High frequency of the p.R34X mutation in the TMC1 gene associated with nonsyndromic hearing loss is due to founder effects.
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.
Ben Saïd
Mariem
M
Targets for Diagnosis and Therapy Unit, Centre of Biotechnology of Sfax, Sfax, Tunisia.
Hmani-Aifa
Mounira
M
Amar
Imen
I
Baig
Shahid Mahmood
SM
Mustapha
Mirna
M
Delmaghani
Sedigheh
S
Tlili
Abdelaziz
A
Ghorbel
Abdelmonem
A
Ayadi
Hammadi
H
Van Camp
Guy
G
Smith
Richard J H
RJ
Tekin
Mustafa
M
Masmoudi
Saber
S
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
D017630:Connexins; C000607042:GJB2 protein, human; D008565:Membrane Proteins; C451751:TMC1 protein, human; D000072259:Connexin 26