title: A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1.
abstract: We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850-3320, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kitajiri
authors.forename: T
authors.initials: T
authors.lastname: Makishima
authors.forename: T B
authors.initials: TB
authors.lastname: Friedman
authors.forename: A J
authors.initials: AJ
authors.lastname: Griffith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002648:Child; D004247:DNA / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; C451751:TMC1 protein, human; D004247:DNA