Affinage

TMC1

Transmembrane channel-like protein 1 · UniProt Q8TDI8

Length
760 aa
Mass
87.8 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMC1 is the pore-forming subunit of the mechanoelectrical transduction (MET) channel of inner-ear hair cells, where it converts stereociliary deflection into cation influx that underlies hearing and balance (PMID:11850618, PMID:23871232, PMID:31761710). Originally identified by positional cloning as the gene disrupted in the deafness (dn) and dominant Beethoven (Bth) mouse mutants, TMC1 is required for hair-cell function and survival, and TMC1 point mutations cause both dominant (DFNA36) and recessive deafness (PMID:11850618, PMID:11850623). TMC1 assembles as a dimer alongside the related TMC2 into heteromeric channels whose Ca2+ permeability, single-channel conductance, and mechanical gating are set by residues lining transmembrane helices TM4–TM7, as established by cysteine-accessibility mapping and systematic pore-region mutagenesis (PMID:23871232, PMID:30138589, PMID:36191207, PMID:35857511); reconstitution of purified TMC1 in liposomes confers intrinsic pressure-sensitive channel activity, demonstrating it is itself a pore-forming mechanosensitive channel (PMID:31761710). TMC1 concentrates at the tips of shorter-row stereocilia near the lower end of the tip link as hair cells mature (PMID:26321635, PMID:30718571), where the channel complex is organized through direct physical interactions with the tip-link protein PCDH15 (PMID:25114259), with LHFPL5 (which stabilizes TMC1 and couples tip-link tension to gating) (PMID:33168709, PMID:36191207), with TMIE (which contributes to the pore and stimulates gating via palmitoylation) (PMID:36191207, PMID:39999170), and with CIB2/CIB3 (which bind cytoplasmic TMC1 domains and undergo Ca2+-dependent conformational changes to stabilize the channel) (PMID:28663585, PMID:39773557, PMID:39889697); LOXHD1 anchors mature TMC1 channels at the tip-link site (PMID:39256406), and trafficking of TMC1 to the bundle requires TOMT acting through the Golgi (PMID:28534737). A cryo-EM structure of the native C. elegans TMC-1 complex confirmed a two-fold symmetric assembly of two TMC, two calmodulin-like, and two TMIE subunits that deforms the surrounding bilayer (PMID:36224384). Beyond ion conduction, TMC1 acts as a cholesterol-regulated lipid scramblase driving phosphatidylserine externalization and membrane homeostasis (PMID:35921424, PMID:40631239, PMID:40073458), and loss of TMC1 Ca2+ permeability reduces stereociliary PMCA2 density, triggering mitochondrial dysfunction and hair-cell apoptosis that explains the deafness caused by TMC1 mutations (PMID:40100636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2002 High

    Established that TMC1 is genetically required for hearing, linking the gene to both recessive hair-cell degeneration and dominant progressive deafness before any molecular function was known.

    Evidence Positional cloning of the dn mouse deletion and identification of the Beethoven missense allele with mouse phenotyping

    PMID:11850618 PMID:11850623

    Open questions at the time
    • Molecular function of the protein unknown
    • No biochemical or electrophysiological role assigned
    • Cellular localization within hair cells undefined
  2. 2006 High

    Defined the cellular consequence of TMC1 loss as failed functional maturation of hair cells, raising the question of whether TMC1 acts in trafficking/signaling versus direct conduction.

    Evidence Whole-cell patch-clamp of K+/Ca2+ currents and exocytosis in dn/dn and Bth/Bth mouse hair cells

    PMID:16627570

    Open questions at the time
    • Did not establish TMC1 as an ion channel
    • Mechanism linking TMC1 to current maturation unresolved
  3. 2013 High

    Identified TMC1 and TMC2 as components of the MET channel and showed they shape its permeation, reframing TMC1 from a maturation factor to a conduction subunit.

    Evidence Single-channel and whole-cell recordings in Tmc1/Tmc2 knockout and Beethoven hair cells with viral rescue

    PMID:23871232

    Open questions at the time
    • Did not prove TMC1 forms the pore versus an auxiliary subunit
    • Stoichiometry and channel architecture unknown
  4. 2014 High

    Connected TMC1 to the tip-link apparatus by demonstrating a direct PCDH15 interaction, establishing how mechanical force could reach the channel.

    Evidence Yeast two-hybrid, co-immunoprecipitation, and zebrafish overexpression with microphonic recordings

    PMID:25114259

    Open questions at the time
    • Interaction interface on TMC1 not mapped
    • Whether PCDH15 directly gates the channel unresolved
  5. 2015 High

    Localized functional TMC1/TMC2 to shorter-row stereocilia tips at the site of active MET, tying molecular position to the transduction apparatus.

    Evidence Live imaging and immunofluorescence of tagged and endogenous TMCs with transgenic rescue in null mice

    PMID:26321635

    Open questions at the time
    • Mechanism restricting TMC1 to shorter rows unknown
    • Relationship to tip-link lower end not yet at ultrastructural resolution
  6. 2016 High

    Placed the Beethoven M412K residue within the permeation pore by showing it alters Ca2+ permeability and aminoglycoside block, providing the first residue-level pore evidence.

    Evidence Whole-cell patch-clamp with dihydrostreptomycin block and BAPTA perfusion in Tmc1Bth/Bth OHCs

    PMID:26758827

    Open questions at the time
    • Single residue; full pore lining not defined
    • No structural model of the pore at this stage
  7. 2015 High

    Linked TMC1 Ca2+ permeability to adaptation and to stereociliary CaATPase density, beginning to connect channel function to downstream Ca2+ handling.

    Evidence Single-channel and whole-cell recordings plus PMCA2 immunolabeling in Beethoven OHCs

    PMID:26324676

    Open questions at the time
    • Causal direction between Ca2+ influx and PMCA2 density not established
    • Adaptation mechanism not molecularly defined
  8. 2017 High

    Identified CIB2 and TOMT as direct TMC1 partners governing channel assembly and trafficking, distinguishing bundle-targeting from in-bundle function.

    Evidence Co-IP, Cib2 and tomt mouse/zebrafish knockouts with MET recordings, SEM, and Golgi localization of TOMT

    PMID:28534737 PMID:28663585

    Open questions at the time
    • How CIB2 contributes to gating versus stabilization unresolved
    • TOMT enzymatic role in trafficking unclear
  9. 2018 High

    Demonstrated TMC1 forms the permeation pathway and assembles as a dimer with a TMEM16-like fold, resolving the long-standing pore-versus-auxiliary question.

    Evidence Cysteine-accessibility mutagenesis with MTSEA in null+rescue hair cells, dextran permeation, dimerization biochemistry, and TMEM16 homology modeling

    PMID:30063209 PMID:30138589

    Open questions at the time
    • Homology model not an experimental structure
    • Number of pores per dimeric complex unresolved
  10. 2018 High

    Showed multiple TMC1 molecules per MET complex scale with a tonotopic conductance gradient, indicating cooperative channel organization along the cochlea.

    Evidence Single-channel recording and single-molecule photobleaching of tagged TMCs in transgenic mice

    PMID:29872055

    Open questions at the time
    • How molecule number sets conductance mechanistically unknown
    • Whether all copies are conductive unresolved
  11. 2019 High

    Mapped the accessory architecture of the complex—TMIE bundle-targeting, LHFPL5 stabilization, ultrastructural tip-link position, and a leak conductance—building a multi-protein model of MET organization.

    Evidence Zebrafish tmie mutants with domain swaps, SiMPull/Co-IP for LHFPL5, immunogold EM, and cysteine mutagenesis of leak residues

    PMID:30718571 PMID:30726219 PMID:30808210 PMID:31649296 PMID:31661074 PMID:33168709

    Open questions at the time
    • Leak conductance channel identity relative to MET unresolved [#16]
    • N-terminal retention signal significance in native cells untested [#19]
    • How each partner contributes to gating versus stability incompletely separated
  12. 2019 High

    Showed TMC1 is intrinsically mechanosensitive by reconstituting purified protein in liposomes, proving pore-forming activity independent of hair-cell-specific partners.

    Evidence Purification and liposome reconstitution of CmTMC1/MuTMC2 with pressure-applied electrophysiology and disease-mutation analysis

    PMID:31761710

    Open questions at the time
    • Used non-mammalian orthologs
    • Native gating force-transfer pathway not reconstituted
  13. 2019 High

    Linked the dominant D569N/D572N mutation to reduced Ca2+ permeability, reduced TMC1 retention via impaired LHFPL5 binding, and apoptosis, connecting a specific allele to a cell-death mechanism.

    Evidence MET current recording, single-channel noise analysis, and immunolabeling in Tmc1 D569N mice; comparative adaptation analysis across genotypes

    PMID:31548403 PMID:31633194

    Open questions at the time
    • Whether apoptosis is driven by Ca2+ loss alone unresolved
    • Adaptation linkage to Ca2+ influx versus channel complex not fully separated [#21]
  14. 2022 High

    Delivered the first near-atomic structure of a native TMC mechanotransduction complex, defining a dimeric TMC + calmodulin-like + TMIE assembly that deforms the membrane.

    Evidence Single-particle cryo-EM of native C. elegans TMC-1 complex with MD simulations

    PMID:36224384

    Open questions at the time
    • Invertebrate complex; vertebrate-specific subunits like LHFPL5/PCDH15 not in this structure
    • Gating-state transitions not captured
  15. 2022 High

    Systematically defined the TMC1 pore by mutagenesis of TM4/TM6 and pore residues, separating effects on Ca2+ permeability, conductance, expression, and mechanical gating, and assigning TMIE a pore contribution.

    Evidence Single-channel recordings and ionic selectivity measurements across many point mutations and Lhfpl5-/-/Tmie-/- mice

    PMID:33824189 PMID:35857511 PMID:36191207

    Open questions at the time
    • Precise gating conformational pathway not directly observed
    • How TMIE residues line the pore structurally unresolved
  16. 2022 High

    Revealed a non-conductive TMC1 role in membrane homeostasis, showing MET inhibition triggers TMC1-dependent phosphatidylserine externalization and TMC1 loss via ectosome release.

    Evidence Annexin-V labeling with pharmacological MET inhibition, tip-link breakage, BAPTA, and Tmc1 vs Tmc2 knockout comparison

    PMID:35921424

    Open questions at the time
    • Molecular basis of PS externalization not yet defined at this stage
    • Whether this is a separate activity from conduction unresolved
  17. 2025 High

    Defined the CIB2/CIB3–TMC1 interface structurally and as a Ca2+-responsive stabilizer of the channel, integrating a cytoplasmic regulatory module into the MET complex.

    Evidence Co-IP, mouse/zebrafish knockouts, NMR of TMC1 fragments with CIB proteins, AlphaFold2 modeling, MD simulations, and ex vivo organotypic cochlea recording

    PMID:39773557 PMID:39889697

    Open questions at the time
    • Conformational change mechanism details limited [#29]
    • How CIB Ca2+ sensing couples to gating versus stability not fully resolved
  18. 2025 High

    Reconstituted mammalian TMC1/TMC2 mechanosensitivity in heterologous cells and showed TMIE stimulates gating via palmitoylation, providing a tractable mammalian channel system.

    Evidence Fyn-lipidation-tagged heterologous expression with single-channel recording and TMIE mutagenesis

    PMID:39999170

    Open questions at the time
    • Force-delivery pathway from tip link not reconstituted
    • Role of other native partners in this system untested
  19. 2025 High

    Established TMC1 as a cholesterol-regulated lipid scramblase and tied scramblase activity to PS externalization and the death pathway, unifying the conduction and membrane-homeostasis roles.

    Evidence Proteoliposome scramblase assays with MD simulations and annexin-V labeling; genetic Tmc1/Tmc2 knockout and human-TMC rescue with PMCA2 quantification, apoptosis markers, and conditional mutant-exon excision

    PMID:40073458 PMID:40100636 PMID:40631239

    Open questions at the time
    • Scramblase structural mechanism not directly resolved
    • Scramblase preprint not yet peer-reviewed [#31]
    • How conduction and scramblase activities are switched in vivo unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A vertebrate cryo-EM structure capturing TMC1 in defined gating states with its full native partner set (PCDH15, LHFPL5, TMIE, CIB2, LOXHD1) and resolving how the pore conducts cations versus how it scrambles lipids remains the central open question.
  • No experimental vertebrate TMC1 structure in open/closed states
  • Structural basis distinguishing conductive from scramblase conformations unknown
  • How force transmitted from tip link gates the pore not directly visualized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0016740 transferase activity 3 GO:0140299 molecular sensor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9709957 Sensory Perception 2
Partners
CIB2CIB3LHFPL5LOXHD1PCDH15TMC2TMIETOMT
Complex memberships
MET (mechanoelectrical transduction) channel complexTMC-CALM-TMIE complexTMC1-CIB2/CIB3 complexTMC1-TMC2 heteromeric channel

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TMC1 is expressed in cochlear and vestibular hair cells and is required for normal function of cochlear hair cells; a 1.6-kb genomic deletion encompassing exon 14 causes loss of auditory responses and hair-cell degeneration in the deafness (dn) mouse mutant. Positional cloning, mouse genetics (dn mutant), in situ hybridization/expression analysis Nature genetics High 11850618
2002 The Beethoven (Bth) mouse carries a missense mutation in Tmc1 and models dominant progressive hearing loss DFNA36, establishing that Tmc1 point mutations are sufficient to cause dominant deafness. Mouse mutant phenotyping, Sanger sequencing, genetic mapping Nature genetics High 11850623
2006 Tmc1 is required for functional maturation of cochlear inner and outer hair cells: dn/dn and Bth/Bth mutants fail to acquire mature K+ currents (BK-type IK,f in IHCs, delayed-rectifier IK,n in both cell types) and show abnormal Ca2+ current and exocytosis, suggesting Tmc1 is involved in trafficking or intracellular signaling for hair cell differentiation. Whole-cell patch-clamp electrophysiology in dn/dn and Bth/Bth mouse hair cells, capacitance measurements of exocytosis The Journal of physiology High 16627570
2013 TMC1 and TMC2 are components of the mechanosensitive transduction channel in hair cells: cells expressing Tmc2 had high Ca2+ permeability and large single-channel currents; cells with mutant Tmc1 (Beethoven) had reduced Ca2+ permeability and reduced single-channel currents; cells expressing both showed a range of conductances consistent with heteromeric assemblies. Whole-cell and single-channel patch-clamp recordings in Tmc1/Tmc2 knockout and mutant mouse hair cells with viral rescue Neuron High 23871232
2014 PCDH15 (tip-link protein protocadherin 15) physically interacts with TMC1 and TMC2; this interaction depends on the common cytoplasmic region of PCDH15 CD1/CD3 isoforms and is conserved between zebrafish and mouse orthologs. Overexpression of the Tmc2a N-terminus mislocalizes Pcdh15a and reduces mechanosensitive responses in zebrafish hair cells. Membrane-based yeast two-hybrid screen, yeast two-hybrid assay, co-immunoprecipitation, zebrafish overexpression with functional assay (microphonic potentials) Proceedings of the National Academy of Sciences of the United States of America High 25114259
2015 TMC1-mCherry and TMC2-AcGFP localize along immature stereocilia but concentrate predominantly at stereocilia tips as hair cells mature, and are absent from tips of the tallest stereocilia where MET activity is absent. Tagged proteins functionally rescued MET currents and hearing in Tmc1/Tmc2-null mice. Live-cell imaging of fluorescent-tagged TMC proteins in transgenic mice, transgenic rescue of MET currents and ABR thresholds, immunofluorescence of endogenous proteins Cell reports High 26321635
2016 The Tmc1 Beethoven M412K point mutation reduces Ca2+ permeability and conductance of the MET channel in outer hair cells and reduces channel sensitivity to block by dihydrostreptomycin applied extracellularly or intracellularly, placing the mutated residue at or near a negatively charged binding site within the channel permeation pore. Whole-cell patch-clamp in Tmc1Bth/Bth OHCs, dihydrostreptomycin block experiments, BAPTA intracellular perfusion The Journal of neuroscience High 26758827
2015 The Beethoven M412K mutation in TMC1 reduces Ca2+-dependent adaptation of the MET channel; outer hair cells show reduced shifts in current-displacement relationship for adapting steps or after lowering extracellular Ca2+, and decreased density of stereociliary CaATPase pumps, attributing impaired adaptation to reduced Ca2+ influx through the channel. Single-channel and whole-cell recordings in Beethoven OHCs, immunolabeling of PMCA2, Ca2+ manipulation experiments The Journal of general physiology High 26324676
2017 CIB2 physically binds to TMC1 and TMC2 and is required for normal mechanotransduction in auditory hair cells; deafness-causing CIB2 mutations disrupt this interaction. Loss of CIB2 causes absence of MET despite intact tip links and causes overgrowth of shorter-row stereocilia. Co-immunoprecipitation, mouse knockouts (Cib2-null and Cib2 deafness-mutation knock-in), electrophysiological recording of MET currents, scanning electron microscopy Nature communications High 28663585
2017 TOMT/LRTOMT directly interacts with TMC1 in HEK293 cells and is required for trafficking of TMC1/2 to the hair bundle in zebrafish; in tomt mutants, Tmc1/2 are excluded from the bundle while other MET complex proteins localize normally. TOMT is enriched in the Golgi, suggesting it regulates TMC trafficking through the secretory pathway. Co-immunoprecipitation in HEK293 cells, zebrafish tomt mutant analysis, GFP-tagged Tmc localization by live imaging, site-directed mutagenesis of TOMT His183 eLife High 28534737
2018 TMC1 forms the permeation pathway of the MET channel: cysteine-modification reagents applied to hair cells expressing cysteine-substituted TMC1 rapidly and irreversibly altered MET permeation properties; biochemical evidence shows TMC1 assembles as a dimer; structural modeling identifies TMC1 similarity to TMEM16 channels with transmembrane domains S4–S7 lining the pore. Hair cells are permeable to 3 kDa dextrans in a TMC1/2-dependent manner. Cysteine mutagenesis + MTSEA modification in hair cells of Tmc1/2-null mice with viral rescue, dextran permeation assay, biochemical dimerization assay, structural homology modeling Neuron High 30138589
2018 TMC1 structural modeling based on TMEM16 X-ray/cryo-EM structures reveals a large cavity near the protein-lipid interface harboring the Beethoven mutation site, consistent with this region being a permeation pathway. Hair cell dextran permeation requires TMC1/2 and functional MET channels. Homology modeling using TMEM16 structures, dextran permeation assay in Tmc1/Tmc2 knockout hair cells eLife Medium 30063209
2018 TMC1-dependent MET channels show a tonotopic apex-to-base conductance gradient in outer hair cells, with a 3-fold increase in TMC1 molecules per stereocilium tip from apex to base. Single-molecule photobleaching indicates ~8 TMC1 molecules at the apex and ~20 at the base per MET complex, suggesting multiple TMC1 molecules per channel operating cooperatively. Single-channel recordings, single-molecule photobleaching of fluorescent-tagged TMCs in transgenic mice, immunofluorescence quantification Nature communications High 29872055
2019 Purified and reconstituted CmTMC1 (green sea turtle) and MuTMC2 (budgerigar) proteins in liposomes possess intrinsic ion channel activity and respond to applied mechanical pressure (membrane tension), demonstrating that TMC proteins are pore-forming mechanosensitive channels without requirement for other hair-cell-specific proteins. CmTMC1 mutants corresponding to human hearing-loss mutations show reduced or absent channel activity. Heterologous expression in insect cells, protein purification, liposome reconstitution, electrophysiology of proteoliposomes with and without pressure, mutagenesis Neuron High 31761710
2019 TMIE is required for targeting and stabilizing TMC1 and TMC2 to hair bundle stereocilia in zebrafish; in tmie mutants, GFP-tagged Tmc1 and Tmc2b fail to target to the bundle, while overexpression of Tmie strongly enhances Tmc bundle targeting. The extracellular region and transmembrane domain of Tmie are required for both mechanosensitivity and Tmc bundle expression. Zebrafish tmie mutant analysis, GFP-tagged Tmc localization, Tmie domain deletion/chimera rescue experiments, mechanosensitivity assay PLoS genetics High 30726219
2019 The dominant TMC1 D572N mutation (D569N in mouse) destabilizes TMC1 expression by disrupting physical interaction with LHFPL5; LHFPL5 physically interacts with and stabilizes TMC1 in heterologous systems and in hair cell soma and bundle. This identifies a direct TMC1–LHFPL5 interaction as part of the mechanotransduction complex organization. Microbead-based single-molecule pulldown (SiMPull) assay, co-immunoprecipitation, immunolabeling 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 in cochlear hair cells distinct from MET channel currents; four amino acids identified by cysteine substitution are required for this leak conductance, which is graded tonotopically and is required for action potential firing in immature hair cells. Whole-cell patch-clamp in Tmc1-knockout and rescue hair cells, cysteine substitution mutagenesis, tonotopic mapping of conductance eLife Medium 31661074
2019 TMC1 localizes at stereocilia tips in neonatal outer hair cells (predominantly shorter rows) and adult outer hair cells, but in adult inner hair cells TMC1 distributes uniformly in both tallest and shorter rows. LHFPL5 co-localizes with TMC1 and persists in the hair bundle after P7. Immunofluorescence with multiple antibodies in neonatal and adult mouse hair cells, confocal microscopy FASEB journal Medium 30808210
2019 TMC1 ultrastructurally localizes near the tip link lower end at stereocilia tips from P9 onwards, coinciding with LHFPL5 acquisition; no labeling at P3 and weak labeling without tip specificity at P6. Tmc1-null mice showed no labeling, confirming antibody specificity. Immunogold transmission electron microscopy with quantification across developmental stages (P3–P21) in wild-type and Tmc1-null mice Scientific reports High 30718571
2019 An uncharacterized region within TMC1 N-terminus (amino acids 138–168) causes intracellular retention and precludes plasma membrane trafficking in heterologous cells; alanine/serine substitutions of residues within this region partially relieve retention. AQP3-GFP fusion reporter assay in HEK293 cells, N-terminal fragment tagging, alanine/serine scanning mutagenesis Scientific reports Medium 31649296
2019 The Tmc1 D569N mutation (homologous to human dominant DFNA36 D572N) reduces MET channel Ca2+ permeability 3-fold and reduces TMC1 expression at the transduction site (assessed by immunolabeling) despite persistent tip links, while unitary conductance is unaffected; reduced Ca2+ permeability correlates with hair-cell apoptosis. Whole-cell MET current recording, single-channel noise analysis, immunolabeling in Tmc1 D569N mice Proceedings of the National Academy of Sciences of the United States of America High 31548403
2019 The adaptation of MET channels is faster and more complete in TMC1-containing than TMC2-containing channels; the TMC1 D569N mutation reduces resting open probability and Ca2+ permeability but improves adaptation, suggesting adaptation is tied to the TMC1 channel complex and not simply to Ca2+ influx magnitude. Whole-cell patch-clamp recording of MET adaptation in Tmc2-/- vs Tmc1-/- mice, Tmc1 D569N mutant characterization The Journal of physiology Medium 31633194
2022 Cryo-EM structure of the native C. elegans TMC-1 mechanosensory transduction complex reveals a two-fold symmetric assembly composed of two TMC-1 subunits, two CALM-1 (calmodulin-like) subunits, and two TMIE subunits; CALM-1 makes extensive contacts with the cytoplasmic face of TMC-1, while TMIE subunits reside peripherally. A subset of complexes includes an arrestin-like protein (ARRD-6) bound to CALM-1. MD simulations show the complex deforms the membrane bilayer, suggesting lipid-protein interactions are critical for force transduction. Single-particle cryo-EM structure determination, molecular dynamics simulations, native complex isolation from C. elegans Nature High 36224384
2022 Six missense mutations in the TMC1 pore region (E520Q, D528N, W554L, D569N, M412K, T416K) all reduce MET channel Ca2+ permeability; E520Q and D528N reduce channel conductance; W554L and D569N lower channel expression without affecting conductance; M412K and T416K reduce only Ca2+ permeability. In Lhfpl5 and Tmie knockout mice, residual MET channels can still be gated; TMIE knockout reduces single-channel conductance, implying TMIE contributes to the pore; LHFPL5 loss shifts the working range of MET, suggesting LHFPL5 couples tip-link to channel. Single-channel recordings and ionic permeability measurements in mice with six defined pore-region point mutations; Lhfpl5-/- and Tmie-/- analysis Proceedings of the National Academy of Sciences of the United States of America High 36191207
2022 Inhibition of MET channels, tip-link breakage, or intracellular Ca2+ buffering induces phosphatidylserine externalization, membrane blebbing, and ectosome release at hair cell stereocilia, leading to TMC1 loss. This membrane homeostasis response requires Tmc1 but not Tmc2, and three deafness-causing Tmc1 mutations cause constitutive phosphatidylserine externalization correlating with deafness severity. Annexin-V labeling in live hair cells, pharmacological MET inhibition, tip-link breakage, BAPTA perfusion, Tmc1/Tmc2 knockout comparison Science advances High 35921424
2022 Mutations within the pore-lining TM4 and TM6 helices of TMC1 modify mechanical gating of MET channels, reducing force sensitivity or shifting open probability, with some also changing single-channel conductance, supporting a model where TM4 and TM6 conformational changes underlie mechanical gating. Whole-cell electrophysiology in Tmc1/2-null mice with virally introduced TMC1 variants (12 mutations), predicted structural models Science advances High 35857511
2021 Human TMC1 T422K (mouse T416K) dominant mutation causes deafness with decreased MET channel Ca2+ permeability and resting open probability but no change in single-channel conductance or expression. Recessive mutations p.W554L and p.D569N reduce channel numbers at stereocilia tips (impaired LHFPL5 binding); p.D528N substantially reduces conductance and DHS block, placing D528 within the pore's narrowest region. Two deafness mechanisms proposed: reduced Ca2+ permeability (common to all) and reduced resting open probability (confined to dominant mutations). Single-channel recordings and MET current analysis in four new Tmc1 point-mutation mouse lines, DHS block experiments The Journal of neuroscience High 33824189
2024 LOXHD1 is essential for maintaining TMC1 (but not TMC2) at the tip-link site in auditory hair cells; without LOXHD1, TMC1 mislocalizes from stereocilia tips. LOXHD1 selectively interacts with TMC1, CIB2, LHFPL5, and PCDH15, defining it as a component that anchors the mature TMC1-driven MET channel complex to the tip link. Mouse Loxhd1 knockout, SUB-immunogold SEM localization of TMC1, co-immunoprecipitation of LOXHD1 with TMC1/CIB2/LHFPL5/PCDH15 Nature communications High 39256406
2025 CIB2 and CIB3 form heteromeric complexes with TMC1 and TMC2 and are integral for MET function in mouse cochlea, vestibular end organs, and zebrafish inner ear/lateral line. AlphaFold2 models validated by NMR spectroscopy show CIB proteins simultaneously interact with at least two cytoplasmic domains of TMC1/2. Molecular dynamics simulations indicate CIB proteins structurally stabilize TMC1/2 to form cation channels. Co-immunoprecipitation, mouse and zebrafish knockout electrophysiology, NMR spectroscopy of TMC1 fragments with CIB2/CIB3, AlphaFold2 structural modeling, molecular dynamics simulations eLife High 39773557
2025 TMC1-CIB2 complex undergoes a Ca2+-induced conformational change; a vertebrate-specific binding site on TMC1 interacts with apo-CIB2, and disruption of CIB2's calcium-binding site perturbs MET channel conductivity in an ex vivo organotypic cochlea model. Dominant TMC1 mutations cluster around the putative ion pore or at TMC1-CIB2 binding interfaces. Structural analysis of TMC1-CIB2 interaction, ex vivo mouse organotypic cochlea electrophysiology, systematic variant mapping Developmental cell Medium 39889697
2025 Mouse TMC1 and TMC2, when targeted to the plasma membrane via a Fyn lipidation tag in heterologous cells, function as mechanosensitive channels without other hair-cell-specific proteins. Mouse TMIE potently stimulates TMC1/2 channel activity by modulating gating; palmitoylation of TMIE C76/C77 is required for this stimulation. mTMC1+mTMIE and mTMC2+mTMIE form 18 pS and 24 pS single channels, respectively, with biophysical properties similar to native MET channels. Heterologous expression with Fyn lipidation tag in cell lines, whole-cell and single-channel patch-clamp, TMIE mutagenesis (palmitoylation sites, N-terminal deletion) Proceedings of the National Academy of Sciences of the United States of America High 39999170
2025 TMC1 (and TMC2) function as cholesterol-regulated lipid scramblases; purified proteins reconstituted in proteoliposomes facilitate phospholipid translocation across membrane bilayers. Scramblase activity is tuned by cholesterol and enhanced by deafness-causing TMC1 mutations. This scramblase activity correlates with TMC1-dependent phosphatidylserine externalization and membrane blebbing in murine auditory hair cells. Proteoliposome reconstitution scramblase assay, molecular dynamics simulations, annexin-V labeling in hair cells with deafness mutations bioRxivpreprint Medium 40631239
2025 TMC1 and TMC2 are necessary for scramblase activity (phosphatidylserine externalization) in auditory hair cells; Tmc1/Tmc2 knockout and Tmie mutant mice lack PS externalization. A dominant Tmc1 mutation evokes constitutive PS externalization while a recessive mutation eliminates it. Exogenous hTMC1 or hTMC2 restores PS externalization in Tmc1/Tmc2 knockout mice. Annexin-V labeling in live hair cells, Tmc1/Tmc2 knockout and rescue with exogenous human TMCs, benzamil pharmacological block, Tmie mutant analysis Hearing research High 40073458
2025 Reduced density of stereociliary PMCA2 Ca2+ pump in Tmc1 mutants (M412K, D569N, T416K) correlates with reduced MET channel Ca2+ permeability and promotes hair cell apoptosis; blocking PMCA2 elicits scramblase activity, and Cre-Lox excision of the M412K exon at P1 preserves hearing and restores PMCA2 density, establishing a causal link between TMC1 Ca2+ permeability, PMCA2 expression, and hair cell survival. PMCA2 immunolabeling quantification, Calcein-AM/MitoTracker/Annexin-V apoptosis assays, PMCA2 pharmacological block, conditional Cre-Lox excision of mutant exon, ABR thresholds 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 355 11850618
2013 TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 344 23871232
2018 TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells. Neuron 257 30138589
2002 Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nature genetics 224 11850623
2015 TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell reports 155 26321635
2017 CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nature communications 149 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 138 25114259
2019 Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders. Nature communications 136 30670701
2019 TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels. Neuron 130 31761710
2013 tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans. Nature 116 23364694
2022 Structures of the TMC-1 complex illuminate mechanosensory transduction. Nature 112 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 100 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 64 26758827
2016 TMC-1 Mediates Alkaline Sensation in C. elegans through Nociceptive Neurons. Neuron 64 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 60 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
2022 Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing. Science advances 47 35921424
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
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 42 20373850
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 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 33 36191207
2012 Identification of three novel hearing loss mouse strains with mutations in the Tmc1 gene. The American journal of pathology 32 22330676
2016 Recessive mutations of TMC1 associated with moderate to severe hearing loss. Neurogenetics 31 26879195
2015 TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment. Nature communications 31 25695879
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
2010 Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population. The Annals of otology, rhinology, and laryngology 29 21250555
2021 New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 33824189
2020 Disruption of tmc1/2a/2b Genes in Zebrafish Reveals Subunit Requirements in Subtypes of Inner Ear Hair Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 32371604
1998 Identification and mutation analysis of a cochlear-expressed, zinc finger protein gene at the DFNB7/11 and dn hearing-loss loci on human chromosome 9q and mouse chromosome 19. Gene 27 9758550
2022 Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth transmembrane helices. Science advances 26 35857511
2022 Optimized AAV Vectors for TMC1 Gene Therapy in a Humanized Mouse Model of DFNB7/11. Biomolecules 26 35883470
2013 Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family. PloS one 26 23690975
2019 TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of auditory hair cells in mice. eLife 25 31661074
2018 Tmc2 expression partially restores auditory function in a mouse model of DFNB7/B11 deafness caused by loss of Tmc1 function. Scientific reports 25 30108230
2018 Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1. Scientific reports 25 30108254
2014 Mutations of TMC1 cause deafness by disrupting mechanoelectrical transduction. Auris, nasus, larynx 25 24933710
2019 Localization of TMC1 and LHFPL5 in auditory hair cells in neonatal and adult mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 30808210
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
2004 Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 24 15354000
1996 TMC-1 A, B, C and D, new antibiotics of the manumycin group produced by Streptomyces sp. Taxonomy, production, isolation, physico-chemical properties, structure elucidation and biological properties. The Journal of antibiotics 24 9031666
2025 Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels. eLife 23 39773557
2000 Refining the DFNB7-DFNB11 deafness locus using intragenic polymorphisms in a novel gene, TMEM2. Gene 22 10767548
2018 Identification of four TMC1 variations in different Chinese families with hereditary hearing loss. Molecular genetics & genomic medicine 21 29654653
2015 A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family. Gene 20 26226225
2019 The contribution of TMC1 to adaptation of mechanoelectrical transduction channels in cochlear outer hair cells. The Journal of physiology 19 31633194
2017 Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes. Journal of genetics 19 29321360
2019 Identification of TMC1 as a relatively common cause for nonsyndromic hearing loss in the Saudi population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 17 31854501
2019 Ultrastructural localization of the likely mechanoelectrical transduction channel protein, transmembrane-like channel 1 (TMC1) during development of cochlear hair cells. Scientific reports 16 30718571
2009 Amino acid 572 in TMC1: hot spot or critical functional residue for dominant mutations causing hearing impairment. Journal of human genetics 16 19180119
2021 Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss. Human genetics 13 34523024
2020 Tmc proteins are essential for zebrafish hearing where Tmc1 is not obligatory. Human molecular genetics 13 32167554
2015 Targeted gene capture and massively parallel sequencing identify TMC1 as the causative gene in a six-generation Chinese family with autosomal dominant hearing loss. American journal of medical genetics. Part A 13 26079994
2024 LOXHD1 is indispensable for maintaining TMC1 auditory mechanosensitive channels at the site of force transmission. Nature communications 12 39256406
2022 Mutation-agnostic RNA interference with engineered replacement rescues Tmc1-related hearing loss. Life science alliance 12 36574989
2016 Tmc1 Is a Dynamically Regulated Effector of the Rpn4 Proteotoxic Stress Response. The Journal of biological chemistry 12 27226598
2016 Exome sequencing identifies a mutation in TMC1 as a novel cause of autosomal recessive nonsyndromic hearing loss. Journal of translational medicine 11 26822030
2025 Mammalian TMC1 or 2 are necessary for scramblase activity in auditory hair cells. Hearing research 10 40073458
2019 Publisher Correction: Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders. Nature communications 10 30737404
2024 Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels. bioRxiv : the preprint server for biology 9 37398045
2025 Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE. Proceedings of the National Academy of Sciences of the United States of America 8 39999170
2023 Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions. BMC medical genomics 8 38066485
2019 An uncharacterized region within the N-terminus of mouse TMC1 precludes trafficking to plasma membrane in a heterologous cell line. Scientific reports 8 31649296
2014 Autosomal recessive non-syndromic hearing loss is caused by novel compound heterozygous mutations in TMC1 from a Tibetan Chinese family. International journal of pediatric otorhinolaryngology 8 25458163
1997 Construction of P1-derived artificial chromosome and yeast artificial chromosome contigs encompassing the DFNB7 and DFNB11 region of chromosome 9q13-21. Genome research 8 9314493
2025 Mechano-electrical transduction components TMC1-CIB2 undergo a Ca2+-induced conformational change linked to hearing loss. Developmental cell 7 39889697
2025 TMC1 and TMC2 function as the mechano-electrical transduction ion channel in hearing. Current opinion in neurobiology 7 40280017
2025 Hair cell apoptosis and deafness in Tmc1 mutations. Proceedings of the National Academy of Sciences of the United States of America 6 40100636
2022 Generation of a gene corrected human isogenic iPSC line (CPGHi001-A-1) from a hearing loss patient with the TMC1 p.M418K mutation using CRISPR/Cas9. Stem cell research 6 35247837
2022 Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants. Journal of clinical medicine 6 35407445
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
2020 Generation of a human induced pluripotent stem cell line (CPGHi001-A) from a hearing loss patient with the TMC1 p.M418K mutation. Stem cell research 6 33217648
2020 Auditory Outcome after Cochlear Implantation in Children with DFNB7/11 Caused by Pathogenic Variants in TMC1 Gene. Audiology & neuro-otology 6 33352559
2019 Next-generation sequencing reveals a novel pathological mutation in the TMC1 gene causing autosomal recessive non-syndromic hearing loss in an Iranian kindred. International journal of pediatric otorhinolaryngology 6 31176026
2017 Identification of a novel homozygous mutation in transmembrane channel like 1 (TMC1) gene, one of the second-tier hearing loss genes after GJB2 in India. The Indian journal of medical research 6 28862181
2017 Mutation spectra and founder effect of TMC1 in patients with non-syndromic deafness in Xiamen area, China. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 6 29533536
2015 A TMC1 (transmembrane channel-like 1) mutation (p.S320R) in a Polish family with hearing impairment. Journal of applied genetics 6 25560804
2014 Allelic heterogeneity among Iranian DFNB7/11 families: report of a new Iranian deaf family with TMC1 mutation identified by next-generation sequencing. Acta oto-laryngologica 6 25423259
2020 Novel homozygous variants in the TMC1 and CDH23 genes cause autosomal recessive nonsyndromic hearing loss. Molecular genetics & genomic medicine 5 33205915
2019 KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity. Journal of cellular physiology 5 30613966
2021 The Caenorhabditis elegans tmc-1 is involved in egg-laying inhibition in response to harsh touch. microPublication biology 4 34414364
2004 Establishment and characterization of a human gastric carcinoma cell line TMC-1. Cells, tissues, organs 4 15237194
2025 TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells. bioRxiv : the preprint server for biology 3 40631239
2024 Genetic correction of induced pluripotent stem cells from a DFNA36 patient results in morphologic and functional recovery of derived hair cell-like cells. Stem cell research & therapy 3 38167128

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