title: Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan.
abstract: Non-syndromic deafness is genetically heterogeneous. We previously reported that mutations of transmembrane channel-like gene 1 (TMC1) cause non-syndromic recessive deafness at the DFNB7/B11 locus on chromosome 9q13-q21 in nine Pakistani families. The goal of this study was to define the identities, origins and frequencies of TMC1 mutations in an expanded cohort of 557 large Pakistani families segregating recessive deafness. We screened affected family members for homozygosity at short-tandem repeats flanking known autosomal recessive (DFNB) deafness loci, followed by TMC1 sequence analysis in families segregating deafness linked to DFNB7/B11. We identified 10 new families segregating DFNB7/B11 deafness and TMC1 mutations, including three novel alleles. Overall, 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. Genotype analysis of p.R34X-linked markers indicates that it arose from a common founder. We also detected p.R34X among normal control samples of African-American and northern European origins, raising the possibility that p.R34X and other mutations of TMC1 are prevalent contributors to the genetic load of deafness across a variety of populations and continents.
authors: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850-3320, USA.
authors: S-I
authors: SI
authors: Kitajiri
authors: R
authors: R
authors: McNamara
authors: T
authors: T
authors: Makishima
authors: T
authors: T
authors: Husnain
authors: A U
authors: AU
authors: Zafar
authors: R A
authors: RA
authors: Kittles
authors: Z M
authors: ZM
authors: Ahmed
authors: T B
authors: TB
authors: Friedman
authors: S
authors: S
authors: Riazuddin
authors: A J
authors: AJ
authors: Griffith
mesh_terms: D000595:Amino Acid Sequence; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D018389:Codon, Nonsense; D003638:Deafness / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; C451751:TMC1 protein, human