title: Recessive mutations of TMC1 associated with moderate to severe hearing loss.
abstract: TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404 + 1G > T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404 + 1G > T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.
authors.affiliation: School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan.|National Institute on Deafness and Other Communication Disorders, National Institutes of Health, USA 20892.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Imtiaz
authors.affiliation: School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan.
authors.forename: Azra
authors.initials: A
authors.lastname: Maqsood
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, USA 20892.
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, USA 20892.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.affiliation: Department of Otolaryngology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Holt
authors.affiliation: National Institute on Deafness and Other Communication Disorders, National Institutes of Health, USA 20892.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.affiliation: School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Naz
mesh_terms: D000293:Adolescent; D002648:Child; D005808:Genes, Recessive; D034381:Hearing Loss / Q000235:genetics* / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C451751:TMC1 protein, human
keywords: DFNB7/11; Mechanosensory transduction; Moderate or severe hearing loss; TMC1