Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction

Nakanishi, Hiroshi; Kurima, Kiyoto; Kawashima, Yasunaru; Griffith, Andrew J.

doi:10.1016/j.anl.2014.04.001

Cited by 24 publications

(22 citation statements)

References 61 publications

(123 reference statements)

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“…There are several differences in phenotypes between the DFNA36 families in terms of age of onset and rate of progression. This difference may reflect varied effects of these substitution variants, different genetic backgrounds, or both (Nakanishi, Kurima, Kawashima, & Griffith, 2014).…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Guan

et al. 2018

Molec Gen & Gen Med

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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.

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Section: Discussionmentioning

confidence: 99%

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

Wang

Guan

et al. 2018

Molec Gen & Gen Med

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“…TMC1 has been identified as the responsible gene for both DFNA36 and DFNB7/B11 deafness [ 25 ]. To date, more than 30 TMC1 mutations have been reported to be associated with ARNSHL in families from mostly middle-eastern countries [ 26 ]. In two studies conducted in 93 and 86 patients the frequencies of TMC1 mutations were found to be 4.3% [ 27 ] and 8.1% [ 28 ] respectively.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

et al. 2015

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Comprehensive genetic testing has the potential to become the standard of care for individuals with hearing loss. In this study, we investigated the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL) in a Turkish cohort including individuals with cochlear implant, who had a pedigree suggestive of an autosomal recessive inheritance. A workflow including prescreening of GJB2 and a targeted next generation sequencing panel (Illumına TruSightTM Exome) covering 2761 genes that we briefly called as mendelian exome sequencing was used. This panel includes 102 deafness genes and a number of genes causing Mendelian disorders. Using this approach, we identified causative variants in 21 of 29 families. Three different GJB2 variants were present in seven families. Remaining 14 families had 15 different variants in other known NSHL genes (MYO7A, MYO15A, MARVELD2, TMIE, DFNB31, LOXHD1, GPSM2, TMC1, USH1G, CDH23). Of these variants, eight are novel. Mutation detection rate of our workflow is 72.4%, confirming the usefulness of targeted sequencing approach in NSHL.

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“…Cas9 integration in transmembrane channel like 1 (TMC1) TMC1, a transmembrane protein, is required for proper functioning of cochlear hair cells, and has been implicated in hearing loss and prelingual deafness 10 . In mice, this gene is located in chr19 (Accid:NG_008213.1)).…”

Section: Resultsmentioning

confidence: 99%

Sequencing data from Massachusetts General Hospital shows Cas9 integration into the genome, highlighting a serious hazard in gene-editing therapeutics

Chakraborty¹

2019

F1000Res

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The ability to edit a specific gene within our genomes using guided-nucleases (Cas9/ZFN/TALEN - CaZiTa) presents huge opportunities for curing many genetic disorders. Delivery of this ‘drug’ within cells is a critical step for such therapies. The ability of recombinant adeno-associated virus (rAAV) to enter cells makes it a perfect choice as a vector for gene therapy. A plasmid comprising the rAAV, the CaZiTa, guide RNAs (for CRISPR) is expected to enter the cell, edit the target gene(s), remain episomal, and thus fade away with time. However, the rather obvious danger of integration of the plasmid into the genome, if the episomal hypothesis is incorrect, is under-reported. A recent report has highlighted that bacterial genes from a plasmid were integrated into bovine genomes. Massachusetts General Hospital has recently published data on CRISPR edits (Accid:PRJNA563918), noting ‘high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks’. However, there is no mention of Cas9 integration. Here, the same data from Massachusetts General Hospital shows Cas9 integration in the exact edit sites provided for two genes - TMC1 and DMD. Also, there is a mis-annotation of one sample as ‘no gRNA’, since Cas9 integrations have been detected in that sample. This is an important distinction between AAV and CaZiTa integration: while AAV integration can be tolerated, Cas9 integration is a huge, and unacceptable, danger.

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Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction

Cited by 24 publications

References 61 publications

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

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

Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

Sequencing data from Massachusetts General Hospital shows Cas9 integration into the genome, highlighting a serious hazard in gene-editing therapeutics

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