Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.

Regie Lyn P. Santos, Muhammad Wajid, Mohammad Nasim Khan, Nathan McArthur, Thanh L. Pham, Attya Bhatti, Kwanghyuk Lee, Saba Irshad, Asif Mir, Kai Yan, Maria H. Chahrour, Muhammad Ansar, Wasim Ahmad, Suzanne M. Leal

Research output: Contribution to journalArticle

45 Citations (Scopus)

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. (c) 2005 Wiley-Liss, Inc.

Original languageEnglish (US)
Number of pages1
JournalHuman mutation.
Volume26
Issue number4
StatePublished - Oct 1 2005

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Cochlea
Hearing Loss
Genes
Inner Auditory Hair Cells
Mutation
DNA Sequence Analysis
Population
Chromosomes
Phosphorylation
Genome
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Santos, R. L. P., Wajid, M., Khan, M. N., McArthur, N., Pham, T. L., Bhatti, A., ... Leal, S. M. (2005). Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment. Human mutation., 26(4).

Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment. / 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.

In: Human mutation., Vol. 26, No. 4, 01.10.2005.

Research output: Contribution to journalArticle

Santos, RLP, Wajid, M, Khan, MN, McArthur, N, Pham, TL, Bhatti, A, Lee, K, Irshad, S, Mir, A, Yan, K, Chahrour, MH, Ansar, M, Ahmad, W & Leal, SM 2005, 'Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment.', Human mutation., vol. 26, no. 4.
Santos RLP, Wajid M, Khan MN, McArthur N, Pham TL, Bhatti A et al. Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment. Human mutation. 2005 Oct 1;26(4).
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. / Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment. In: Human mutation. 2005 ; Vol. 26, No. 4.
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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. (c) 2005 Wiley-Liss, Inc.",
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AU - Bhatti, Attya

AU - Lee, Kwanghyuk

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