Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment

作者：Hilgert Nele; Monahan Kelly; Kurima Kiyoto; Li Cindy; Friedman Rick A; Griffith Andrew J; Van Camp Guy^*

来源：Journal of Human Genetics, 2009, 54(3): 188-190.

DOI：10.1038/jhg.2009.1

• D527N
• DFNA36
• hereditary hearing loss
• hot spot
• TMC1

Two different missense mutations, p. D572N and p. D572H, affecting the same nucleotide and codon of the TMC1 gene were earlier reported to cause autosomal dominant hearing impairment at locus DFNA36 in two North American families. No other dominant mutations of human TMC1 have been published. We ascertained a third North American family segregating autosomal dominant nonsyndromic hearing impairment at the DFNA36 locus. We identified the p. D572N mutation of TMC1 co-segregating with hearing loss in our study family. A comparative haplotype analysis of linked single nucleotide polymorphisms and short tandem repeats in the two families segregating p. D572N was not consistent with a founder effect. These findings can be explained in two ways. Either nucleotide 1714 is a hot spot for mutations or, alternatively, missense mutations at this site confer a specific pathogenic gain-of-function or dominant-negative effect.

• 出版日期2009-3