A transversion mutation in non-coding exon 3 of the TMC1 gene in two ethnically related Iranian deaf families from different geographical regions; evidence for founder effect

Abstract Objectives Transmembrane channel-like 1 (TMC1) gene is a member of the transmembrane channel-like (TMC) gene family that encodes an integral membrane protein of the inner ear. It is suggested that mutation in this gene is one of the main causes of autosomal recessive non-syndromic hearing loss (ARNSHL) in different populations. The aim of this study was to determine the contribution of the TMC1 gene mutations in causing hearing loss in Iran. Methods In total 54 unrelated Iranian families containing 159 affected individuals with ARNSHL detected by audiometric and otologic examinations were analyzed. Haplotype analysis of all members of 45 GJB2- & GJB6-negative families, using four microsatellite markers linked to DFNB7/11 was performed. Results Co-segregation of hearing loss with all investigated markers for the DFNB7/11 locus was found in one family. DNA sequencing of all coding and non-coding exons and intron boundaries of the TMC1 gene identified c.-258A>C mutation in non-coding exon 3 only in individuals with hearing loss. This mutation has been previously reported in another Iranian family (G9) that share similar ethnicity. This variant was not detected in 300 ethnically matched healthy controls. Conclusions These results increase the probability that this nucleotide variation may be a pathogenic mutation. This study showed that the ethnicity may be more useful than geographical location to design research strategy for determining which genes should be considered when a heterogeneous disorder is under investigation.