A mutation causing Alport syndrome with tardive hearing loss is common in the western United States

Author(s): Pruchno, C. J., Jiang, X., Atkin, C. L., Stone, E. M., Denison, L. C., Fain, P. R., Gregory, M. C.

Journal/Book: Am J Hum Genet. 1996; 58: 5720 S Woodlawn Ave, Chicago, IL 60637. Univ Chicago Press. 1157-1165.

Abstract: Mutations in the COL4A5 gene, located at Xq22, cause Alport syndrome (AS), a nephritis characterized by progressive deterioration of the glomerular basement membrane and usually associated with progressive hearing loss. We have identified a novel mutation, L1649R, present in 9 of 121 independently ascertained families. Affected males shared the same haplotype of eight polymorphic markers tightly linked to COL4A5, indicating common ancestry. Genealogical studies place the birth of this ancestor > 200 years ago. The L1649R mutation is a relatively common cause of Alport syndrome in the western United States, in part because of the rapid growth and migratory expansion of mid-nineteenth-century pioneer populations carrying the gene. L1649R affects a highly conserved residue in the NC1 domain, which is involved in key inter- and intramolecular interactions, but results in a relatively mild disease phenotype. Renal failure in an L1649R male typically occurs in the 4th or 5th decade and precedes the onset of significant hearing loss by similar to 10 years.

Note: Article DF Barker, Univ Utah, Hlth Sci Ctr, Dept Physiol, Res Pk, 410 Chipeta Way, Salt Lake City, UT 84108 USA

Keyword(s): ALPHA-5(IV) COLLAGEN CHAIN; SINGLE-BASE MUTATION; HUMAN-X-CHROMOSOME; IV COLLAGEN; OSTEOGENESIS IMPERFECTA; POINT MUTATIONS; GENOMIC DNA; GENE; DOMAIN; IDENTIFICATION

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