title: Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.
abstract: Though many hearing impairment genes have been identified, only a few of these genes have been screened in population studies. For this study, 168 Pakistani families with autosomal recessive hearing impairment not due to mutations in the GJB2 (Cx26) gene underwent a genome scan. Two-point and multipoint parametric linkage analyses were carried out. Twelve families had two-point or multipoint LOD scores of 1.4 or greater within the transmembrane cochlear expressed gene 1 (TMC1) region and were subjected to further screening with direct DNA sequencing. Five novel putatively functional non-synonymous sequence variants, c.830A>G (p.Y277C), c.1114G>A (p.V372M), c.1334G>A (p.R445H), c.2004T>G (p.S668R), and c.2035G>A (p.E679K), were found to segregate within seven families, but were not observed in 234 Pakistani control chromosomes. The variants c.830A>G (p.Y277C), c.1114G>A (p.V372M), and c.1334G>A (p.R445H) occurred at highly conserved regions and were predicted to lie within hydrophobic transmembrane domains, while non-synonymous variants c.2004T>G (p.S668R) and c.2035G>A (p.E679K) occurred in extracellular regions that were not highly conserved. There is evidence that the c.2004T>G (p.S668R) variant may have occurred at a phosphorylation site. One family has the known splice site mutation c.536 -8T>A. The prevalence of non-syndromic hearing impairment due to TMC1 in this Pakistani population is 4.4% (95%CI: 1.9, 8.6%). The TMC1 protein might have an important function in K(+) channels of inner hair cells, which would be consistent with the hypothetical structure of protein domains in which sequence variants were identified.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wajid
authors.forename: Mohammad Nasim
authors.initials: MN
authors.lastname: Khan
authors.forename: Nathan
authors.initials: N
authors.lastname: McArthur
authors.forename: Thanh L
authors.initials: TL
authors.lastname: Pham
authors.forename: Attya
authors.initials: A
authors.lastname: Bhatti
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Saba
authors.initials: S
authors.lastname: Irshad
authors.forename: Asif
authors.initials: A
authors.lastname: Mir
authors.forename: Kai
authors.initials: K
authors.lastname: Yan
authors.forename: Maria H
authors.initials: MH
authors.lastname: Chahrour
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000072259:Connexin 26; D017630:Connexins; D003241:Consanguinity; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D014644:Genetic Variation; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010154:Pakistan; D020539:Sequence Analysis, Protein
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26