Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11

Abstract

Hearing loss is the most frequent sensorineural disorder, affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait, with about 100 gene localizations and 44 gene identifications for nonsyndromic hearing loss. TMC1 has been identified as the disease-causing gene for autosomal dominant and autosomal recessive nonsyndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, two dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in one family with dominant and 10 families with recessive nonsyndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767_768del and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene, or alternatively, at least one additional deafness-causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open.

High Frequency of the p.R34X Mutation in the TMC1 Gene Associated with Nonsyndromic Hearing Loss Is Due to Founder Effects

“…Of the 29 reported mutations in this gene, the p.R34X mutation is the most frequent and accounts for over 30% of all TMC1 ARNSHL-causing mutations. This mutation has been reported in hearing-impaired persons originating from Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey (Scott et al, 1996;Kurima et al, 2002;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009), and we have also identified this mutation in Algeria. Its detection in normal control samples of African-American and northern European origin raises the probability that p.R34X is a prevalent contributor to the genetic load of hearing loss in multiple world populations (Kitajiri et al, 2007).…”

“…Two Algerian and one Pakistani patients carrying the p.R34X mutation were detected. In addition to these three cases, eight hearing-impaired subjects carrying the p.R34X mutation and originating from Tunisia (n ¼ 4), Iraq (n ¼ 1), Iran (n ¼ 1), Lebanon (n ¼ 1), and Turkey (n ¼ 1) were included into this study (Scott et al, 1996;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009).The p.R34X mutation in all family probands from these populations was confirmed by direct sequencing.…”

“…Mutations in TMC1 are a common cause of ARNSHL in India, Pakistan, Tunisia, and Turkey where they account for the hearing-loss phenotype in 3-6% of families (Kurima et al, 2002;Kalay et al, 2005;Santos et al, 2005;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). Of the 29 reported mutations in this gene, the p.R34X mutation is the most frequent and accounts for over 30% of all TMC1 ARNSHL-causing mutations.…”

“…Twenty-nine different mutations of the transmembrane channel-like gene 1 (TMC1) gene (GenBank accession number: NM_138691.2) have been reported in 48 families with ARNSHL (Kurima et al, 2002;Kalay et al, 2005;Meyer et al, 2005;Santos et al, 2005;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). The most common recessive mutation for hearing loss in the TMC1 gene is p.R34X.…”

“…T) and is located in exon 7. It accounts for over 30% of mutant alleles of TMC1 and occurs in populations throughout Asia and North Africa (Kurima et al, 2002;Kitajiri et al, 2007;Hilgert et al, 2008;Tlili et al, 2008;Sirmaci et al, 2009). The high frequency of the p.R34X mutation in Tunisian and Pakistani populations has been related to a common ancestral founder (Kitajiri et al, 2007;Tlili et al, 2008).…”