Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: A report of five novel mutations

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Abstract

Genome wide homozygosity mapping using Affymetrix 10K arrays revealed the DFNB7/11 locus including the TMC1 gene in 5 of 35 Turkish families with autosomal recessive nonsyndromic severe to profound congenital or prelingual-onset sensorineural hearing loss (SNHL). Additional 51 families were later screened for co-segregation of the locus with the phenotype using microsatellite markers. GJB2 and mtDNA A1555G mutations were negative in probands from each family. Mutation analysis was performed in families showing co-segregation of autosomal recessive SNHL with haplotypes at the DFNB7/11 locus. A total of six different mutations in seven families were identified, including novel missense alterations, p.G444R (c.1330G>A), p.R445C (c.1333C>T), and p.I677T (c.2030T>C), one novel splice site mutation IVS6+2 T>A (c.64+2T>A), and a novel large deletion of approximately 31 kb at the 3′ region of the gene including exons 19–24, as well as a previously reported nonsense mutation, p.R34X (c.100C>T). All identified mutations co-segregated with autosomal recessive SNHL in all families and were not found in Turkish hearing controls. These results expand the mutation spectrum of TMC1 with five novel mutations and provide data for the significant contribution of TMC1 mutations in hearing loss.

Introduction

The prevalence and causes of profound congenital and prelingual hearing loss can vary widely at different times and among populations. Clinically significant hearing loss has been estimated to be present in at least 1.9 per 1000 infants at birth and rises to at least 2.7 per 1000 births by the age of 4 in the USA [1]. Genetic causes are estimated to account for at least 50% of all cases with congenital or prelingual hearing loss; autosomal recessive, dominant, and X-linked genes being responsible for 75–77%, 22%, and 1% of the genetic cases, respectively, in Western populations [2]. It has recently been demonstrated that genetic causes are responsible in 76% of probands with hearing loss in Turkey, 93% of which are inherited with autosomal recessive transmission [3]. At least 70% of individuals with congenital or prelingual-onset severe to profound hearing loss are considered to have no additional findings (nonsydromic hearing loss). Mutations in more than 45 genes have been identified as a cause of dominant or recessive nonsyndromic hearing loss (hereditary hearing loss homepage—http://webh01.ua.ac.be/hhh/). However, frequencies of mutations in most of these genes among individuals with hearing loss have remained unknown. Some of these genes, such as GJB2, are associated with both dominant and recessive transmission. Mutations in the transmembrane cochlear expressed gene 1 (TMC1) were, similarly, found to be associated with both autosomal dominant and autosomal recessive sensorineural hearing loss (ARSNHL) with no additional findings [4].

In this study, we aimed to find the prevalence of biallelic mutations in the TMC1 gene in a large group of multiplex families with nonsyndromic ARSNHL, after mapping this gene in 5 of 35 families.

Section snippets

Families

A total of 86 families from Turkey were included in this study. A signed informed consent was obtained from each participant. The study and consent forms were approved by Ankara University Ethics Committee. A standardized history taking and clinical examination were performed on each participant. Laboratory investigations were performed when required. None of the affected individuals was diagnosed with a syndrome in these families. Each family included at least two affected siblings born to

Results

Homozygous SNP haplotypes flanking the TMC1 gene were demonstrated in five families, out of 35, during initial studies. Microsatellite genotyping confirmed co-segregation in four of these families. Affected members were found to be homozygous for all typed microsatellites in additional seven families. Therefore, 11 families were screened for mutations in the TMC1 gene. A total of six different homozygous mutations in seven families were identified (Fig. 1; Table 2). These include three

Discussion

Biallelic mutations in TMC1 are associated with nonsyndromic ARSNHL, DFNB7/11, whereas two heterozygous missense alleles in the same gene cause autosomal dominant progressive postlingual hearing loss, DFNA36 [4]. To date 31 mutations, including those described in this report, have been reported in this gene as a cause of hearing loss (Fig. 4; Table 6). In silico prediction of the TMC1 protein showed six transmembrane segments, similar to those observed in ion channels or transporters,

Acknowledgements

This study was supported by Turkish Research and Technology Council (TUBITAK) and Ankara University Scientific Research Projects Unit with contract grant numbers 105S464 and 20060809242, respectively.

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