DETERMINATION OF THE GENOMIC STRUCTURE OF THE COL4A4 GENE AND OF NOVEL MUTATIONS CAUSING AUTOSOMAL RECESSIVE ALPORT-SYNDROME

Autosomal recessive Alport syndrome is a progressive hematuric glomeru lonephritis characterized by glomerular basement membrane abnormalitie s and associated with mutations in either the COL4A3 or the COL4A4 gen e, which encode the alpha 3 and alpha 4 type IV collagen chains, respe ctively. To date, mutation screening in the two genes has been hampere d by the lack of genomic structure information. We report here the com plete characterization of the 48 exons of the COL4A4 gene, a comprehen sive gene screen, and the subsequent detection of 10 novel mutations i n eight patients diagnosed with autosomal recessive Abort syndrome. Fu rthermore, we identified a glycine to alanine substitution in the coll agenous domain that is apparently silent in the heterozygous carriers, in 11.5% of all control individuals, and in one control individual ho mozygous for this glycine substitution. There has been no previous fin ding of a glycine substitution that is not associated with any obvious phenotype in homozygous individuals.