Affinage

TMC1

Transmembrane channel-like protein 1 · UniProt Q8TDI8

Length
760 aa
Mass
87.8 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMC1 is the pore-forming subunit of the mechanoelectrical transduction (MET) channel in inner-ear hair cells, essential for hearing and vestibular function. It assembles as a dimer with ten transmembrane domains structurally related to TMEM16 channels, and residues in TM4–TM7 line the ion conduction pore, defining Ca²⁺ permeability, single-channel conductance, and mechanical gating sensitivity (PMID:30138589, PMID:36191207, PMID:35857511); purified TMC1 reconstituted into liposomes forms a pressure-sensitive channel, and full-length mammalian TMC1 functions as a mechanosensitive channel in heterologous cells when co-expressed with the gating modulator TMIE (PMID:31761710, PMID:39999170). TMC1 operates within a macromolecular complex at shorter-row stereocilia tips comprising PCDH15 (tip-link force coupler), LHFPL5 (mechanical coupling stabilizer), CIB2/CIB3 (Ca²⁺-sensing cytoplasmic stabilizers whose interaction with TMC1 is structurally resolved), TMIE (pore contributor and palmitoylation-dependent gating modulator), and LOXHD1 (required to retain TMC1 at the transduction site in mature hair cells) (PMID:25114259, PMID:36224384, PMID:39889697, PMID:39256406). Loss-of-function and dominant missense mutations in TMC1 cause autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic deafness, with reduced MET channel Ca²⁺ permeability leading to decreased stereociliary PMCA2 density, constitutive phosphatidylserine externalization, mitochondrial dysfunction, and hair-cell apoptosis (PMID:11850618, PMID:40100636, PMID:35921424).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 High

    Positional cloning established TMC1 as a gene required for cochlear hair-cell function and auditory transduction, resolving the genetic basis of the deafness (dn) mouse and human DFNB7/11 loci.

    Evidence Positional cloning of dn mouse and DFNA36/DFNB7 human families with expression analysis

    PMID:11850618 PMID:11850623

    Open questions at the time
    • Whether TMC1 was a channel subunit, a regulatory factor, or a trafficking molecule was unknown
    • No protein localization data within the hair cell
  2. 2006 High

    Electrophysiological characterization of Tmc1 mutant hair cells revealed that TMC1 is required for functional maturation of hair-cell ion channels and synaptic machinery, but whether TMC1 was the transduction channel itself or an upstream regulatory factor remained unresolved.

    Evidence Whole-cell patch-clamp of IHCs and OHCs in dn/dn and Bth/Bth mice measuring K⁺, Ca²⁺ currents and exocytosis

    PMID:16627570

    Open questions at the time
    • No direct evidence TMC1 was part of the MET channel complex
    • Whether the maturational defects were primary or secondary to loss of MET was unclear
  3. 2013 High

    Single-channel recordings from hair cells expressing TMC1 alone, TMC2 alone, or both in a Tmc1/2-null background demonstrated that TMC1 and TMC2 directly define MET channel permeation properties—Ca²⁺ selectivity and conductance—establishing them as channel components rather than accessory factors.

    Evidence Single-channel and whole-cell recordings in genetically controlled Tmc1/2-null mouse hair cells

    PMID:23871232

    Open questions at the time
    • Whether TMC1 itself formed the pore or modulated a separate pore-forming protein was unresolved
    • No structural data
  4. 2014 High

    Identification of a physical interaction between TMC1 and the tip-link component PCDH15 placed TMC1 within the mechanotransduction apparatus and explained how mechanical force from the tip link could be transmitted to the channel.

    Evidence Membrane yeast two-hybrid, co-immunoprecipitation, and zebrafish dominant-negative functional assay

    PMID:25114259

    Open questions at the time
    • Stoichiometry and structural basis of the PCDH15–TMC1 interaction were unknown
    • Whether the interaction was direct or scaffolded in vivo was not established
  5. 2015 High

    Fluorescently tagged TMC1 localized specifically to shorter-row stereocilia tips—the site of mechanotransduction—and rescued MET currents and hearing, directly linking TMC1 protein position to its channel function; simultaneously, the Beethoven M412K mutation was shown to alter pore permeation and blocker accessibility, placing this residue inside the channel pore.

    Evidence Transgenic TMC1-mCherry mice with functional rescue; dihydrostreptomycin block and Ca²⁺ permeability measurements in Bth/Bth OHCs

    PMID:26321635 PMID:26758827

    Open questions at the time
    • Direct pore-lining evidence (e.g., cysteine accessibility) was still lacking
    • The overall topology and oligomeric state of TMC1 were unknown
  6. 2017 High

    CIB2 was identified as a physically interacting partner of TMC1 required for MET, and TOMT was shown to be a chaperone required for TMC1 trafficking to the hair bundle, establishing both an accessory subunit and a trafficking pathway for the TMC1-containing channel.

    Evidence Co-immunoprecipitation of CIB2–TMC1 and TOMT–TMC1; Cib2 KO and zebrafish tomt mutant analyses with MET current and localization readouts

    PMID:28534737 PMID:28663585

    Open questions at the time
    • Structural basis of CIB2–TMC1 interaction was unknown
    • Whether CIB2 modulated channel gating or only complex assembly was unclear
  7. 2018 High

    Cysteine-modification experiments identified specific residues in TM4–TM7 of TMC1 that line the ion conduction pore, and biochemical assays showed TMC1 assembles as a dimer, definitively establishing TMC1 as the pore-forming subunit of the MET channel; single-molecule counting revealed a tonotopic gradient of TMC1 molecules per stereocilium.

    Evidence MTSET/MTSES cysteine modification in Tmc1/2-null hair cells expressing TMC1 variants; single-molecule photobleaching of TMC1-mCitrine; structural modeling on TMEM16

    PMID:29872055 PMID:30138589

    Open questions at the time
    • No high-resolution experimental structure of mammalian TMC1
    • Mechanism by which TMC1 number scales tonotopically was unknown
  8. 2019 High

    Multiple lines of evidence converged: purified TMC1 reconstituted into liposomes formed mechanosensitive channels; TMC1 was shown to carry a background leak conductance distinct from MET; TMIE was established as essential for TMC1 trafficking to the bundle; and the D569N mutation was shown to reduce Ca²⁺ permeability as a proximate cause of hair-cell death.

    Evidence Liposome reconstitution electrophysiology with pressure stimulation; cysteine mutagenesis identifying leak-conductance residues; zebrafish tmie mutant localization; single-channel recordings in D569N mice

    PMID:30726219 PMID:31548403 PMID:31661074 PMID:31761710 PMID:33168709

    Open questions at the time
    • Full mammalian TMC1 complex structure not yet determined
    • Mechanism linking reduced Ca²⁺ permeability to apoptosis was not molecularly defined
  9. 2022 High

    The cryo-EM structure of the native C. elegans TMC-1 complex revealed a 2:2:2 TMC-1/CALM-1/TMIE assembly that deforms the lipid bilayer, providing the first atomic-resolution view of a TMC complex; mutagenesis of six pore-region residues plus genetic deletion of LHFPL5 and TMIE dissected their distinct contributions to conductance and mechanical coupling; TMC1 was shown to regulate membrane homeostasis through lipid scramblase activity.

    Evidence Cryo-EM of native C. elegans complex; single-channel analysis across six Tmc1 mutants plus Lhfpl5 and Tmie knockouts; annexin-V PS externalization assays in Tmc1/Tmc2 mutant mice

    PMID:35857511 PMID:35921424 PMID:36191207 PMID:36224384

    Open questions at the time
    • No mammalian TMC1 complex structure
    • Lipid scramblase mechanism and its relationship to channel gating unresolved
    • Whether TMIE contributes to the pore directly or via allosteric modulation was debated
  10. 2024 High

    LOXHD1 was identified as a maintenance factor that selectively retains TMC1 (but not TMC2) at the transduction site in mature hair cells, interacting with TMC1, CIB2, LHFPL5, and PCDH15, revealing a previously unknown mechanism for long-term MET complex stability.

    Evidence SUB-immunogold SEM in Loxhd1 mutant mice; co-immunoprecipitation/pulldown of LOXHD1 with multiple MET complex components

    PMID:39256406

    Open questions at the time
    • Structural basis of LOXHD1–TMC1 interaction unknown
    • Whether LOXHD1 is a stoichiometric complex member or a dynamic maintenance factor is unclear
  11. 2025 High

    Structural resolution of the CIB2–TMC1 interface by X-ray crystallography and NMR revealed Ca²⁺-dependent conformational regulation of the complex; full-length mammalian TMC1 was reconstituted as a mechanosensitive channel in heterologous cells with TMIE as a palmitoylation-dependent gating modulator; and a mechanistic pathway from reduced TMC1 Ca²⁺ permeability through decreased PMCA2 density to mitochondrial dysfunction and hair-cell apoptosis was established by conditional genetic rescue.

    Evidence X-ray crystallography and NMR of CIB2–TMC1; heterologous TMC1+TMIE electrophysiology with Fyn-tag; conditional Cre-Lox rescue of Bth allele with PMCA2 immunolabeling and ABR

    PMID:39773557 PMID:39889697 PMID:39999170 PMID:40073458 PMID:40100636

    Open questions at the time
    • Full mammalian TMC1 complex cryo-EM structure at high resolution is still lacking
    • How TMC1 lipid scramblase activity is mechanistically coupled to or independent of ion channel gating remains unresolved
    • Mechanism by which TMC1 Ca²⁺ flux regulates PMCA2 density is not molecularly defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the intact mammalian TMC1 complex with all known partners (TMIE, CIB2, PCDH15, LHFPL5) is needed to understand gating mechanics, and the molecular pathway linking TMC1-mediated Ca²⁺ entry to PMCA2 maintenance and scramblase activation remains to be elucidated.
  • No mammalian TMC1 holo-complex structure
  • Scramblase mechanism and its structural basis in TMC1 unresolved
  • Molecular link between Ca²⁺ permeation and PMCA2 trafficking unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 8 GO:0140299 molecular sensor activity 2
Localization
GO:0005929 cilium 4 GO:0005886 plasma membrane 3
Pathway
R-HSA-9709957 Sensory Perception 6 R-HSA-382551 Transport of small molecules 5
Partners
CIB2CIB3LHFPL5LOXHD1PCDH15TMC2TMIETOMT
Complex memberships
MET channel complex (TMC1/TMIE/CIB2/LHFPL5/PCDH15)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TMC1 is required for normal cochlear hair-cell function; a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse causes loss of auditory responses and hair-cell degeneration. Tmc1 mRNA is expressed specifically in hair cells of the postnatal mouse cochlea and vestibular end organs. Positional cloning, mouse mutant characterization, mRNA expression analysis Nature genetics High 11850618 11850623
2006 Tmc1 is required for functional maturation of both inner and outer hair cells; mutant mice fail to acquire mature K+ currents (BK-type IK,f in IHCs; delayed rectifier IK,n in both types) and show abnormal Ca2+ current and exocytosis, suggesting Tmc1 is involved in trafficking molecules to the plasma membrane or serves as an intracellular regulatory signal for hair cell differentiation. Whole-cell patch-clamp electrophysiology, compound action potential recordings, scanning electron microscopy, in dn/dn and Bth/Bth mouse models The Journal of physiology High 16627570
2013 TMC1 and TMC2 are components of the mechanosensitive ion channel in hair cells; cells expressing Tmc2 had high calcium permeability and large single-channel currents, cells with mutant Tmc1 had reduced calcium permeability and reduced single-channel currents, and cells expressing both showed a broad range of single-channel conductances consistent with heteromeric assemblies, demonstrating TMC1/2 contribute to channel permeation properties. Whole-cell and single-channel current recordings from mouse hair cells expressing Tmc1, Tmc2, or mutant Tmc1 in Tmc1/2 null background Neuron High 23871232
2014 Tip-link protein PCDH15 physically interacts with TMC1 and TMC2; interaction detected by membrane-based yeast two-hybrid screen, confirmed by yeast two-hybrid assays and co-immunoprecipitation between mouse PCDH15-CD3 and TMC1 or TMC2; overexpression of Tmc2a N-terminal fragment caused mislocalization of Pcdh15a in zebrafish hair bundles and reduced mechanosensitive responses. Membrane-based two-hybrid screen, yeast two-hybrid assay, co-immunoprecipitation, zebrafish overexpression with FM dye/microphonic potential functional readout Proceedings of the National Academy of Sciences of the United States of America High 25114259
2015 TMC1 and TMC2 localize to the tips of shorter-row stereocilia at the site of mechanotransduction; tagged TMC1-mCherry and TMC2-AcGFP rescue MET currents and hearing in Tmc1/2 null mice, and both proteins are absent from tips of tallest stereocilia where MET is not detectable, consistent with them being components of the MET channel complex. Transgenic mice expressing fluorescently tagged TMC1/TMC2, electrophysiological rescue of MET currents, immunofluorescence, live imaging Cell reports High 26321635
2015 The Beethoven mutation (M412K) in TMC1 reduces Ca2+ permeability and conductance of the mechanoelectrical transducer channel in outer hair cells, and reduces sensitivity to block by the permeant MET channel blocker dihydrostreptomycin applied from either side of the membrane, placing the mutated residue at or near a negatively charged binding site within the channel permeation pore. Whole-cell patch-clamp in Tmc1Bth/Bth mouse OHCs, dihydrostreptomycin block experiments, Ca2+ permeability measurements The Journal of neuroscience High 26758827
2017 CIB2 physically interacts with TMC1 and TMC2 as shown by co-immunoprecipitation; loss of CIB2 abolishes mechanotransduction in auditory hair cells despite presence of tip links, and deafness-causing CIB2 mutations disrupt TMC1/2 binding, establishing CIB2 as a required component of the MET complex. Knockout and knock-in mouse models, co-immunoprecipitation, electrophysiological MET current recordings Nature communications High 28663585
2017 TOMT (Transmembrane O-methyltransferase) is required for trafficking of Tmc1/2 to the hair bundle; in tomt mutants, Tmc1/2 are excluded from the hair bundle while other MET complex proteins localize normally; mouse TOMT and TMC1 directly interact in HEK293 cells, and this interaction is modulated by His183 in TOMT. Zebrafish tomt mutant analysis, GFP-tagged protein localization in hair bundles, co-immunoprecipitation in HEK293 cells, mutagenesis of TOMT eLife High 28534737
2018 TMC1 forms the pore of the mechanosensory transduction channel; cysteine mutagenesis in transmembrane domains S4–S7 followed by cysteine-modification reagent application in Tmc1/2-null hair cells expressing mutant TMC1 rapidly and irreversibly altered channel permeation properties, and TMC1 assembles as a dimer structurally similar to TMEM16 channels with ten transmembrane domains. Cysteine mutagenesis, MTSET/MTSES modification of expressed TMC1 variants in hair cells of Tmc1/2-null mice, dextran permeation assays, biochemical dimerization assay, structural modeling based on TMEM16 cryo-EM structures Neuron High 30138589
2018 TMC1-dependent MET channels show a tonotopic conductance gradient from cochlear apex to base; the number of TMC1 molecules per stereocilium tip increases ~3-fold from apex to base, as determined by single-molecule photobleaching (~8 TMC1 molecules at apex, ~20 at base), indicating variable numbers of TMC1-containing channels per MET complex that operate cooperatively. Single-channel recordings, single-molecule photobleaching of fluorescently tagged TMC1, immunofluorescence in mice expressing TMC1-mCitrine Nature communications High 29872055
2018 TMC1 structural modeling based on TMEM16 X-ray and cryo-EM structures reveals a large cavity near the protein-lipid interface harboring the Beethoven mutation; hair cells are permeable to 3 kDa dextrans in a TMC1/2-dependent and MET-channel-dependent manner, supporting TMC1 as a large-pore pore-forming subunit. Homology modeling on TMEM16 structures, dextran permeation assay in Tmc1/2 knockout hair cells eLife Medium 30063209
2019 Purified TMC1 (from green sea turtle) and TMC2 (from budgerigar) reconstituted into liposomes exhibit ion channel activity and respond to applied pressure (mechanical stimuli), directly demonstrating that TMC proteins are pore-forming subunits of mechanosensitive ion channels; human hearing-loss mutations in CmTMC1 reduce or abolish channel activity. Heterologous expression in insect cells, protein purification, liposome reconstitution, electrophysiology with pressure application, mutagenesis of hearing-loss residues Neuron High 31761710
2019 TMC1 is required to maintain LHFPL5 (lipoma HMGIC fusion partner-like 5) binding and protein stability; the dominant deafness mutation D572N (D569N in mouse) severely disrupts LHFPL5–TMC1 physical interaction and destabilizes TMC1 expression in hair cells and heterologous systems, as demonstrated by single-molecule pulldown (SiMPull) assay. Microbead-based single-molecule pulldown (SiMPull) assay, heterologous co-expression, immunofluorescence in hair cells Proceedings of the National Academy of Sciences of the United States of America High 33168709
2019 TMC1 provides a background leak conductance distinct from MET channel properties; cysteine substitution in TMC1 identified four amino acids required for the leak conductance; this conductance is graded along the cochlear tonotopic axis and is required for action potential firing in hair cells. Whole-cell patch-clamp in Tmc1 and Tmc2 knockout mouse hair cells, cysteine substitution mutagenesis with functional recording eLife High 31661074
2019 TMIE is required for Tmc1 and Tmc2b to localize to the hair bundle in zebrafish; in tmie mutants Tmc1/2b-GFP fail to reach stereocilia, while overexpression of TMIE enhances Tmc targeting; deletion analysis identified the extracellular region and transmembrane domain of TMIE as critical for both mechanosensitivity and Tmc2b bundle expression. Zebrafish tmie mutant analysis, GFP-tagged Tmc localization, TMIE domain deletion and chimera analysis with functional rescue assays PLoS genetics High 30726219
2019 TMC1 localizes near the tip link (lower end) in outer hair cells of adult mice; TMC1 and LHFPL5 co-localize at stereocilia tips in neonatal hair cells and persist at shorter-row stereocilia tips in adult outer hair cells; in adult inner hair cells, TMC1 is uniformly distributed across tallest and shorter rows while LHFPL5 remains at shorter rows. Immunofluorescence with multiple antibodies, super-resolution microscopy in neonatal and adult mouse hair cells FASEB journal Medium 30808210
2019 Ultrastructural localization by immunogold TEM shows TMC1 is absent from hair bundles at P3, weakly present at P6, increases at P9 with specific stereocilia tip labeling on shorter rows, and is refined to stereocilia tips by P12/P21, coinciding temporally with MET channel localization and LHFPL5 presence. Immunofluorescence and immunogold transmission electron microscopy in cochleae of multiple postnatal ages, including Tmc1-/- negative control Scientific reports Medium 30718571
2019 A Tmc1 D569N mutation reduces MET channel Ca2+ permeability 3-fold and reduces expression of TMC1 at the transduction site (assessed by immunolabeling despite persistent tip links), and reduces maximum MET current amplitude to one-third of wild type without affecting unitary conductance; reduced Ca2+ permeability is proposed as a proximate cause of hair-cell apoptosis. Single-channel recordings, MET current measurements, noise analysis, immunolabeling for TMC1 channel expression in Tmc1 p.D569N mutant mice Proceedings of the National Academy of Sciences of the United States of America High 31548403
2022 Cryo-EM structure of the native C. elegans TMC-1 mechanosensory transduction complex reveals a two-fold symmetric assembly of two TMC-1, two CALM-1 (calmodulin-like), and two TMIE subunits; CALM-1 makes extensive contacts with the cytoplasmic face of TMC-1, TMIE subunits reside on the periphery; the complex deforms the membrane bilayer, suggesting lipid-protein interactions are critical for mechanical force transduction to channel gating. Single-particle cryo-EM, molecular dynamics simulations, native complex isolation from C. elegans Nature High 36224384
2022 Six missense mutations in the purported pore region of mouse TMC1 all reduce MET channel Ca2+ permeability; Tmc1 p.E520Q and p.D528N reduce channel conductance; Tmc1 p.W554L and p.D569N lower channel expression without affecting conductance; LHFPL5 deletion does not affect single-channel conductance but reduces MET working range and half-saturation, suggesting LHFPL5 is part of mechanical coupling between tip-link and MET channel; TMIE deletion reduces single-channel conductance, implying TMIE contributes to the pore. Single-channel analysis, ionic permeability measurements, MET current recordings in Lhfpl5-/- and Tmie-/- knockout mice alongside Tmc1 missense mutant mice Proceedings of the National Academy of Sciences of the United States of America High 36191207
2022 Mutations in TM4 and TM6 helices of TMC1 modify mechanical gating of the transduction current, reducing force sensitivity or shifting open probability and in some cases altering single-channel conductance, indicating TM4 and TM6 are involved in mechanical gating of the transduction channel. Whole-cell electrophysiology in Tmc1/2-null hair cells expressing virally introduced TMC1 variants with targeted mutations in TM4 and TM6, guided by predicted structural models Science advances High 35857511
2022 Inhibition of MET channels, tip-link breakage, or intracellular Ca2+ buffering induces phosphatidylserine externalization, membrane blebbing, and ectosome release in hair cell stereocilia culminating in loss of TMC1; three deafness-causing Tmc1 mutations cause constitutive phosphatidylserine externalization; this membrane homeostasis role requires Tmc1 but not Tmc2, demonstrating TMC1 as a regulator of membrane homeostasis in addition to forming the MET channel pore. Pharmacologic MET inhibition, tip-link breakage, Ca2+ buffering, annexin-V labeling, Tmc1 and Tmc2 knockout mouse analysis, Tmc1 deafness mutation characterization Science advances High 35921424
2024 LOXHD1 is essential for maintaining TMC1 at the tip link in mature auditory hair cells; in Loxhd1 mutant mice, TMC1 mislocalizes away from the tip-link site as shown by SUB-immunogold-SEM, while TMC2 localization is unaffected; LOXHD1 selectively interacts with TMC1, CIB2, LHFPL5, and PCDH15 in pulldown assays. Mouse knockout models, SUB-immunogold scanning electron microscopy, co-immunoprecipitation/pulldown assays Nature communications High 39256406
2025 CIB2 and CIB3 form heteromeric complexes with TMC1 and TMC2 that are integral for MET function; AlphaFold2 models predict CIB proteins simultaneously contact at least two cytoplasmic domains of TMC1/2, validated by NMR spectroscopy of TMC1 fragments with CIB2/3; MD simulations show CIB proteins structurally stabilize TMC dimers to form cation channels; CIB2/3 complexes with TMC1/2 are required for MET in mouse cochlea, vestibular organs, and zebrafish inner ear and lateral line. Co-immunoprecipitation, NMR spectroscopy of TMC1 peptide fragments with CIB2/3, AlphaFold2 modeling, molecular dynamics simulations, mouse and zebrafish mutant analysis with MET current recordings eLife High 39773557
2025 The TMC1-CIB2 complex undergoes a Ca2+-induced conformational change; X-ray crystallography of the mammalian CIB2-TMC1 complex shows Ca2+-bound CIB2 forms a negatively charged surface interacting with a positively charged TMC1 N-terminus; Ca2+ modulates CIB2 interaction with both N-terminal domain and loop 1 of TMC1; disruption of the CIB2 calcium-binding site perturbs MET channel conductivity in ex vivo cochlear explants; dominant TMC1 deafness mutations cluster around the ion pore or CIB2 binding interfaces. X-ray crystallography of CIB2-TMC1 complex, ex vivo mouse organotypic cochlea electrophysiology, pathogenic variant analysis Developmental cell High 39889697
2025 Full-length mouse TMC1 and TMC2 function as mechanosensitive channels when membrane-targeted via a Fyn lipidation tag in heterologous cells; TMIE potently stimulates TMC1/2 channel activity by modulating gating; TMIE palmitoylation at C76/C77 is required for this stimulation; TMC1+TMIE and TMC2+TMIE form 18 pS and 24 pS single channels, respectively, with pharmacological properties similar to native MET channels. Heterologous expression with lipidation tag, whole-cell and single-channel electrophysiology, mechanical stimulation, TMIE deletion and palmitoylation site mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 39999170
2025 TMC1 and TMC2 are necessary for scramblase activity (phosphatidylserine externalization) in auditory hair cells; Tmc1/Tmc2 double knockout mice lack PS externalization; expression of either hTMC1 or hTMC2 restores externalization; a dominant Tmc1 mutation causes constitutive PS externalization while a recessive mutation eliminates it. Annexin-V labeling of PS in live hair cells, pharmacologic MET blockade (benzamil), Tmc1/Tmc2 knockout mice, AAV-mediated rescue with human TMC constructs Hearing research High 40073458
2025 Hair cells in Tmc1 mutants (p.T416K, p.M412K, p.D569N) exhibit early mitochondrial dysfunction and apoptosis; reduced PMCA2 Ca2+ pump density in stereocilia of Tmc1 mutants correlates with reduced MET channel Ca2+ permeability; blocking stereociliary PMCA2 elicits scramblase activity; Cre-Lox excision of the mutant M412K allele at P1 fully preserves hearing and rescues PMCA2 density, establishing a mechanistic link between TMC1 Ca2+ permeability, PMCA2 density, and hair cell apoptosis. Calcein-AM, MitoTracker, Annexin-V, MitoLight labeling; FCCP uncoupler experiments; Cre-Lox conditional allele rescue; stereociliary PMCA2 immunolabeling; ABR testing Proceedings of the National Academy of Sciences of the United States of America High 40100636

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nature genetics 351 11850618
2013 TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 340 23871232
2018 TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells. Neuron 254 30138589
2002 Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nature genetics 223 11850623
2015 TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell reports 154 26321635
2017 CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nature communications 146 28663585
2014 Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proceedings of the National Academy of Sciences of the United States of America 137 25114259
2019 Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders. Nature communications 135 30670701
2019 TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels. Neuron 128 31761710
2013 tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans. Nature 113 23364694
2022 Structures of the TMC-1 complex illuminate mechanosensory transduction. Nature 106 36224384
2006 Tmc1 is necessary for normal functional maturation and survival of inner and outer hair cells in the mouse cochlea. The Journal of physiology 105 16627570
2018 Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins. eLife 98 30063209
2018 Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea. Nature communications 83 29872055
2019 Targeted Allele Suppression Prevents Progressive Hearing Loss in the Mature Murine Model of Human TMC1 Deafness. Molecular therapy : the journal of the American Society of Gene Therapy 71 30686588
2016 Tmc1 Point Mutation Affects Ca2+ Sensitivity and Block by Dihydrostreptomycin of the Mechanoelectrical Transducer Current of Mouse Outer Hair Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 26758827
2016 TMC-1 Mediates Alkaline Sensation in C. elegans through Nociceptive Neurons. Neuron 63 27321925
2020 Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice. Molecular therapy : the journal of the American Society of Gene Therapy 59 33212302
2014 A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family. PloS one 59 24827932
2007 Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan. Clinical genetics 58 17877751
2008 Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11. Clinical genetics 56 18616530
2015 The effects of Tmc1 Beethoven mutation on mechanotransducer channel function in cochlear hair cells. The Journal of general physiology 52 26324676
2009 Mutations in TMC1 contribute significantly to nonsyndromic autosomal recessive sensorineural hearing loss: a report of five novel mutations. International journal of pediatric otorhinolaryngology 52 19187973
2008 TMC1 but not TMC2 is responsible for autosomal recessive nonsyndromic hearing impairment in Tunisian families. Audiology & neuro-otology 52 18259073
2005 Novel sequence variants in the TMC1 gene in Pakistani families with autosomal recessive hearing impairment. Human mutation 52 16134132
2017 Integration of Tmc1/2 into the mechanotransduction complex in zebrafish hair cells is regulated by Transmembrane O-methyltransferase (Tomt). eLife 50 28534737
2014 Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE. PloS one 49 24416283
2019 Subunits of the mechano-electrical transduction channel, Tmc1/2b, require Tmie to localize in zebrafish sensory hair cells. PLoS genetics 47 30726219
2005 Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss. Human mutation 46 16287143
2019 A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells. Proceedings of the National Academy of Sciences of the United States of America 44 31548403
2022 Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing. Science advances 43 35921424
2007 A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1. Clinical genetics 42 17250663
2010 High frequency of the p.R34X mutation in the TMC1 gene associated with nonsyndromic hearing loss is due to founder effects. Genetic testing and molecular biomarkers 41 20373850
2010 Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1. Audiology & neuro-otology 37 21252500
2016 Is TMC1 the Hair Cell Mechanotransducer Channel? Biophysical journal 36 27410728
2006 Multiple quantitative trait loci modify cochlear hair cell degeneration in the Beethoven (Tmc1Bth) mouse model of progressive hearing loss DFNA36. Genetics 35 16648588
2005 Novel TMC1 structural and splice variants associated with congenital nonsyndromic deafness in a Sudanese pedigree. Human mutation 34 15605408
2022 The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells. Proceedings of the National Academy of Sciences of the United States of America 32 36191207
2015 TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment. Nature communications 31 25695879
2012 Identification of three novel hearing loss mouse strains with mutations in the Tmc1 gene. The American journal of pathology 31 22330676
2016 Recessive mutations of TMC1 associated with moderate to severe hearing loss. Neurogenetics 30 26879195
2020 Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding. Proceedings of the National Academy of Sciences of the United States of America 29 33168709
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2013 Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family. PloS one 26 23690975
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2013 A transversion mutation in non-coding exon 3 of the TMC1 gene in two ethnically related Iranian deaf families from different geographical regions; evidence for founder effect. International journal of pediatric otorhinolaryngology 24 23523375
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2025 Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels. eLife 22 39773557
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2017 Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes. Journal of genetics 19 29321360
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2021 Reclassification of a TMC1 synonymous substitution as a variant disrupting splicing regulatory elements associated with recessive hearing loss. European journal of human genetics : EJHG 6 34857896
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