title: High frequency of the p.R34X mutation in the TMC1 gene associated with nonsyndromic hearing loss is due to founder effects.
abstract: Founder mutations, particularly 35delG in the GJB2 gene, have to a large extent contributed to the high frequency of autosomal recessive nonsyndromic hearing loss (ARNSHL). Mutations in transmembrane channel-like gene 1 (TMC1) cause ARNSHL. The p.R34X mutation is the most frequent known mutation in the TMC1 gene. To study the origin of this mutation and determine whether it arose in a common ancestor, we analyzed 21 polymorphic markers spanning the TMC1 gene in 11 unrelated individuals from Algeria, Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey who carry this mutation. In nine individuals, we observed significant linkage disequilibrium between p.R34X and five polymorphic markers within a 220 kb interval, suggesting that p.R34X arose from a common founder. We estimated the age of this mutation to be between 1075 and 1900 years, perhaps spreading along the third Hadramaout population movements during the seventh century. A second founder effect was observed in Turkish and Lebanese individuals with markers in a 920 kb interval. Screening for the TMC1 p.R34X mutation is indicated in the genetic evaluation of persons with ARNSHL from North African and Southwest Asia.
authors.affiliation: Targets for Diagnosis and Therapy Unit, Centre of Biotechnology of Sfax, Sfax, Tunisia.
authors.forename: Mariem
authors.initials: M
authors.lastname: Ben Saïd
authors.forename: Mounira
authors.initials: M
authors.lastname: Hmani-Aifa
authors.forename: Imen
authors.initials: I
authors.lastname: Amar
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.forename: Mirna
authors.initials: M
authors.lastname: Mustapha
authors.forename: Sedigheh
authors.initials: S
authors.lastname: Delmaghani
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Tlili
authors.forename: Abdelmonem
authors.initials: A
authors.lastname: Ghorbel
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Saber
authors.initials: S
authors.lastname: Masmoudi
mesh_terms: D000352:Africa, Northern; D001211:Asia, Western; D000072259:Connexin 26; D017630:Connexins; D018703:Founder Effect; D005787:Gene Frequency; D005808:Genes, Recessive; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26