ALPORT SYNDROME--GENETICS OF X-LINKED AND AUTOSOMAL FORM

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Medical genetic understanding of the inherited nephritis, Alport syndrome, has advanced rapidly in the past four years, with the discovery in 1990 of the minor basement membrane (BM) collagen gene COL4A5, located at the q22 band of the X chromosome. To date, over 50 different Alport syndrome mutations have been found in COL4A5. It now appears that mutations in COL4A5 or a second BM collagen gene COL4A6, that is located immediately adjacent to COL4A5, will be shown to account for the majority of Alport syndrome, since the majority of families show genetic linkage to Xq22. Not all Alport syndrome is caused by defects at Xq22, however. A rare autosomal recessive form of the disease has been shown to be caused by mutations in the COL4A3 or COL4A4 genes on chromosome 2. There is also genetic evidence that an autosomal dominant form may account for about 15% of cases. Two major achievements of the initial period of this project have been the accumulation of substantial genetic evidence for the genetic heterogeneity of Alport syndrome and the collection of samples from a set of kindreds suitable for a genomic linkage search for the autosomal dominant gene(s). Primary objectives of the further research proposed here are to continue the genetic triage of Alport families, to identify additional autosomal kindreds and to include them with those already identified in a genomic linkage search for the site of the autosomal dominant locus. Families with the X-linked form of the disease will be included in mutation studies to determine the nature of the COL4A5 (or COL4A6) defect. Efforts will be directed toward developing simple, effective mutation screening strategies for the COL4A5 gene (and COL4A6, if appropriate) to improve genetic diagnostic potential. A second purpose of the mutation-screening initiative is to provide an independent test of whether families that appear to be 'unlinked' to Xq22 by genetic marker analysis may still include some affected individuals with a COL4A5 alteration. At later stages of the proposed project, we plan to perform genetic fine-mapping to refine the localization of any new Alport gene)s) identified by the genomic search and then conduct mutation-screening of appropriate genes.