Association ofTMTC2With Human Nonsyndromic Sensorineural Hearing Loss

Abstract

IMPORTANCE Sensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL. OBJECTIVE To identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent. DESIGN, SETTING, AND PARTICIPANTS In this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined. MAIN OUTCOMES AND MEASURES Sensorineural hearing loss. RESULTS Nine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10−4). CONCLUSIONS AND RELEVANCE A previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

TMTC2 variant associated with sensorineural hearing loss and auditory neuropathy spectrum disorder in a family dyad

“…Phenotype characteristics and effective intervention outcomes for S60 and S61 were similar to those previously reported for an unrelated family of Northern European descent who also harbored the TMTC2 rs35725509 variant (Runge et al., ). Objective ECAP measures and speech perception abilities indicated effective stimulation of the auditory system with cochlear implants, and are consistent with postlingual hearing loss onset.…”

“…TMTC2 is a gene that, outside this and one other study (Runge et al, 2016), had not been previously implicated in hearing loss. In both cases, a strong association of the rs35725509 variant to the nonsyndromic SNHL phenotype was uncovered.…”

“…Apart from their relatively high MAF values, these two additional variants are predicted to be benign in their impact on normal gene function, and have not previously been reported as likely mutations causing SNHL. In contrast, rs35725509 in the TMTC2 gene was recently identified in another unrelated family with SNHL (Runge et al., ). The rs35725509 variant was the only mutation (nonsynonymous or synonymous) found in the coding region of the TMTC2 gene in S60 or S61.…”

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

“…This connection may extend to hearing loss in patients as well. In parallel with our work recently, a missense mutation (rs35725509; Val136Ile) in the human ortholog TMTC2 was linked to nonsyndromic sensorineural hearing loss both in a 6-generation family and in a cohort of unrelated individuals with SNHL (179 affected vs. 186 matched controls) (19,35). This mutation was also recently identified in another family dyad with hearing loss (35).…”

“…These published data also demonstrate that the level of Tmtc4 (both mRNA and protein) in the cochlea is higher than the other 3 isoforms (Tmtc1,2,3), although all 4 are expressed in the cochlea (18). Given the broad expression of all isoforms in the cochlea and the recently published linkage of TMTC2 to hearing loss in humans (19), we also tested whether inactivation of Tmtc4 led to a change in the abundance of other isoforms. As measured by quantitative PCR (qPCR), we found that there was a significant increase in the levels of Tmtc1, Tmtc2, and Tmtc3 mRNA in the cochlea of Tmtc4-KO mice compared with littermate WT controls, suggesting possible shared functions (Supplemental Figure 3).…”