DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss

Abstract

The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant non-syndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from ADNSHL families. Three additional families (Spanish, Belgian and English) known to be linked to DFNA8/12 were also included in the screening. In an additional cohort of 835 American ADNSHL families, we preselected 73 probands for TECTA screening based on audiometric data. In aggregate, we identified 23 TECTA mutations in this process. Remarkably 20 of these mutations are novel, more than doubling the number of reported TECTA ADNSHL mutations from 13 to 33. Mutations lie in all domains of the α-tectorin protein, including those for the first time identified in the entactin domain, the vWFD1, vWFD2 and vWFD3 repeats, and the D1-D2 and TIL2 connectors. While the majority are private mutations, four of them – p.Cys1036Tyr, p.Cys1837Gly, p.Thr1866Met and p.Arg1890Cys – were observed in more than one unrelated family. For two of these mutations founder effects were also confirmed. Our data validate previously observed genotype-phenotype correlations in DFNA8/12 and introduce new correlations. Specifically, mutations in the N-terminal region of α-tectorin (entactin domain, vWFD1 and vWFD2) lead to mid frequency NSHL, a phenotype previously associated only with mutations in the ZP domain. Collectively, our results indicate that DFNA8/12 hearing loss is a frequent type of ADNSHL.

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

“…33 It was recently reported to generate aberrant splicing products by exon 16 skipping, but not by reading frame disruption, in lymphoblastoid cell lines from affected subjects in a Brazilian family. 34 Mutations in the TECTA gene result in either AD (DFNA8/12) or AR (DFNB21) SNHL.…”

A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

“…Although the TM is detached from the spiral limbus in the Otoa EGFP/EGFP mouse, it remains in close proximity to the sensory epithelium, possibly via its attachment to the hair bundles of the OHCs. This is in contrast to the situation in the Tecta ΔENT/ΔENT mouse, in which a residual TM is completely divorced from the organ of Corti and ectopically associated with Reissner's membrane (20). Otoancorin is not expressed in OHCs, and another protein must therefore mediate adhesion of the OHC stereocilia to the TM.…”

“…Collagens are still present in the detached TMs of the Tecta ΔENT/ΔENT mouse (20), so limbal attachment is unlikely to be mediated by this class of protein. All the major noncollagenous proteins of the TM (Tecta, Tectb, and Ceacam16) are absent from the residual, detached TMs of the Tecta ΔENT/ΔENT mouse (20), and the TM remains limbally attached in the Tectb −/− mouse, the Otog −/− mouse, and the Ceacam16 −/− mouse (13,22,32). One can therefore deduce that Tecta is a likely interaction partner of otoancorin, although the more recently identified TM protein otolin (15) may also mediate adherence of the TM to the limbus via otoancorin.…”

“…The timing of the forces that are fed back to the cochlear partition by the OHCs is crucial for cochlear amplification to be effective (20,(33)(34)(35), and depends on whether the OHC hair bundles are driven by the elastic or inertial forces delivered by the TM (33). For frequencies well below the characteristic frequency (CF; i.e., the frequency that produces the most sensitive response), the TM imposes an elastic load on the OHC bundles and they are displaced maximally in the excitatory direction (i.e., toward the tallest row of stereocilia) during maximum displacement of the cochlear partition toward the scala vestibuli (1,(36)(37)(38)(39)(40).…”

“…Mutations in Tecta cause recessive (DFNB21) and dominant (DFNA8/12) forms of human hereditary deafness (17)(18)(19), and a dominant missense mutation in Ceacam16 (DFNA4) has been identified recently as a cause of late-onset progressive hearing loss in an American family (15). Mutations in Tecta are one of the most common causes of autosomal-dominant, nonsyndromic hereditary hearing loss (20), and mouse models for the recessive (21) and dominant (22) forms of deafness arising from mutations in Tecta have been created. Together with data from a Tectb-null mutant mouse (23), these studies have provided evidence that the TM plays multiple roles in hearing (24).…”