{"gene":"TECTB","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2010,"finding":"TECTB is required for normal tectorial membrane (TM) travelling wave propagation: loss of TECTB (Tectb−/− mice) reduces the spatial extent and propagation velocity of TM travelling waves, which decreases the spread of excitation (increasing frequency selectivity) and reduces the number of hair cells that effectively couple energy to the basilar membrane (reducing sensitivity).","method":"Tectb knockout mouse model; measurement of TM travelling wave spatial extent and propagation velocity; auditory functional testing","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout model with direct mechanical measurements of TM wave properties linked to defined cochlear functional phenotypes, two orthogonal methods (wave mechanics + hearing thresholds/tuning)","pmids":["20981024"],"is_preprint":false},{"year":2008,"finding":"TECTB requires interaction with alpha-tectorin (TECTA) for its incorporation into the tectorial membrane striated-sheet matrix. In Tecta(A349D/A349D) mice, mutated TECTA is incorporated into the TM but cannot interact with TECTB (or otogelin), resulting in a TM that is deficient in TECTB, lacks a striated-sheet matrix, and is detached from the organ of Corti.","method":"Spontaneous missense knock-in mouse model (Tecta A349D); immunohistochemistry; electron microscopy; protein detection in TM","journal":"Journal of the Association for Research in Otolaryngology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with protein-level readout using multiple histological methods; single lab but orthogonal approaches (EM + immunostaining)","pmids":["18452040"],"is_preprint":false},{"year":2014,"finding":"TECTB interacts with CEACAM16. Loss of CEACAM16 reduces TECTB levels in the TM and abolishes development of the striated-sheet matrix and Hensen's stripe, indicating CEACAM16 stabilizes interactions between TECTA and TECTB within the TM extracellular matrix.","method":"Ceacam16 null mouse model; protein interaction assay (Co-IP/pulldown implied by 'interact'); immunohistochemistry; electron microscopy of TM structure","journal":"The Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null mouse model combined with protein-level interaction evidence and structural TM analysis; single lab, multiple orthogonal methods","pmids":["25080593"],"is_preprint":false},{"year":2019,"finding":"TECTB contributes to the anisotropic mechanical properties of the tectorial membrane. Tectb−/− mice show significantly reduced TM stiffness in shear and in the transverse direction (perpendicular to collagen fibers) but no decrease in stiffness along the fiber direction, making the mutant TM significantly more anisotropic across audio frequencies.","method":"Isolated TM mechanical measurements using harmonic radial excitation, longitudinal displacement imaging, and finite-element modeling with least-squares fitting in Tectb−/− vs. wild-type mice","journal":"Biophysical Journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biophysical measurement with modeling in knockout vs. WT mice; single lab but rigorous quantitative approach with anisotropic finite-element modeling","pmids":["30665694"],"is_preprint":false},{"year":2021,"finding":"The tectorial membrane (which requires both TECTA and TECTB for attachment) is not required for normal functional maturation of OHC mechanoelectrical transducer (MET) channels or for resting hair bundle position: in Tecta/Tectb double-knockout mice, OHC MET channel resting open probability (~50%) and OHC resting potential are normal. However, the TM (requiring TECTB/TECTA) is required for Ca2+ regulation near stereocilia during prolonged sound stimulation, as adaptation of MET-dependent otoacoustic emissions to repetitive stimulation fails in Tecta/Tectb−/− mice.","method":"Tecta/Tectb double-knockout mouse model; in vitro patch-clamp MET channel recordings; cochlear microphonics; distortion product otoacoustic emissions with repetitive stimulation paradigm","journal":"The Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockout with multiple orthogonal functional assays (electrophysiology + OAEs); single lab; mechanistic inference about Ca2+ regulation is partly indirect","pmids":["33559882"],"is_preprint":false},{"year":2024,"finding":"Hepsin (TMPRSS1) serine protease activity is required for proper incorporation of TECTB (and TECTA) into the tectorial membrane. Hepsin KO mice show decreased TECTB and TECTA immunostaining in the TM; restoration of wild-type hepsin (but not protease-dead hepsin) in transgenic rescue mice partially restores TECTB/TECTA levels and TM morphology, suggesting hepsin mediates proteolytic processing/maturation of TECTB.","method":"Hepsin knockout mice; transgenic rescue with wild-type vs. protease-dead hepsin; immunostaining for TECTB and TECTA in TM; histological TM morphology analysis","journal":"Hearing Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment comparing wild-type vs. catalytic-dead protease with direct protein-level readout; single lab, multiple transgenic lines","pmids":["39437584"],"is_preprint":false},{"year":2025,"finding":"A missense variant in the zona pellucida (ZP) domain of TECTB (c.674G>A, p.Cys225Tyr), affecting one of eight conserved cysteines, causes autosomal dominant non-syndromic hearing loss. In Tectb-C225Y knock-in mice, homozygotes show severe hearing loss and profound TM morphology disruption; heterozygotes show decreased TM matrix content and increased susceptibility to noise-induced hearing loss despite normal auditory thresholds. This establishes a structural role for TECTB's ZP domain cysteines in TM matrix assembly and resilience.","method":"Human genetics (multigenerational family with co-segregation); Tectb-C225Y knock-in mouse model; auditory brainstem responses; TM histology/morphology; noise-exposure functional testing","journal":"medRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with orthogonal methods (genetics + histology + auditory function); preprint, not yet peer-reviewed","pmids":["40832383"],"is_preprint":true}],"current_model":"TECTB (β-tectorin) is a secreted zona-pellucida domain glycoprotein that is an essential non-collagenous component of the tectorial membrane (TM) extracellular matrix: it interacts with α-tectorin (TECTA) and CEACAM16 to form and stabilize the striated-sheet matrix, its incorporation requires hepsin-mediated proteolytic processing, it determines the anisotropic mechanical (shear/transverse stiffness) properties of the TM and thereby governs travelling-wave propagation velocity and spatial extent that set cochlear frequency selectivity and sensitivity, and its ZP-domain cysteine integrity is required for TM matrix assembly and resilience to noise-induced hearing loss."},"narrative":{"mechanistic_narrative":"TECTB (β-tectorin) is a secreted glycoprotein that serves as an essential structural component of the tectorial membrane (TM), the acellular extracellular matrix overlying the organ of Corti, where it shapes the cochlear mechanics underlying frequency selectivity and sensitivity [PMID:20981024]. Its incorporation into the striated-sheet matrix of the TM depends on direct interaction with α-tectorin (TECTA): a TECTA mutation that abolishes TECTA–TECTB binding yields a TM deficient in TECTB that lacks the striated-sheet matrix and detaches from the organ of Corti [PMID:18452040]. CEACAM16 stabilizes the TECTA–TECTB association, since loss of CEACAM16 reduces TM TECTB levels and abolishes striated-sheet matrix and Hensen's stripe formation [PMID:25080593], and proper deposition of TECTB further requires the proteolytic activity of the serine protease hepsin (TMPRSS1), as catalytically active but not protease-dead hepsin restores TECTB incorporation [PMID:39437584]. Functionally, TECTB confers anisotropic mechanical properties on the TM, selectively contributing to shear and transverse stiffness without affecting stiffness along the collagen-fiber axis [PMID:30665694]; through this, it sets the spatial extent and propagation velocity of TM travelling waves, tuning the trade-off between frequency selectivity and sensitivity [PMID:20981024]. The integrity of the conserved cysteines within TECTB's zona pellucida (ZP) domain is required for TM matrix assembly: a ZP-domain missense variant (p.Cys225Tyr) causes autosomal dominant non-syndromic hearing loss, with disrupted TM morphology and heightened susceptibility to noise-induced hearing loss [PMID:40832383].","teleology":[{"year":2008,"claim":"Established that TECTB does not assemble into the TM autonomously but requires a physical interaction with TECTA, defining the molecular basis of striated-sheet matrix formation.","evidence":"Spontaneous Tecta A349D missense knock-in mouse with TM immunohistochemistry and electron microscopy","pmids":["18452040"],"confidence":"Medium","gaps":["Does not map the TECTA–TECTB interaction interface or domains","Interaction inferred from co-deficiency rather than direct binding assay"]},{"year":2010,"claim":"Linked TECTB's structural role to a defined mechanical function, showing it governs TM travelling-wave spread and velocity that tune the selectivity–sensitivity trade-off in the cochlea.","evidence":"Tectb knockout mouse with TM travelling-wave measurements and auditory functional testing","pmids":["20981024"],"confidence":"High","gaps":["Does not resolve which biophysical TM property mediates the wave change","Molecular contribution of TECTB to matrix architecture not directly visualized here"]},{"year":2014,"claim":"Identified CEACAM16 as a stabilizer of the TECTA–TECTB association, explaining how the striated-sheet matrix and Hensen's stripe are maintained.","evidence":"Ceacam16 null mouse with protein interaction readout, immunohistochemistry, and electron microscopy","pmids":["25080593"],"confidence":"Medium","gaps":["Direct ternary complex of TECTA/TECTB/CEACAM16 not biochemically reconstituted","Stoichiometry and binding sites unknown"]},{"year":2019,"claim":"Resolved the specific mechanical contribution of TECTB, demonstrating it provides shear and transverse stiffness and sets TM anisotropy rather than overall stiffness.","evidence":"Isolated TM biophysical measurements with harmonic radial excitation and anisotropic finite-element modeling in Tectb−/− vs. wild-type","pmids":["30665694"],"confidence":"Medium","gaps":["Does not connect anisotropy changes to molecular matrix organization","Single-lab measurement"]},{"year":2021,"claim":"Delimited the functional reach of the TECTB-dependent TM, showing it is dispensable for MET channel maturation and resting bundle position but required for Ca2+ regulation near stereocilia during sustained stimulation.","evidence":"Tecta/Tectb double-knockout mouse with patch-clamp MET recordings, cochlear microphonics, and distortion product otoacoustic emissions","pmids":["33559882"],"confidence":"Medium","gaps":["Ca2+ regulation role is inferred indirectly from OAE adaptation failure","Cannot isolate TECTB-specific from TECTA-specific contributions in the double knockout"]},{"year":2024,"claim":"Defined a maturation step for TECTB, showing hepsin protease activity is required for its proteolytic processing and incorporation into the TM.","evidence":"Hepsin knockout mice rescued with wild-type vs. protease-dead hepsin, with TECTB/TECTA immunostaining and TM morphology","pmids":["39437584"],"confidence":"Medium","gaps":["Direct cleavage of TECTB by hepsin not demonstrated biochemically","Cleavage site and processed product unidentified"]},{"year":2025,"claim":"Tied TECTB to human disease and assigned a structural role to its ZP-domain cysteines, showing a cysteine-disrupting variant causes dominant hearing loss and noise susceptibility.","evidence":"Multigenerational family genetics with co-segregation plus Tectb-C225Y knock-in mouse with ABR, TM histology, and noise-exposure testing (preprint)","pmids":["40832383"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Molecular consequence of the cysteine substitution on disulfide bonding/folding not directly resolved"]},{"year":null,"claim":"The biochemical details of TECTB assembly remain open: how its ZP domain mediates polymerization, the precise hepsin cleavage event, and the structural organization of the TECTA/TECTB/CEACAM16 matrix are not directly defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted structure of the TECTB-containing matrix","Hepsin cleavage site on TECTB unmapped","ZP-domain polymerization mechanism uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3,6]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,4]}],"complexes":["tectorial membrane striated-sheet matrix"],"partners":["TECTA","CEACAM16","HPN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PL2","full_name":"Beta-tectorin","aliases":[],"length_aa":329,"mass_kda":37.0,"function":"One of the major non-collagenous components of the tectorial membrane (By similarity). The tectorial membrane is an extracellular matrix of the inner ear that covers the neuroepithelium of the cochlea and contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals","subcellular_location":"Cell membrane; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q96PL2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TECTB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TECTB","total_profiled":1310},"omim":[{"mim_id":"614591","title":"CEA CELL ADHESION MOLECULE 16; CEACAM16","url":"https://www.omim.org/entry/614591"},{"mim_id":"602653","title":"TECTORIN, BETA; TECTB","url":"https://www.omim.org/entry/602653"},{"mim_id":"602574","title":"TECTORIN, ALPHA; TECTA","url":"https://www.omim.org/entry/602574"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TECTB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96PL2","domains":[{"cath_id":"2.60.40.3210","chopping":"28-124","consensus_level":"high","plddt":85.4198,"start":28,"end":124},{"cath_id":"2.60.40.4100","chopping":"126-136_144-269","consensus_level":"high","plddt":79.7884,"start":126,"end":269}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PL2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PL2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PL2-F1-predicted_aligned_error_v6.png","plddt_mean":67.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TECTB","jax_strain_url":"https://www.jax.org/strain/search?query=TECTB"},"sequence":{"accession":"Q96PL2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PL2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PL2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PL2"}},"corpus_meta":[{"pmid":"25122905","id":"PMC_25122905","title":"Characterization of transcriptomes of cochlear inner and outer hair cells.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25122905","citation_count":164,"is_preprint":false},{"pmid":"20981024","id":"PMC_20981024","title":"Tectorial membrane travelling waves underlie abnormal hearing in Tectb mutant mice.","date":"2010","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/20981024","citation_count":66,"is_preprint":false},{"pmid":"19692489","id":"PMC_19692489","title":"Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression.","date":"2009","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19692489","citation_count":57,"is_preprint":false},{"pmid":"25080593","id":"PMC_25080593","title":"Loss of the tectorial membrane protein CEACAM16 enhances spontaneous, stimulus-frequency, and transiently evoked otoacoustic emissions.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25080593","citation_count":56,"is_preprint":false},{"pmid":"33559882","id":"PMC_33559882","title":"MET currents and otoacoustic emissions from mice with a detached tectorial membrane indicate the extracellular matrix regulates Ca2+ near stereocilia.","date":"2021","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33559882","citation_count":22,"is_preprint":false},{"pmid":"18452040","id":"PMC_18452040","title":"Characterization of a spontaneous, recessive, missense mutation arising in the Tecta gene.","date":"2008","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/18452040","citation_count":19,"is_preprint":false},{"pmid":"34349220","id":"PMC_34349220","title":"GATA3 maintains the quiescent state of cochlear supporting cells by regulating p27kip1.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34349220","citation_count":8,"is_preprint":false},{"pmid":"32492250","id":"PMC_32492250","title":"Analysis of FGF20-regulated genes in organ of Corti progenitors by translating ribosome affinity purification.","date":"2020","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/32492250","citation_count":8,"is_preprint":false},{"pmid":"30665694","id":"PMC_30665694","title":"Anisotropic Material Properties of Wild-Type and Tectb-/- Tectorial Membranes.","date":"2019","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/30665694","citation_count":5,"is_preprint":false},{"pmid":"34555361","id":"PMC_34555361","title":"Age-related degradation of tectorial membrane dynamics with loss of CEACAM16.","date":"2021","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/34555361","citation_count":5,"is_preprint":false},{"pmid":"12812054","id":"PMC_12812054","title":"[In silicon cloning of the human TECTB gene].","date":"2003","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/12812054","citation_count":4,"is_preprint":false},{"pmid":"37247388","id":"PMC_37247388","title":"Accelerated Evolution Analysis Uncovers PKNOX2 as a Key Transcription Factor in the Mammalian Cochlea.","date":"2023","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/37247388","citation_count":4,"is_preprint":false},{"pmid":"39437584","id":"PMC_39437584","title":"Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: Insights from transgenic mouse models.","date":"2024","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/39437584","citation_count":1,"is_preprint":false},{"pmid":"40672507","id":"PMC_40672507","title":"Brain network and blood transcriptomic correlations underpin psychopathological phenotypes: A Preliminary Study.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40672507","citation_count":1,"is_preprint":false},{"pmid":"40832383","id":"PMC_40832383","title":"The TECTB-C225Y Variant Causing Autosomal Dominant Deafness in a Nicaraguan Family Enhances Sensitivity to Noise-Induced Hearing Loss in Mice.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40832383","citation_count":0,"is_preprint":false},{"pmid":"40901670","id":"PMC_40901670","title":"Tectorial membrane: structure, function, and its implications for hearing loss.","date":"2025","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40901670","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.13.25333146","title":"The <i>TECTB-C225Y</i> Variant Causing Autosomal Dominant Deafness in a Nicaraguan Family Enhances Sensitivity to Noise-Induced Hearing Loss in Mice","date":"2025-08-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.13.25333146","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10946,"output_tokens":2096,"usd":0.032139,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9158,"output_tokens":2667,"usd":0.056232,"stage2_stop_reason":"end_turn"},"total_usd":0.088371,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"TECTB is required for normal tectorial membrane (TM) travelling wave propagation: loss of TECTB (Tectb−/− mice) reduces the spatial extent and propagation velocity of TM travelling waves, which decreases the spread of excitation (increasing frequency selectivity) and reduces the number of hair cells that effectively couple energy to the basilar membrane (reducing sensitivity).\",\n      \"method\": \"Tectb knockout mouse model; measurement of TM travelling wave spatial extent and propagation velocity; auditory functional testing\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout model with direct mechanical measurements of TM wave properties linked to defined cochlear functional phenotypes, two orthogonal methods (wave mechanics + hearing thresholds/tuning)\",\n      \"pmids\": [\"20981024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TECTB requires interaction with alpha-tectorin (TECTA) for its incorporation into the tectorial membrane striated-sheet matrix. In Tecta(A349D/A349D) mice, mutated TECTA is incorporated into the TM but cannot interact with TECTB (or otogelin), resulting in a TM that is deficient in TECTB, lacks a striated-sheet matrix, and is detached from the organ of Corti.\",\n      \"method\": \"Spontaneous missense knock-in mouse model (Tecta A349D); immunohistochemistry; electron microscopy; protein detection in TM\",\n      \"journal\": \"Journal of the Association for Research in Otolaryngology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with protein-level readout using multiple histological methods; single lab but orthogonal approaches (EM + immunostaining)\",\n      \"pmids\": [\"18452040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TECTB interacts with CEACAM16. Loss of CEACAM16 reduces TECTB levels in the TM and abolishes development of the striated-sheet matrix and Hensen's stripe, indicating CEACAM16 stabilizes interactions between TECTA and TECTB within the TM extracellular matrix.\",\n      \"method\": \"Ceacam16 null mouse model; protein interaction assay (Co-IP/pulldown implied by 'interact'); immunohistochemistry; electron microscopy of TM structure\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null mouse model combined with protein-level interaction evidence and structural TM analysis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25080593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TECTB contributes to the anisotropic mechanical properties of the tectorial membrane. Tectb−/− mice show significantly reduced TM stiffness in shear and in the transverse direction (perpendicular to collagen fibers) but no decrease in stiffness along the fiber direction, making the mutant TM significantly more anisotropic across audio frequencies.\",\n      \"method\": \"Isolated TM mechanical measurements using harmonic radial excitation, longitudinal displacement imaging, and finite-element modeling with least-squares fitting in Tectb−/− vs. wild-type mice\",\n      \"journal\": \"Biophysical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biophysical measurement with modeling in knockout vs. WT mice; single lab but rigorous quantitative approach with anisotropic finite-element modeling\",\n      \"pmids\": [\"30665694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The tectorial membrane (which requires both TECTA and TECTB for attachment) is not required for normal functional maturation of OHC mechanoelectrical transducer (MET) channels or for resting hair bundle position: in Tecta/Tectb double-knockout mice, OHC MET channel resting open probability (~50%) and OHC resting potential are normal. However, the TM (requiring TECTB/TECTA) is required for Ca2+ regulation near stereocilia during prolonged sound stimulation, as adaptation of MET-dependent otoacoustic emissions to repetitive stimulation fails in Tecta/Tectb−/− mice.\",\n      \"method\": \"Tecta/Tectb double-knockout mouse model; in vitro patch-clamp MET channel recordings; cochlear microphonics; distortion product otoacoustic emissions with repetitive stimulation paradigm\",\n      \"journal\": \"The Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockout with multiple orthogonal functional assays (electrophysiology + OAEs); single lab; mechanistic inference about Ca2+ regulation is partly indirect\",\n      \"pmids\": [\"33559882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepsin (TMPRSS1) serine protease activity is required for proper incorporation of TECTB (and TECTA) into the tectorial membrane. Hepsin KO mice show decreased TECTB and TECTA immunostaining in the TM; restoration of wild-type hepsin (but not protease-dead hepsin) in transgenic rescue mice partially restores TECTB/TECTA levels and TM morphology, suggesting hepsin mediates proteolytic processing/maturation of TECTB.\",\n      \"method\": \"Hepsin knockout mice; transgenic rescue with wild-type vs. protease-dead hepsin; immunostaining for TECTB and TECTA in TM; histological TM morphology analysis\",\n      \"journal\": \"Hearing Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment comparing wild-type vs. catalytic-dead protease with direct protein-level readout; single lab, multiple transgenic lines\",\n      \"pmids\": [\"39437584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A missense variant in the zona pellucida (ZP) domain of TECTB (c.674G>A, p.Cys225Tyr), affecting one of eight conserved cysteines, causes autosomal dominant non-syndromic hearing loss. In Tectb-C225Y knock-in mice, homozygotes show severe hearing loss and profound TM morphology disruption; heterozygotes show decreased TM matrix content and increased susceptibility to noise-induced hearing loss despite normal auditory thresholds. This establishes a structural role for TECTB's ZP domain cysteines in TM matrix assembly and resilience.\",\n      \"method\": \"Human genetics (multigenerational family with co-segregation); Tectb-C225Y knock-in mouse model; auditory brainstem responses; TM histology/morphology; noise-exposure functional testing\",\n      \"journal\": \"medRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with orthogonal methods (genetics + histology + auditory function); preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40832383\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TECTB (β-tectorin) is a secreted zona-pellucida domain glycoprotein that is an essential non-collagenous component of the tectorial membrane (TM) extracellular matrix: it interacts with α-tectorin (TECTA) and CEACAM16 to form and stabilize the striated-sheet matrix, its incorporation requires hepsin-mediated proteolytic processing, it determines the anisotropic mechanical (shear/transverse stiffness) properties of the TM and thereby governs travelling-wave propagation velocity and spatial extent that set cochlear frequency selectivity and sensitivity, and its ZP-domain cysteine integrity is required for TM matrix assembly and resilience to noise-induced hearing loss.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TECTB (β-tectorin) is a secreted glycoprotein that serves as an essential structural component of the tectorial membrane (TM), the acellular extracellular matrix overlying the organ of Corti, where it shapes the cochlear mechanics underlying frequency selectivity and sensitivity [#0]. Its incorporation into the striated-sheet matrix of the TM depends on direct interaction with α-tectorin (TECTA): a TECTA mutation that abolishes TECTA–TECTB binding yields a TM deficient in TECTB that lacks the striated-sheet matrix and detaches from the organ of Corti [#1]. CEACAM16 stabilizes the TECTA–TECTB association, since loss of CEACAM16 reduces TM TECTB levels and abolishes striated-sheet matrix and Hensen's stripe formation [#2], and proper deposition of TECTB further requires the proteolytic activity of the serine protease hepsin (TMPRSS1), as catalytically active but not protease-dead hepsin restores TECTB incorporation [#5]. Functionally, TECTB confers anisotropic mechanical properties on the TM, selectively contributing to shear and transverse stiffness without affecting stiffness along the collagen-fiber axis [#3]; through this, it sets the spatial extent and propagation velocity of TM travelling waves, tuning the trade-off between frequency selectivity and sensitivity [#0]. The integrity of the conserved cysteines within TECTB's zona pellucida (ZP) domain is required for TM matrix assembly: a ZP-domain missense variant (p.Cys225Tyr) causes autosomal dominant non-syndromic hearing loss, with disrupted TM morphology and heightened susceptibility to noise-induced hearing loss [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that TECTB does not assemble into the TM autonomously but requires a physical interaction with TECTA, defining the molecular basis of striated-sheet matrix formation.\",\n      \"evidence\": \"Spontaneous Tecta A349D missense knock-in mouse with TM immunohistochemistry and electron microscopy\",\n      \"pmids\": [\"18452040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not map the TECTA–TECTB interaction interface or domains\", \"Interaction inferred from co-deficiency rather than direct binding assay\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked TECTB's structural role to a defined mechanical function, showing it governs TM travelling-wave spread and velocity that tune the selectivity–sensitivity trade-off in the cochlea.\",\n      \"evidence\": \"Tectb knockout mouse with TM travelling-wave measurements and auditory functional testing\",\n      \"pmids\": [\"20981024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which biophysical TM property mediates the wave change\", \"Molecular contribution of TECTB to matrix architecture not directly visualized here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified CEACAM16 as a stabilizer of the TECTA–TECTB association, explaining how the striated-sheet matrix and Hensen's stripe are maintained.\",\n      \"evidence\": \"Ceacam16 null mouse with protein interaction readout, immunohistochemistry, and electron microscopy\",\n      \"pmids\": [\"25080593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ternary complex of TECTA/TECTB/CEACAM16 not biochemically reconstituted\", \"Stoichiometry and binding sites unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the specific mechanical contribution of TECTB, demonstrating it provides shear and transverse stiffness and sets TM anisotropy rather than overall stiffness.\",\n      \"evidence\": \"Isolated TM biophysical measurements with harmonic radial excitation and anisotropic finite-element modeling in Tectb−/− vs. wild-type\",\n      \"pmids\": [\"30665694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not connect anisotropy changes to molecular matrix organization\", \"Single-lab measurement\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Delimited the functional reach of the TECTB-dependent TM, showing it is dispensable for MET channel maturation and resting bundle position but required for Ca2+ regulation near stereocilia during sustained stimulation.\",\n      \"evidence\": \"Tecta/Tectb double-knockout mouse with patch-clamp MET recordings, cochlear microphonics, and distortion product otoacoustic emissions\",\n      \"pmids\": [\"33559882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ca2+ regulation role is inferred indirectly from OAE adaptation failure\", \"Cannot isolate TECTB-specific from TECTA-specific contributions in the double knockout\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a maturation step for TECTB, showing hepsin protease activity is required for its proteolytic processing and incorporation into the TM.\",\n      \"evidence\": \"Hepsin knockout mice rescued with wild-type vs. protease-dead hepsin, with TECTB/TECTA immunostaining and TM morphology\",\n      \"pmids\": [\"39437584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cleavage of TECTB by hepsin not demonstrated biochemically\", \"Cleavage site and processed product unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tied TECTB to human disease and assigned a structural role to its ZP-domain cysteines, showing a cysteine-disrupting variant causes dominant hearing loss and noise susceptibility.\",\n      \"evidence\": \"Multigenerational family genetics with co-segregation plus Tectb-C225Y knock-in mouse with ABR, TM histology, and noise-exposure testing (preprint)\",\n      \"pmids\": [\"40832383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Molecular consequence of the cysteine substitution on disulfide bonding/folding not directly resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical details of TECTB assembly remain open: how its ZP domain mediates polymerization, the precise hepsin cleavage event, and the structural organization of the TECTA/TECTB/CEACAM16 matrix are not directly defined.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted structure of the TECTB-containing matrix\", \"Hepsin cleavage site on TECTB unmapped\", \"ZP-domain polymerization mechanism uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [\"tectorial membrane striated-sheet matrix\"],\n    \"partners\": [\"TECTA\", \"CEACAM16\", \"HPN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}