Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.
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.
Santos
Regie Lyn P
RL
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Wajid
Muhammad
M
Khan
Mohammad Nasim
MN
McArthur
Nathan
N
Pham
Thanh L
TL
Bhatti
Attya
A
Lee
Kwanghyuk
K
Irshad
Saba
S
Mir
Asif
A
Yan
Kai
K
Chahrour
Maria H
MH
Ansar
Muhammad
M
Ahmad
Wasim
W
Leal
Suzanne M
SM
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
D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26