A founder TMIE mutation is a frequent cause of hearing loss in southeastern Anatolia

Abstract

Using Affymetrix 10K arrays, we searched for regions of homozygosity in 51 Turkish families including at least three members with either congenital or prelingual autosomal recessive non-syndromic sensorineural hearing loss (ARNSSNHL), and identified four families whose deafness mapped to the DFNB6 locus on 3p21 containing the TMIE gene. Mutation analysis revealed the p.R84W mutation in all four families. Screening of this mutation in 254 families with ARNSSNHL, without GJB2 mutations, revealed four additional affected families. A novel mutation was found in a non-complementary marriage between a deaf couple who were homozygous for p.R84W and p.W57X, respectively with two affected children who were compound heterozygotes. Six of the TMIE families originated from southeastern Anatolia, making p.R84W a common cause of hearing loss in that region with a relative frequency of 10.3% (95% CI is 2.5-18.1%). The overall prevalence of the p.R84W mutation in ARNSSNHL in Turkey is 2.4% (95% CI is 0.7-4.0%). Genotyping of single-nucleotide polymorphisms flanking the TMIE gene revealed a conserved haplotype, suggesting a single origin for p.R84W from a common ancestor 1250 years ago (95% CI is 650-2500 years). We conclude that p.R84W could be a common mutation in other Middle Eastern populations and should be included in mutation screening offered to individuals with ARNSSNHL.

Research of genetic bases of hereditary non-syndromic hearing loss

“…When the regional distribution was evaluated, the highest percentage was observed in Southeastern Anatolia (10.3%). It was thought that this mutation, which was observed in exon 3, occured more commonly as a result of the founder effect in Anatolia and it was recommended that the mutation should be added to non-syndromic hearing loss screening programs in Middle Eastern populations (34). The fact that this mutation was found in a limited study group consisting of 21 families supports this recommendation.…”

“…The TMIE gene encodes a protein named transmembrane inner ear protein. The gene is composed of 4 exons in the 3p21 chromosomal region (34). The inner ear pathology observed in studies performed with mice in which the TMIE gene was affected showed that the gene was essential for maturation of sensory hair cells in the cochlea and development of steriocilia in the maturation process following a normal delivery (35).…”

Screening of 38 Genes Identifies Mutations in 62% of Families with Nonsyndromic Deafness in Turkey

“…Screening revealed the same mutations as those identified in the probands in nine of nine such individuals tested. Preliminary results of mutation screening in this study have been previously reported (Sirmaci et al, 2009a(Sirmaci et al, , 2009bCengiz et al, 2010).…”

Review Synthetic Report: Genomic architecture of deafness in Turkey reflects its rich past

“…We found this mutation in eight of 258 unrelated families with autosomal recessive non-syndromic deafness ascertained from all parts of Turkey. The overall prevalence was 2.4%, but it was higher (10.3%) in Southeastern Turkey (Sirmaci et al, 2009a). We also showed that the haplotypes associated with this mutation are conserved and the mutation was estimated to have arisen about 1,250 years ago, quite likely in the southeastern region of the country (Sirmaci et al, 2009a).…”

“…The overall prevalence was 2.4%, but it was higher (10.3%) in Southeastern Turkey (Sirmaci et al, 2009a). We also showed that the haplotypes associated with this mutation are conserved and the mutation was estimated to have arisen about 1,250 years ago, quite likely in the southeastern region of the country (Sirmaci et al, 2009a). Interestingly, in a non-complementary family producing all deaf children, both parents, who were themselves the offspring of unrelated consanguineous parents, were autozygous for two different TMIE mutations resulting in affected allozygous children.…”