A MUTATION CAUSING ALPORT SYNDROME WITH TARDIVE HEARING-LOSS IS COMMON IN THE WESTERN UNITED-STATES

Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome ( AS), a nephritis characterized by progressive deterioration of the glo merular basement membrane and usually associated with progressive hear ing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the sam e haplotype of eight polymorphic markers tightly linked to COL4A5, ind icating common ancestry. Genealogical studies place the birth of this ancestor >200 years ago. The L1649R mutation is a relatively common ca use of Alport syndrome in the western United States, in part because o f the rapid growth and migratory expansion of mid-nineteenth-century p ioneer populations carrying the gene. L1649R affects a highly conserve d residue in the NC1 domain, which is involved in key inter- and intra molecular interactions, but results in a relatively mild disease pheno type. Renal failure in an L1649R male typically occurs in the 4th or 5 th decade and precedes the onset of significant hearing loss by simila r to 10 years.