TMC1 – Nonsyndromic Genetic Hearing Loss

Transmembrane channel‐like protein 1 (TMC1) is a pore-forming subunit of the mechanoelectrical transduction (MET) channel in cochlear hair cells. Biallelic mutations in TMC1 cause autosomal recessive nonsyndromic hearing loss (DFNB7/11; MONDO:0019497), whereas heterozygous variants at codon Asp572 confer autosomal dominant hearing loss (DFNA36).

Autosomal recessive inheritance is established by segregation of TMC1 variants in multiple consanguineous and outbred families worldwide. To date, 35 distinct homozygous mutations have been identified in over 60 families with prelingual sensorineural hearing loss ([PMID:26822030]). Founder mutations such as c.100C>T (p.Arg34Ter) recur in Saudi cohorts ([PMID:31854501]), and compound heterozygous deletions and frameshifts (e.g., c.1396_1398del (p.Asn466del)) segregate in Chinese families ([PMID:25458163]).

The variant spectrum includes missense (e.g., c.596A>T (p.Asn199Ile)) ([PMID:36568409]), splice-site (c.536-8T>A), nonsense (c.256G>T (p.Glu86Ter)), and frameshift alleles. Recurrent founder variants and population-specific alleles have been documented in Pakistani, Chinese, Iranian, and Saudi cohorts.

Functional studies in mouse models demonstrate that Tmc1 p.Asp569Asn (homologous to human p.Asp572Asn) and Beethoven (p.Met412Lys) mutants exhibit profoundly reduced MET currents, altered Ca2+ permeability, and outer hair cell loss ([PMID:31548403]). Heterologous expression combined with CRISPR screening confirms that human TMC1/2 are mechanically gated ion channels ([PMID:39674179]). Disruption of TMC1–LHFPL5 interactions by p.Asp572Asn further destabilizes channel localization and function ([PMID:33168709]).

No credible conflicting evidence has emerged; the full allelic series and experimental concordance over >15 years support a definitive gene–disease relationship.

Key take‐home: TMC1 genetic testing is clinically actionable for early diagnosis and management of autosomal recessive nonsyndromic hearing loss.

References

• Journal of Translational Medicine • 2016 • Exome sequencing identifies a mutation in TMC1 as a novel cause of autosomal recessive nonsyndromic hearing loss. PMID:26822030
• Proceedings of the National Academy of Sciences of the United States of America • 2019 • A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells. PMID:31548403
• Neuron • 2025 • Human TMC1 and TMC2 are mechanically gated ion channels. PMID:39674179
• Saudi Journal of Biological Sciences • 2023 • Functional consequences of Genetics variant in TMC1 and TMC2 within a United Arab Emirates family with Pre-lingual hearing loss. PMID:36568409
• American Journal of Medical Genetics Part B • 2020 • Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population. PMID:31854501

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