1.A.17.4.15
The mechanoelectric-transduction (MT or MET) complex in auditory hair cells converts the mechanical stimulation of sound waves into neural signals. Tmc1 is of 760 aas and 10 TMSs and is 96% identical to mouse TMC1 (TC# 1.A.17.4.6). Novel TMC1 structural and splice variants are associated with congenital nonsyndromic deafness (Meyer et al. 2005). Variants responsible for hereditary hearing loss have been identified (Wang et al. 2018). There are varying numbers of channels per MET complex, each requiring multiple TMC1 molecules, and together operating in a coordinated, cooperative manner (Beurg et al. 2018). Ballesteros et al. 2018 generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that harbors the Beethoven mutation, suggesting that it functions as a permeation pathway. Hair cells are permeable to 3 kDa dextrans, and dextran permeation requires TMC1/2 proteins and functional MET channels (Ballesteros et al. 2018). TMC1 is a pore-forming component of MET channels in auditory and vestibular hair cells (Pan et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). A Tmc1 mutation reduces calcium permeability and expression of MET channels in cochlear hair cells (Beurg et al. 2019). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding (Yu et al. 2020). Homozygous variants in the TMC1 and CDH23 (3354 aas and at least two TMSs, one N-terminal and one near the C-terminus; Q9H251) genes cause autosomal recessive nonsyndromic hearing loss (Zardadi et al. 2020). TMC1 forms a complex with protocadherin 15 (PCDH15, TC# 1.A.82.1.1), lipoma HMGIC fusion partner-like 5 (LHFPL5, TC# 1.A.82.1.1), and transmembrane inner ear protein (TMIE, TC# 8.A.116.1.2). Splicing isoforms of TMC1, LHFPL5, and TMIE have been identified (Zhou et al. 2021). There are four alternative splicing events for the genes encoding these three proteins. The alternative splicing of TMC1 and LHFPL5 is cochlear-specific and occurs in both neonatal and adult (mouse) cochleae (Zhou et al. 2021). Tmc1 deafness mutations impact mechanotransduction in auditory hair cells (Beurg et al. 2021). A TMC1 synonymous substitution is a variant disrupting splicing regulatory elements associated with recessive hearing loss (Vaché et al. 2021). The roles of solute carriers in auditory function have been reviewed (Qian et al. 2022). Autosomal recessive and dominant non-syndromic hearing loss can be due to pathogenic TMC1 variants (Kraatari-Tiri et al. 2022). Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth TMSs (Akyuz et al. 2022). Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing (Ballesteros and Swartz 2022). The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells has been examined, and it was concluded that each PCDH15 (see 1.A.17.4.13 and 1.A.82.1.1) and LHFPL5 (see 1.A.17.4.15 and 1.A.82.1.1) monomer may contact two channels, irrespective of location (Yu et al. 2020). Homozygous variants in the TMC1 and CDH23 (3354 aas and at least two TMSs, one N-terminal and one near the C-terminus; Q9H251) genes cause autosomal recessive nonsyndromic hearing loss (Zardadi et al. 2020). TMC1 forms a complex with protocadherin 15 (PCDH15, TC# 1.A.82.1.1), lipoma HMGIC fusion partner-like 5 (LHFPL5, TC# 1.A.82.1.1), and transmembrane inner ear protein (TMIE, TC# 8.A.116.1.2). Splicing isoforms of TMC1, LHFPL5, and TMIE have been identified (Zhou et al. 2021). There are four alternative splicing events for the genes encoding these three proteins. The alternative splicing of TMC1 and LHFPL5 is cochlear-specific and occurs in both neonatal and adult (mouse) cochleae (Zhou et al. 2021). Tmc1 deafness mutations impact mechanotransduction in auditory hair cells (Beurg et al. 2021). A TMC1 synonymous substitution is a variant disrupting splicing regulatory elements associated with recessive hearing loss (Vaché et al. 2021). The roles of solute carriers in auditory function have been reviewed (Qian et al. 2022). Autosomal recessive and dominant non-syndromic hearing loss can be due to pathogenic TMC1 variants (Kraatari-Tiri et al. 2022). Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth TMSs (Akyuz et al. 2022). Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing (Ballesteros and Swartz 2022). The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells has been examined, and it was concluded that each PCDH15 (see 1.A.17.4.13 and 1.A.82.1.1) and LHFPL5 (see 1.A.17.4.15 and 1.A.82.1.1) monomer may contact two channels, irrespective of location (Fettiplace et al. 2022). .