of the 52 COL4A3 exons in 41 unrelated patients diagnosed as having auto somal Alport syndrome. This resulted in the identification of 21 mutations that are expected to be causative. Furthermore, it is shown that heterozygo us COL4A3 missense mutations, when symptomatic, can be associated with a br oad range of phenotypes, from familial benign hematuria to the complete fea tures of Alport syndrome nephropathy.