Premium
Novel sequence variants in the TMC 1 gene in Pakistani families with autosomal recessive hearing impairment
Author(s) -
Santos Regie Lyn P.,
Wajid Muhammad,
Khan Mohammad Nasim,
McArthur Nathan,
Pham Thanh L.,
Bhatti Attya,
Lee Kwanghyuk,
Irshad Saba,
Mir Asif,
Yan Kai,
Chahrour Maria H.,
Ansar Muhammad,
Ahmad Wasim,
Leal Suzanne M.
Publication year - 2005
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9374
Subject(s) - biology , genetics , gene , population , allele , point mutation , mutation , genetic linkage , medicine , environmental health
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 GJB 2 ( 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. © 2005 Wiley‐Liss, Inc.