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Hum Genet. 2002 Dec;111(6):548-54. Epub 2002 Sep 14.

Unusual deep intronic mutations in the COL4A5 gene cause X linked Alport syndrome.

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Division of Medical and Molecular Genetics, 7th Floor Guy's Tower, GKT school of Medicine, King's College, SE1 9RT London, UK.


The X-linked form of Alport syndrome is caused by mutations in the COL4A5 gene in Xq22. This large multiexonic gene has, in the past, been difficult to screen, with several studies detecting only about 50% of mutations. We report three novel intronic mutations that may, in part, explain this poor success rate and demonstrate that single base changes deep within introns can, and do, cause disease: one mutation creates a new donor splice site within an intron resulting in the inclusion of a novel in-frame cryptic exon; a second mutation results in a new exon splice enhancer sequence (ESE) that promotes splicing of a cryptic exon containing a stop codon; a third patient exhibits exon skipping as a result of a base substitution within the polypyrimidine tract that precedes the acceptor splice site. All three cases would have been missed using an exon-by-exon DNA screening approach.

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