Identification of four TMC1 variations in different Chinese families with hereditary hearing loss

Abstract

BackgroundVariants in TMC1 (transmembrane channel‐like 1) can cause both autosomal dominant and recessive hearing loss in human population. Mice with Tmc1 variants have been shown to be ideal animal models for gene therapy. In this article, we report four TMC1 variants in four different Chinese families and the follow‐up auditory phenotype of a previously reported family.MethodsFour families with TMC1 variants, as well as a previously described family with TMC1 variant orthologous to the Beethoven mouse, were recruited in this study. A comprehensive auditory evaluation was performed on all ascertained family members. High‐throughput sequencing was conducted using genomic DNA from the probands and other family members to identify probable deafness genes.ResultsWe identified four TMC1 (NM_138691.2) variations, including two pathogenic variants, c.1714G>A, and c.1253T>A, one likely pathogenic variant, c.[797T>C];[797T>C], and one single nucleotide polymorphism (SNP), c.2276G>A. Among these variants, c.[797T>C];[797T>C] is a novel likely pathogenic variant, and c.1714G>A and c.1253T>A are known pathogenic variants at the DFNB7/11 (DFNA36) locus. Phenotype‐genotype correlation analysis of TMC1 variants showed that the TMC1 dominant variation‐related phenotype was late‐onset, progressive, high frequency to all frequency sensorineural hearing loss, while the TMC1 recessive variant was related to congenital all frequency sensorineural hearing impairment.ConclusionsTwo pathogenic, one likely pathogenic variants and one SNP of TMC1 were identified in four Chinese families with hereditary hearing loss, indicating that TMC1 may be a more frequent cause of hearing loss than expected. TMC1 variants related to hearing loss result in specific phenotypes. The TMC1 c.1253T>A (p.M418K) variation, homologous to the Tmc1 c. 1235 T> A (p.M412K) variant in Beethoven mice, was the second report of this variant in human patients with hearing loss, suggesting the possibility to translational gene therapy from Beethoven mice to human patients.

New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells

“…A previously described dominant mouse mutation, Tmc1 p.M412K ( Beethoven ), leads to early hearing loss and hair cell degeneration ( Vreugde et al, 2002 ). The homologous human deafness mutation is TMC1 p.M418K ( Zhao et al, 2014b ; Wang et al, 2018 ), the mutation site is adjacent to two other missense mutations causing deafness: TMC1 p.L416R ( Chen et al, 2015 ) and TMC1 p.G417R ( Yang et al, 2010 ). Here we report a fourth deafness mutation in the same region, TMC1 p.T422K and we generate and characterize the homologous mouse mutation Tmc1 p.T416K.…”

Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families

“…These two mutations were not detected in 200 Chinese Han normal-hearing controls and are not present in 1000 Genomes and ExAC databases. The p.R34X mutation with minor allele frequency (MAF) of 0.0002 in ExAC has been previously detected in many patients from Pakistan, Iran, Turkey, and Tunisia but is relatively rare in China [ 16 , 27 – 29 ]. On the other hand, while the p.M413T mutation is novel.…”

“…It has been reported that mutations in TMC1 may cause both prelingual profound autosomal recessive deafness DFNB7/11 and postlingual progressive autosomal dominant deafness DFNA36 [13]. To date, more than 60 mutations in TMC1 are reported worldwide [15], with the recessive mutations predominantly associated with prelingual severe-to-profound hearing loss [15,16].…”

Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness

“…8,16 In human TMC1 deafness (DFNA36), although HL is severe to profound by 60 years of age, its onset varies from 5 to 28 years. 4,5 Because deterioration of HL is much slower in humans than in Tmc1 Bth/+ mice, there may be a greater temporal window for successful therapeutic intervention, which could allow for rescue of the mid to high frequencies.…”

“…Bth mice carry a dominant-negative missense mutation, c.1235T > A (p.Met412Lys), in the transmembrane channel-like gene 1 (Tmc1) gene 3 that is orthologous to the c.1253T > A (p.Met418Lys) variant reported in human TMC1 in two Chinese families segregating early-onset progressive HL. 4,5 The progression of HL in Bth-heterozygous mice (Tmc1 Bth/+ ) is reflected by degeneration of cochlear inner hair cells (IHCs) in a base-to-apex gradient ( Figure 1A). Outer hair cells (OHCs) remain intact in a middle-to-apical region for at least the first 20 weeks of life.…”