Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation

Abstract

Mutations of the transmembrane channel-like 1 (TMC1) gene can cause dominant and recessive forms of deafness in humans and mice. TMC1 is one of eight mammalian TMC genes of unknown function. The multi-pass transmembrane topologic structure of the proteins they encode suggests roles as a receptor, transporter, channel or pump. Tmc1 and the closely related Tmc2 gene are expressed in neurosensory hair cells of the auditory and vestibular end organs of the mouse inner ear. Recent studies have demonstrated that Tmc1 and Tmc2 are specifically required for mechanoelectrical transduction in hair cells. The exact role of these proteins in mechanoelectrical transduction is unknown. TMC1 and TMC2 are viable candidates for the mechanoelectrical transduction channel of hair cells, whose component molecules have eluded identification for over 30 years. We expect that studies of TMC proteins will yield insights into molecular components and mechanisms of mechanosensation in auditory and vestibular hair cells, as well as in other tissues and organs.

Transmembrane channel-like ( tmc ) gene regulates Drosophila larval locomotion

“…It remains to be shown whether TMC1 and TMC2 can yield channel activities in heterologous expression systems (52,53), and they likely require other proteins for their function in mechanotransduction (54)(55)(56). We have attempted to ectopically express the Drosophila tmc gene product in a variety of heterologous systems.…”

The Genetic Basis of Nonsyndromic Hearing Loss in Indian and Pakistani Populations

“…TMC proteins may act as ion channels, ion pumps, or transporters depending on their structure. Data obtained from the tmc1 mutant mice suggest a possible role for TMC1 in mechanoelectrical transduction of sound by cochlear hair cells (Kawashima et al, 2015). In their screening of 374 families, Ganapathy et al (2014) identified eight TMC1 mutations.…”

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents

“…Mutations in TMC1 have been linked to recessive and dominant genetic deafness 17 . A dominant-negative missense mutation in TMC1 (p.M418K, c.T1253A) causes reduced single-channel current levels and calcium permeability 16 and progressive post-lingual sensorineural hearing loss in humans 18–20 . The Bth/+ mouse model carries the orthologous missense mutation (p.M412K, c.T1235A) in the mouse Tmc1 gene and exhibits progressive auditory response threshold elevation and progressive hair cell loss beginning at one month 21 .…”