Alternative titles; symbols
HGNC Approved Gene Symbol: TMC1
Cytogenetic location: 9q21.13 Genomic coordinates (GRCh38): 9:72,521,608-72,838,297 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q21.13 | Deafness, autosomal dominant 36 | 606705 | Autosomal dominant | 3 |
| Deafness, autosomal recessive 7 | 600974 | Autosomal recessive | 3 |
TMC1, a 6-pass integral membrane protein, is a component of mechanotransduction channels in hair cells of inner ear (Pan et al., 2013).
By positional cloning, Kurima et al. (2002) identified the gene mutant in a form of autosomal dominant deafness (DFNA36; 606705) and of recessive deafness (DFNB7/B11; 600974) that map to the same interval on 9q13-q21. The authors evaluated several candidate genes in the critical region but found no mutations in the deaf families. To identify additional DFNA36/B7/B11 candidate genes based upon sequence similarity to related genes elsewhere in the genome, they initiated a systematic BLAST analysis of segments of genomic DNA sequence in the critical region. One sequence was found to be similar to a predicted gene (subsequently named TMC2; 606707) on 20p13. They used conserved sequences between TMC2 and the query sequence (subsequently named TMC1) on chromosome 9q13-q21 to design primers for amplifying potential TMC1 transcripts from a human fetal brain cDNA library. Kurima et al. (2002) found the longest open reading frame to be 2,283 nucleotides, predicting an 87-kD protein. The TMC1 protein is predicted to contain 6 transmembrane domains and to have cytoplasmic orientation of N and C termini. Kurima et al. (2002) obtained the orthologous mouse Tmc1 cDNA by RT-PCR and 5-prime and 3-prime RACE of mouse inner-ear cDNA. They found that in the mouse, Tmc1 mRNA is expressed in hair cells of the postnatal cochlea and vestibular end organs and is required for normal function of cochlear hair cells.
Kawashima et al. (2011) stated that mice express 2 Tmc1 splice variants that differ in the presence or absence of exon 2 and in the use of translation initiation codons in either exon 1 or exon 2. Using quantitative RT-PCR and in situ hybridization, they found that expression of both Tmc1 and Tmc2 increased in mouse cochlear hair cells within 5 days of birth and that the dominant species switched from Tmc2 to Tmc1 by postnatal day 8. Tmc2 was also expressed in hair cells of vestibular sensory organs.
By alignment of the TMC1 cDNA with genomic sequences, Kurima et al. (2002) showed that 24 exons probably encode full-length mRNA, including 4 exons encoding sequence upstream of a methionine codon in exon 5. There are many in-frame stop codons directly upstream of this methionine codon, which was predicted to be an adequate Kozak translation initiation codon.
By genomic sequence analysis, Kurima et al. (2002) mapped the TMC1 gene to chromosome 9q13-q21.
Gross (2016) mapped the TMC1 gene to chromosome 9q21.13 based on an alignment of the TMC1 sequence (GenBank AF417578) with the genomic sequence (GRCh38).
Kurima et al. (2002) identified mutations in the TMC1 gene in 1 family with DFNA36 (see 606706.0001) and in 10 families with DFNB7/11 (see, e.g., 606706.0002 and 606706.0003).
In a North American Caucasian family with autosomal dominant nonsyndromic postlingual progressive sensorineural hearing loss, Kitajiri et al. (2007) found linkage to the DFNA36 locus on chromosome 9q13-q21; analysis of the TMC1 gene revealed heterozygosity for a missense mutation (D572H; 606706.0004).
Kitajiri et al. (2007) identified mutations in the TMC1 gene (see, e.g., 606706.0002; 606706.0005; 606706.0006) in affected members of 10 Pakistani families with autosomal recessive DFNB7/11. The R34X mutation (606706.0002) was present in 1.8% of Pakistani families.
Hilgert et al. (2008) identified mutations in the TMC1 gene in 7 Turkish families with DFNB7/11.
In affected members of a large 6-generation Chinese family with DFNA36, Zhao et al. (2014) identified a heterozygous missense mutation in the TMC1 gene (M418K; 606706.0007) that segregated with the disorder in the family. The substitution was homologous to the M412K mutation in the Bth mouse (see ANIMAL MODEL). The mutation was found by whole-exome sequencing.
From a large Japanese cohort with nonsyndromic hearing loss, Nishio and Usami (2022) identified 26 probands with mutations in the TMC1 gene. Among these probands, 15 were from families with autosomal dominant inheritance and 11 were from families with autosomal recessive inheritance or sporadic cases. Overall, prevalence of TMC1-associated hearing loss was 0.17% for all patients with bilateral nonsyndromic hearing loss, 0.61% for autosomal dominant families, and 0.07% for autosomal recessive families. Of the 17 identified variants, 7 were novel, of which 5 were classified as pathogenic or likely pathogenic and 2 as variants of uncertain significance. The most common variant, identified in 11 unrelated families with DFNA36, was a heterozygous missense mutation (D543N; 606706.0008). The same haplotype was present in all 11 families, suggesting that the variant occurred as a founder mutation.
In the mouse deaf mutant 'Beethoven' (Bth), Vreugde et al. (2002) identified a met412-to-lys (M412K) missense mutation in the Tmc1 gene; thus, Bth is a mouse model for autosomal dominant DFNA36. Similarly, the recessive deafness mutation 'dn,' which maps to mouse chromosome 19, is a model of profound congenital deafness, DFNB7/DFNB11 (600974), caused by mutations in the TMC1 gene.
Kawashima et al. (2011) found that Tmc1 -/- mice were deaf. In contrast, Tmc2 -/- mice developed normally without hearing loss and showed normal motor behavior. Tmc1 -/- Tmc2 -/- double-knockout mice were viable, but they exhibited severely abnormal vestibular behaviors. Vestibular and cochlear hair cells of Tmc1 -/- Tmc2 -/- mice appeared overtly normal, but they completely lacked voltage-dependent mechanotransduction currents. Hair cells with intermediate genotypes, Tmc1 +/- Tmc2 -/- or Tmc1 -/- Tmc2 +/-, had reduced current amplitudes relative to wildtype controls. Exogenous expression of either Tmc1 or Tmc2 restored mechanotransduction in Tmc1 -/- Tmc2 -/- vestibular or cochlear hair cells.
By recording whole-cell and single-channel mechanotransduction currents from hair cells of mice with targeted deletion of Tmc1, Tmc2, or both, as well mice with the Bth mutation in Tmc1, Pan et al. (2013) determined that both channels were required to create the heterogeneity of single-channel properties in cochlear hair cells and vestibular hair cells. The amplitude of single-channel conductance in Tmc2-expressing cells was approximately double that of Tmc1-expressing cells. Tmc1 and Tmc2 appeared to form homo- or heterotrimeric channels. The authors noted that, in postnatal mice, development of endocochlear potential occurs just prior to the onset of hearing and coincides with the switch from high-conductance Tmc2 channels to low-conductance Tmc1 channels. They hypothesized that the counterbalance between the high- to low-conductance switch and development of the endocochlear potential may function to ensure stable transduction current amplitudes during development and into adulthood.
Shibata et al. (2016) found that a single intracochlear injection of an artificial microRNA carried in a viral vector slowed progression of hearing loss for up to 35 weeks in the Bth mouse. Initial studies showed that the microRNA chosen selectively suppressed the dominant gain-of-function mutant M412K allele, which is homologous to human M418K (606706.0007). Treated mice also showed improved hair cell survival compared to untreated mice. The findings demonstrated the feasibility of RNA interference-mediated suppression of an endogenous deafness-causing allele to slow progression of autosomal dominant hearing loss before cochlear damage occurs.
Gao et al. (2018) designed and validated, both in vitro and in primate fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 Bth mouse model, even though the mutant Tmc1(Bth) allele differs from the wildtype allele at only a single basepair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1(Bth) allele into the cochlea of neonatal Tmc1(Bth)/+ mice substantially reduced progressive hearing loss. Gao et al. (2018) observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1(Bth)/+ mice. Gao et al. (2018) concluded their findings suggested that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.
In a large North American family with autosomal dominant nonsyndromic sensorineural hearing loss that was arbitrarily designated DFNA36 (606705), Kurima et al. (2002) found a 1714G-A transition in the TMC1 gene resulting in an asp572-to-asn amino acid substitution (D572N). Sensorineural hearing loss began at 5 to 10 years of age and rapidly progressed to profound deafness within 10 to 15 years. These was no evidence of vestibular deficits. No polymorphisms at this codon were found in 902 control chromosomes.
Hilgert et al. (2009) identified the D572N mutation in another North American Caucasian family with autosomal dominant hearing loss. Comparison of haplotypes with the family reported by Kurima et al. (2002) excluded a founder effect. One asymptomatic individual in the family reported by Hilgert et al. (2009) carried the disease haplotype, indicating reduced penetrance.
Yu et al. (2020) examined physical and functional interactions between proteins encoded by TMC1 and LHFPL5 (609427), a gene whose variants are associated with autosomal recessive deafness-67 (DFNB67; 610265) and found that TMC1 expression is stabilized by LHFPL5 binding both in heterologous expression systems and in hair cells. The D572N variant in TMC1 disrupted the interaction between TMC1 and LHFPL5, resulting in destabilized TMC1 expression.
In 5 different families from Pakistan, Kurima et al. (2002) found that members with autosomal recessive nonsyndromic neurosensory deafness (DFNB7; 600974) had a 100C-T transition in the TMC1 gene, resulting in an arg34-to-ter (R34X) nonsense mutation. Comparison of linked haplotypes in these families with those in Pakistani individuals with normal hearing confirmed a specific association of R34X with a single identical haplotype. Thus, the R34X mutation in these apparently unrelated families was probably derived from a common founder. The mutation was homozygous in these cases.
Kitajiri et al. (2007) identified the R34X mutation in 5 consanguineous Pakistani families with DFNB7. Combined with the results of the report by (Kurima et al., 2002), Kitajiri et al. (2007) estimated that the R34X accounted for 1.8% of deafness in Pakistan. Haplotype analysis indicated a founder effect.
In a family with autosomal recessive deafness-7 (DFNB7; 600974), Kurima et al. (2002) identified a homozygous mutation of the TMC1 gene: 1960A-G transition predicted to substitute valine for a conserved methionine at position 654 (M654V).
In affected members of a North American Caucasian family with autosomal dominant nonsyndromic sensorineural deafness (DFNA36; 606705), Kitajiri et al. (2007) identified heterozygosity for a 1714G-C transversion in the TMC1 gene, resulting in an asp572-to-his (D572H) substitution in the conserved TMC domain within a predicted cytoplasmic loop.
In 4 affected members of a consanguineous Pakistani family with autosomal recessive deafness-7 (DFNB7; 600974), Kitajiri et al. (2007) identified a homozygous G-to-T transversion in intron 5 of the TMC1 gene, resulting in a donor splice site mutation.
In affected members of 2 different consanguineous Pakistani families with autosomal recessive deafness-7 (DFNB7; 600974), Kitajiri et al. (2007) identified a homozygous 1543T-C transition in exon 17 of the TMC1 gene, resulting in a cys515-to-arg (C515R) substitution in a highly conserved residue.
In affected members of a large 6-generation Chinese family with autosomal dominant deafness-36 (DFNA36; 606705), Zhao et al. (2014) identified a heterozygous c.1253T-A transversion in exon 16 of the TMC1 gene, resulting in a met418-to-lys (M418K) substitution at a highly conserved residue in the second extracellular loop between the third and fourth transmembrane domains. The substitution was homologous to the M412K mutation in the Bth mouse (see ANIMAL MODEL). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the dbSNP (build 132) or 1000 Genomes Project databases, or in 100 controls. Functional studies of the variant were not performed. The patients had onset of postlingual, progressive sensorineural hearing loss, as well as tinnitus, between ages 5 and 28 years.
Among a large Japanese cohort with nonsyndromic hearing loss, Nishio and Usami (2022) identified 11 unrelated probands with autosomal dominant hearing loss-36 (DFNA36; 606705) who were heterozygous for a c.1627G-A transition (c.1627G-A, NM_138691) in the TMC1 gene, resulting in an asp543-to-asn (D543N) substitution. The same haplotype was present in all 11 families, suggesting that the variant was a founder mutation.
Gao, X., Tao, Y., Lamas, V., Huang, M., Yeh, W.-H., Pan, B., Hu, Y.-J., Hu, J. H., Thompson, D. B., Shu, Y., Li, Y., Wang, H., Yang, S., Xu, Q., Polley, D. B., Liberman, M. C., Kong, W.-J., Holt, J. R., Chen, Z.-Y., Liu, D. R. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature 553: 217-221, 2018. [PubMed: 29258297] [Full Text: https://doi.org/10.1038/nature25164]
Gross, M. B. Personal Communication. Baltimore, Md. 2/29/2016.
Hilgert, N., Alasti, F., Dieltjens, N., Pawlik, B., Wollnik, B., Uyguner, O., Delmaghani, S., Weil, D., Petit, C., Danis, E., Yang, T., Pandelia, E., Petersen, M. B., Goossens, D., Favero, J. D., Sanati, M. H., Smith, R. J. H., Van Camp, G. Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11. Clin. Genet. 74: 223-232, 2008. [PubMed: 18616530] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01053.x]
Hilgert, N., Monahan, K., Kurima, K., Li, C., Friedman, R. A., Griffith, A. J., Van Camp, G. Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. J. Hum. Genet. 54: 188-190, 2009. [PubMed: 19180119] [Full Text: https://doi.org/10.1038/jhg.2009.1]
Kawashima, Y., Geleoc, G. S. G., Kurima, K., Labay, V., Lelli, A., Asai, Y., Makishima, T., Wu, D. K., Della Santina, C. C., Holt, J. R., Griffith, A. J. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J. Clin. Invest. 121: 4796-4809, 2011. [PubMed: 22105175] [Full Text: https://doi.org/10.1172/JCI60405]
Kitajiri, S., Makishima, T., Friedman, T. B., Griffith, A. J. A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clin. Genet. 71: 148-152, 2007. [PubMed: 17250663] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00739.x]
Kitajiri, S., McNamara, R., Makishima, T., Husnain, T., Zafar, A. U., Kittles, R. A., Ahmed, Z. M., Friedman, T. B., Riazuddin, S., Griffith, A. J. Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan. Clin. Genet. 72: 546-550, 2007. [PubMed: 17877751] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00895.x]
Kurima, K., Peters. L. M., Yang, Y., Riazuddin, S., Ahmed, Z. M., Naz, S., Arnaud, D., Drury, S., Mo, J., Makishima, T., Ghosh, M., Menon, P. S. N., and 13 others. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nature Genet. 30: 277-284, 2002. [PubMed: 11850618] [Full Text: https://doi.org/10.1038/ng842]
Nishio, S. Y., Usami, S. I. Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss. Hum. Genet. 141: 929-937, 2022. [PubMed: 34523024] [Full Text: https://doi.org/10.1007/s00439-021-02364-2]
Pan, B., Geleoc, G. S., Asai, Y., Horwitz, G. C., Kurima, K., Ishikawa, K., Kawashima, Y., Griffith, A. J., Holt, J. R. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79: 504-515, 2013. [PubMed: 23871232] [Full Text: https://doi.org/10.1016/j.neuron.2013.06.019]
Shibata, S. B., Ranum, P. T., Moteki, H., Pan, B., Goodwin, A. T., Goodman, S. S., Abbas, P. J., Holt, J. R., Smith, R. J. H. RNA interference prevents autosomal-dominant hearing loss. Am. J. Hum. Genet. 98: 1101-1113, 2016. [PubMed: 27236922] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.028]
Vreugde, S., Erven, A., Kros, C. J., Marcotti, W., Fuches, H., Kurima, K., Wilcox, E. R., Friedman, T. B., Griffith, A. J., Balling, R., de Angelis, M. H., Avraham, K. B., Steel, K. P. Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nature Genet. 30: 257-258, 2002. [PubMed: 11850623] [Full Text: https://doi.org/10.1038/ng848]
Yu, X., Zhao, Q., Li, X., Chen, Y., Tian, Y., Liu, S., Xiong, W., Huang, P. Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. Proc. Nat. Acad. Sci. 117: 29894-29903, 2020. [PubMed: 33168709] [Full Text: https://doi.org/10.1073/pnas.2011147117]
Zhao, Y., Wang, D., Zong, L., Zhao, F., Guan, L., Zhang, P., Shi, W., Lan, L., Wang, H., Li, Q., Han, B., Yang, L., Jin, X., Wang, J., Wang, J., Wang, Q. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family. PLoS One 9: e97064, 2014. Note: Electronic Article. [PubMed: 24827932] [Full Text: https://doi.org/10.1371/journal.pone.0097064]