Abstract
In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.
Highlights
There are a total of 278 million people suffering from hearing loss in the world, while in China the number amounts to 2.78 million
Six years later after gene mapped, we successfully identified a novel causative gene for this type of hearing loss in family F013, TNC (Tenascin-C, NC_000009.11, NM_002160.2, NP_002151.2), applying the combined strategy of linkage analysis and whole-exome sequencing
autosomal dominant nonsyndromic sensorineural hearing loss (ADNSHL) was investigated from the Department of Otolaryngology, Head and Neck Surgery, the Chinese PLA (People’s Liberation Army) General Hospital, China (Figure 1)
Summary
There are a total of 278 million people suffering from hearing loss in the world, while in China the number amounts to 2.78 million. More than 60 loci and 27 responsible genes for autosomal dominant hearing loss had been identified (hereditary Hearing Loss homepage, http://hereditaryhearingloss.org/). Most of these genes were identified through the traditional positional cloning and sequencing each gene in the critical interval one by one according to the gene function and expression pattern. The scope of this method is limited, especially in situations where there are a large number of genes in the mapped region. Combinational strategy using linkage analysis and exome sequencing provides a powerful and affordable means to identify causative genes especially in autosomal dominant mode
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