{"gene":"TECTA","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1999,"finding":"A splice-site mutation in TECTA (GT donor site of intron 9) predicts a truncated alpha-tectorin protein of 971 amino acids and causes autosomal recessive deafness (DFNB21), establishing that TECTA mutations can cause both dominant and recessive deafness and providing genetic evidence that alpha-tectorin forms homo- or heteromeric structures.","method":"Linkage analysis and TECTA gene sequencing in a consanguineous Lebanese family; comparison of heterozygous carrier phenotype with dominant DFNA8/12 phenotype","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequencing-based mutation identification in family, functional inference from phenotype comparison; single lab but two orthogonal lines of evidence (genotyping + phenotype comparison)","pmids":["9949200"],"is_preprint":false},{"year":1998,"finding":"The TECTA gene encoding alpha-tectorin, a major noncollagenous component of the tectorial membrane, was mapped to human chromosome 11q and mouse chromosome 9, placing it within the DFNA12 candidate interval and consistent with a role in tectorial membrane structure required for hearing.","method":"Chromosomal mapping using YAC clones and physical linkage to marker D11S925; mouse-human synteny analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical mapping with YAC clones, single lab, consistent with genetic interval data","pmids":["9503015"],"is_preprint":false},{"year":2001,"finding":"TECTA mRNA expression in mouse cochlea peaks at postnatal day 3 and dramatically decreases by P15, indicating TECTA is transcribed at particularly high levels during tectorial membrane morphogenesis.","method":"Quantitative non-radioactive RT-PCR across developmental time points (E15 through adulthood) in mouse cochlea","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct quantitative expression assay with temporal resolution, single lab, single method","pmids":["11711860"],"is_preprint":false},{"year":2003,"finding":"Tecta(deltaENT/deltaENT) mice with detached tectorial membranes (TM) show markedly reduced distortion product otoacoustic emissions only detectable above 65 dB SPL and loss of normal TM-dependent hair cell excitation, demonstrating that TECTA-dependent TM attachment is required for normal outer hair cell mechanotransduction via the TM.","method":"DPOAE recording in wild-type vs. Tecta(deltaENT/deltaENT) mutant mice with detached TMs; electrophysiological comparison","journal":"Journal of neurophysiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional comparison in genetic mouse model with well-defined TM detachment phenotype; multiple DPOAE parameters measured","pmids":["14523068"],"is_preprint":false},{"year":2008,"finding":"A missense mutation in the Tecta gene (c.1046C>A, p.A349D) in mouse is recessive and causes tectorial membrane (TM) detachment, loss of striated-sheet matrix, and deficiency of beta-tectorin and otogelin in the TM. Mutated Tecta (A349D) protein is incorporated into the TM but is unable to interact with beta-tectorin or otogelin, identifying these as functional binding partners of alpha-tectorin in TM assembly.","method":"Characterization of spontaneous mouse Tecta missense mutant; immunolabeling for Tecta, Tectb (beta-tectorin), and otogelin; electron microscopy of TM structure; comparison with Tecta(deltaENT/deltaENT) mouse","journal":"Journal of the Association for Research in Otolaryngology : JARO","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with direct protein localization by immunolabeling and ultrastructural analysis; multiple orthogonal methods (EM, immunolabeling, phenotype comparison)","pmids":["18452040"],"is_preprint":false},{"year":2010,"finding":"The Tecta(Y1870C/+) heterozygous missense mutation reduces tectorin content and glycoconjugate content of the tectorial membrane (TM), decreases fixed charge concentration, reduces osmotic pressure response, and decreases both radial and longitudinal TM shear impedance by ~10 dB, consistent with increased TM porosity; these mechanical changes underlie the 60-dB hearing threshold shift in these mice.","method":"Force spectroscopy, osmotic pressure response measurement, fixed charge concentration measurement, lectin/immunolabeling (wheat germ agglutinin) in TMs from Tecta(Y1870C/+) vs. wild-type mice","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biomechanical measurements combined with molecular labeling in defined genetic mouse model; multiple orthogonal methods in one study","pmids":["21081075"],"is_preprint":false},{"year":2011,"finding":"The Tecta C1509G mutation causes altered collagen architecture and stereocilin-labeling patterns in the TM. Heterozygous TM attaches only to the first row of outer hair cells (OHCs) and homozygous TM does not attach to any OHCs. The axial Young's modulus of the mutant TM is significantly reduced in the basal region, and modeling shows this reduces OHC stereociliary deflection, mechanistically linking alpha-tectorin to TM mechanical coupling with OHC stereocilia.","method":"Second- and third-harmonic imaging, scanning electron microscopy, immunolabeling (stereocilin), force spectroscopy with Young's modulus measurements, and mechanical modeling in wild-type, heterozygous, and homozygous Tecta C1509G mice","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (SHG/THG imaging, SEM, immunolabeling, force spectroscopy, modeling) in defined genetic mouse model, single rigorous study","pmids":["21575588"],"is_preprint":false},{"year":2012,"finding":"ZP-domain missense mutations in TECTA affect intracellular localization of alpha-tectorin in vitro, suggesting that these mutations impair protein secretion and reduce incorporation of alpha-tectorin into the tectorial membrane.","method":"In vitro expression of wild-type and mutant alpha-tectorin; comparison of intracellular localization patterns between wild-type and missense mutants","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — in vitro localization study, single lab, single method (cell-based localization assay); no reconstitution or structural validation","pmids":["22718023"],"is_preprint":false},{"year":2013,"finding":"ZP-domain mutations in Tecta (L1820F/G1824D and C1837G) cause distinct structural TM changes including elevated auditory thresholds of 30–40 dB in 8–40 kHz range, while a ZA-domain mutation (C1619S) elevates thresholds by 20–30 dB, establishing domain-specific structural phenotypes in the TM and an allelic series linking genotype to phenotype and TM structural changes.","method":"Creation and characterization of three knock-in mouse models; auditory brainstem response (ABR) threshold measurements; structural analysis of TM in domain-specific mutants","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knock-in mouse models, ABR measurements, TM structural analysis; three independent mutations tested with consistent domain-specific phenotypes","pmids":["24363064"],"is_preprint":false},{"year":2008,"finding":"A synonymous TECTA mutation (c.5331G>A; p.L1777L) causes loss of an exonic splice enhancer (ESE), leading to aberrant exon 16 skipping and an in-frame deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin just N-terminal of the ZP domain, demonstrating that the protein deletion likely impairs ZP domain processing and function.","method":"RT-PCR of aberrant TECTA transcript from affected individual; splice enhancer prediction; segregation analysis","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RT-PCR directly demonstrates aberrant splicing; single lab with two orthogonal methods (RT-PCR + ESE prediction + segregation)","pmids":["18575463"],"is_preprint":false},{"year":2011,"finding":"A splice site mutation (c.6162+3insT) in TECTA causes exon skipping leading to a truncated protein, as demonstrated by exon-trapping analysis in vitro; compound heterozygous mutations (p.C1691F missense + splice mutation) in TECTA cause recessive nonsyndromic hearing loss.","method":"Exon-trapping in vitro functional assay for splice site mutation; Sanger sequencing for missense mutation; segregation analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro functional splice assay, single lab, single functional method","pmids":["22037481"],"is_preprint":false},{"year":2018,"finding":"Tecta(Y1870C/+) heterozygous mice are prolific emitters of spontaneous otoacoustic emissions (SOAEs) despite moderate hearing loss, and Kimura's membrane separates from the main body of the TM except at apical locations. Second-harmonic SOAEs are present and are not spatially separated from their primaries, demonstrating that the alpha-tectorin Y1870C mutation disrupts TM structural integrity in a way that alters how OHC amplification is controlled by the TM.","method":"SOAE recording from ear canal in Tecta(Y1870C/+) knock-in mice; suppressor tone experiments; structural analysis of TM","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional OAE measurements in defined genetic mouse model with structural analysis; multiple parameters measured; single lab","pmids":["30627650"],"is_preprint":false},{"year":2024,"finding":"A novel splice-site variant c.5383+6T>A in TECTA causes aberrant splicing with exon 16 skipping, as confirmed by minigene-based splicing analysis and in vivo RNA analysis; quantitative RT-PCR shows no significant reduction in mRNA levels, indicating the dominant-negative effect rather than haploinsufficiency underlies DFNA8/12 in this family.","method":"Minigene splicing assay; in vivo RNA analysis from patient samples; quantitative RT-PCR; protein structure prediction by molecular modeling; whole-exome sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional RNA analyses (minigene + in vivo RT-PCR + qPCR), single lab, single study","pmids":["38676628"],"is_preprint":false},{"year":2025,"finding":"A novel TECTA variant c.5999G>A (p.Gly2000Glu) causes aberrant splicing of exon 20, resulting in two in-frame deletions. Quantitative RT-PCR shows no significant reduction in mRNA levels in lymphoblasts from carriers, supporting a dominant-negative rather than haploinsufficiency mechanism for DFNA8/12 caused by splicing variants.","method":"In vivo RNA analysis; exome sequencing; qRT-PCR of lymphoblast-derived RNA; pedigree analysis in five-generation Chinese family","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo RNA functional analysis with qRT-PCR, two splice variants compared, single lab","pmids":["40583560"],"is_preprint":false},{"year":2004,"finding":"A cysteine-to-glycine substitution in the vWFD4 domain of alpha-tectorin (C1509G) causes progressive high-frequency hearing loss, while mutations outside the vWFD domains cause mid-frequency hearing impairment, establishing a domain-specific genotype-phenotype correlation; the vWFD domain cysteines are proposed to participate in disulfide bonds and protein-protein interactions critical for TM function.","method":"TECTA gene sequencing; linkage analysis (LOD 4.6); comparison across three families with conserved cysteine mutations in vWFD domain","journal":"Cellular physiology and biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — clinical/genetic correlation across multiple families, no direct biochemical validation of disulfide bond or protein interaction","pmids":["15319541"],"is_preprint":false}],"current_model":"Alpha-tectorin (TECTA) is the major non-collagenous glycoprotein of the cochlear tectorial membrane (TM), essential for normal hearing; it forms the striated-sheet matrix of the TM where it interacts with beta-tectorin and otogelin, mediates TM attachment to outer hair cell stereocilia, and controls TM mechanical properties (shear impedance, fixed charge, porosity) that couple sound-induced vibration to hair cell mechanotransduction — with domain-specific mutations in the ZP domain causing mid-frequency hearing loss and ZA/vWFD domain mutations causing high-frequency hearing loss, and dominant mutations acting via dominant-negative rather than haploinsufficiency mechanisms."},"narrative":{"mechanistic_narrative":"TECTA encodes alpha-tectorin, the major non-collagenous glycoprotein of the cochlear tectorial membrane (TM), where it builds the striated-sheet matrix required for normal hearing [PMID:18452040, PMID:21575588]. Within the TM, alpha-tectorin interacts with beta-tectorin and otogelin, and a recessive A349D substitution that is incorporated into the TM yet cannot bind these partners abolishes striated-sheet assembly and depletes beta-tectorin and otogelin, identifying them as functional partners in matrix construction [PMID:18452040]. Tecta is transcribed at high levels during TM morphogenesis, peaking at postnatal day 3 [PMID:11711860]. Functionally, TECTA-dependent TM attachment mechanically couples sound-induced vibration to outer hair cell mechanotransduction: detachment of the TM abolishes normal TM-dependent hair cell excitation and otoacoustic emissions [PMID:14523068], and point mutations that alter TM composition reduce fixed charge, raise porosity, lower shear impedance and axial stiffness, and degrade OHC stereociliary coupling and amplification [PMID:21081075, PMID:21575588, PMID:30627650]. Mutations show domain-specific genotype-phenotype relationships, with knock-in alleles in distinct domains producing characteristic threshold and structural phenotypes [PMID:24363064], and dominant disease alleles act through a dominant-negative mechanism rather than haploinsufficiency, since splicing variants produce altered protein without reducing mRNA levels [PMID:38676628, PMID:40583560].","teleology":[{"year":1998,"claim":"Establishing the genomic location of TECTA was needed to test whether this TM glycoprotein underlies an inherited deafness locus.","evidence":"YAC-based physical mapping and mouse-human synteny analysis placing TECTA in the DFNA12 candidate interval","pmids":["9503015"],"confidence":"Medium","gaps":["Mapping alone does not prove causation","No functional consequence of any allele established"]},{"year":1999,"claim":"A recessive splice-site mutation showed TECTA loss can cause deafness and implied alpha-tectorin functions in homo- or heteromeric assemblies.","evidence":"Linkage and gene sequencing in a consanguineous family with carrier-versus-dominant phenotype comparison","pmids":["9949200"],"confidence":"Medium","gaps":["Protein truncation inferred, not directly observed","Oligomeric partners not identified at this stage"]},{"year":2001,"claim":"Defining when TECTA is expressed clarified its developmental window of action in TM formation.","evidence":"Quantitative RT-PCR across mouse cochlear developmental time points","pmids":["11711860"],"confidence":"Medium","gaps":["mRNA timing does not establish protein dynamics","No link to specific assembly events"]},{"year":2003,"claim":"Whether TM attachment is required for hair cell function was tested by examining a TM-detached mutant, showing the TM mechanically couples sound to OHC excitation.","evidence":"DPOAE recording in Tecta(deltaENT/deltaENT) mice with detached TMs","pmids":["14523068"],"confidence":"High","gaps":["Does not resolve which molecular interactions mediate attachment","Mechanism distinct from frank TM absence not dissected"]},{"year":2004,"claim":"Cross-family correlation linked vWFD-domain cysteine mutations to high-frequency loss versus mid-frequency loss for other mutations, introducing domain-specific genotype-phenotype mapping.","evidence":"TECTA sequencing and linkage across three families with conserved cysteine substitutions","pmids":["15319541"],"confidence":"Low","gaps":["No direct biochemical validation of proposed disulfide bonds or interactions","Clinical correlation only, no functional assay"]},{"year":2008,"claim":"Identifying alpha-tectorin's TM binding partners answered how the matrix is assembled: the A349D protein incorporates but fails to bind beta-tectorin and otogelin, abolishing the striated-sheet matrix.","evidence":"Spontaneous mouse missense mutant with immunolabeling for Tectb and otogelin and EM of TM ultrastructure","pmids":["18452040"],"confidence":"High","gaps":["Direct biochemical interaction surfaces not mapped","Stoichiometry of the matrix network unresolved"]},{"year":2008,"claim":"A synonymous variant disrupting an exonic splice enhancer showed that splicing defects deleting sequence near the ZP domain impair alpha-tectorin function.","evidence":"RT-PCR of aberrant transcript, ESE prediction, and segregation analysis","pmids":["18575463"],"confidence":"Medium","gaps":["Effect on protein folding/secretion inferred, not measured","Mechanism of ZP-domain impairment not shown directly"]},{"year":2010,"claim":"How a dominant mutation degrades hearing was answered biophysically: Y1870C lowers tectorin and glycoconjugate content, fixed charge, and shear impedance, tying TM material properties to threshold shifts.","evidence":"Force spectroscopy, osmotic pressure and fixed-charge measurement, and lectin/immunolabeling in Tecta(Y1870C/+) TMs","pmids":["21081075"],"confidence":"High","gaps":["Molecular basis of porosity increase not resolved at structural level","Heterozygous protein interaction defect not directly visualized"]},{"year":2011,"claim":"The C1509G allele linked alpha-tectorin directly to OHC mechanical coupling, showing dose-dependent loss of TM-OHC attachment and reduced TM stiffness that lowers stereociliary deflection.","evidence":"SHG/THG imaging, SEM, stereocilin immunolabeling, force spectroscopy, and modeling across genotypes","pmids":["21575588"],"confidence":"High","gaps":["Molecular interface between TM and stereocilin/stereocilia not defined","Causal link from stiffness to amplification is model-based"]},{"year":2011,"claim":"A splice-site variant producing a truncated protein in compound heterozygosity confirmed recessive nonsyndromic hearing loss from TECTA disruption.","evidence":"In vitro exon-trapping assay and Sanger sequencing with segregation analysis","pmids":["22037481"],"confidence":"Medium","gaps":["Truncated protein not characterized at protein level","TM consequences not examined"]},{"year":2012,"claim":"Why ZP-domain missense mutations are pathogenic was addressed by showing they alter intracellular localization, implicating impaired secretion and reduced TM incorporation.","evidence":"In vitro expression and localization comparison of wild-type versus mutant alpha-tectorin","pmids":["22718023"],"confidence":"Medium","gaps":["Single cell-based localization assay without reconstitution or structural validation","Secretion defect inferred from localization only"]},{"year":2013,"claim":"An allelic series of knock-in mice established that ZP- versus ZA-domain mutations produce distinct TM structural and threshold phenotypes, formalizing domain-specific pathology.","evidence":"Three knock-in mouse models with ABR thresholds and TM structural analysis","pmids":["24363064"],"confidence":"High","gaps":["Molecular mechanism distinguishing domain effects not fully resolved","Frequency mapping to TM regions not mechanistically dissected"]},{"year":2018,"claim":"How a structural TM defect alters cochlear amplification was probed by showing Y1870C/+ mice over-emit SOAEs with separated Kimura's membrane, indicating dysregulated OHC amplification control.","evidence":"SOAE recording, suppressor-tone experiments, and TM structural analysis in knock-in mice","pmids":["30627650"],"confidence":"Medium","gaps":["Causal chain from TM separation to SOAE emission not fully mechanistic","Single lab"]},{"year":2025,"claim":"Whether dominant splicing variants act by loss of dosage or dominant-negative effect was resolved: aberrant splicing alters protein without reducing mRNA, supporting a dominant-negative mechanism for DFNA8/12.","evidence":"Minigene and in vivo RNA analysis with qRT-PCR for two splice variants (c.5383+6T>A and c.5999G>A)","pmids":["38676628","40583560"],"confidence":"Medium","gaps":["Direct demonstration of mutant protein poisoning wild-type assembly not shown","Effect on TM not examined in patient tissue"]},{"year":null,"claim":"The atomic-level interaction surfaces by which alpha-tectorin binds beta-tectorin, otogelin, and the OHC stereociliary apparatus, and the molecular basis of dominant-negative interference, remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the alpha-tectorin matrix network","Disulfide bonding and ZP-domain processing not biochemically resolved","Mechanism of dominant-negative protein interaction not directly demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[4,5,6]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4]}],"complexes":["tectorial membrane striated-sheet matrix"],"partners":["TECTB","OTOG","STRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75443","full_name":"Alpha-tectorin","aliases":[],"length_aa":2155,"mass_kda":239.5,"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/O75443/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TECTA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TECTA","total_profiled":1310},"omim":[{"mim_id":"621411","title":"TRANSMEMBRANE PROTEIN 184B; TMEM184B","url":"https://www.omim.org/entry/621411"},{"mim_id":"621154","title":"NEURODEVELOPMENTAL DISORDER WITH POOR GROWTH, SEIZURES, AND BRAIN ABNORMALITIES; NEDGSB","url":"https://www.omim.org/entry/621154"},{"mim_id":"618859","title":"NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT AUTISTIC FEATURES AND/OR STRUCTURAL BRAIN ABNORMALITIES; NEDASB","url":"https://www.omim.org/entry/618859"},{"mim_id":"618492","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY AND STRUCTURAL BRAIN ANOMALIES; NEDMIBA","url":"https://www.omim.org/entry/618492"},{"mim_id":"618003","title":"DEAFNESS, AUTOSOMAL RECESSIVE 57; DFNB57","url":"https://www.omim.org/entry/618003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in some","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TECTA"},"hgnc":{"alias_symbol":[],"prev_symbol":["DFNA12","DFNA8","DFNB21"]},"alphafold":{"accession":"O75443","domains":[{"cath_id":"-","chopping":"24-269","consensus_level":"high","plddt":89.8278,"start":24,"end":269},{"cath_id":"-","chopping":"317-507","consensus_level":"medium","plddt":84.3141,"start":317,"end":507},{"cath_id":"-","chopping":"886-974","consensus_level":"medium","plddt":81.4804,"start":886,"end":974},{"cath_id":"-","chopping":"1485-1658","consensus_level":"medium","plddt":78.1722,"start":1485,"end":1658},{"cath_id":"-","chopping":"1667-1760","consensus_level":"medium","plddt":69.4419,"start":1667,"end":1760},{"cath_id":"2.60.40.3210","chopping":"1803-1902","consensus_level":"high","plddt":67.2577,"start":1803,"end":1902},{"cath_id":"2.60.40.4100","chopping":"1918-2055_2072-2083","consensus_level":"high","plddt":77.7666,"start":1918,"end":2083},{"cath_id":"1.10.150","chopping":"509-595","consensus_level":"medium","plddt":84.5684,"start":509,"end":595},{"cath_id":"3.40.1000","chopping":"711-879","consensus_level":"high","plddt":82.0182,"start":711,"end":879},{"cath_id":"2.10.70","chopping":"1038-1087","consensus_level":"medium","plddt":78.3004,"start":1038,"end":1087}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75443","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75443-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75443-F1-predicted_aligned_error_v6.png","plddt_mean":77.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TECTA","jax_strain_url":"https://www.jax.org/strain/search?query=TECTA"},"sequence":{"accession":"O75443","fasta_url":"https://rest.uniprot.org/uniprotkb/O75443.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75443/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75443"}},"corpus_meta":[{"pmid":"9949200","id":"PMC_9949200","title":"An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9949200","citation_count":136,"is_preprint":false},{"pmid":"21520338","id":"PMC_21520338","title":"DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21520338","citation_count":71,"is_preprint":false},{"pmid":"6980968","id":"PMC_6980968","title":"Anatomy and physiology of experimentally produced striped tecta.","date":"1981","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/6980968","citation_count":67,"is_preprint":false},{"pmid":"9405688","id":"PMC_9405688","title":"N-methyl-D-aspartate receptor activation and visual activity induce elongation factor-2 phosphorylation in amphibian tecta: a role for N-methyl-D-aspartate receptors in controlling protein synthesis.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9405688","citation_count":58,"is_preprint":false},{"pmid":"9150164","id":"PMC_9150164","title":"A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24.","date":"1997","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9150164","citation_count":50,"is_preprint":false},{"pmid":"24363064","id":"PMC_24363064","title":"Three deaf mice: mouse models for TECTA-based human hereditary deafness reveal domain-specific structural phenotypes in the tectorial membrane.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24363064","citation_count":47,"is_preprint":false},{"pmid":"15319541","id":"PMC_15319541","title":"A 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structures.\",\n      \"method\": \"Linkage analysis and TECTA gene sequencing in a consanguineous Lebanese family; comparison of heterozygous carrier phenotype with dominant DFNA8/12 phenotype\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequencing-based mutation identification in family, functional inference from phenotype comparison; single lab but two orthogonal lines of evidence (genotyping + phenotype comparison)\",\n      \"pmids\": [\"9949200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The TECTA gene encoding alpha-tectorin, a major noncollagenous component of the tectorial membrane, was mapped to human chromosome 11q and mouse chromosome 9, placing it within the DFNA12 candidate interval and consistent with a role in tectorial membrane structure required for hearing.\",\n      \"method\": \"Chromosomal mapping using YAC clones and physical linkage to marker D11S925; mouse-human synteny analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical mapping with YAC clones, single lab, consistent with genetic interval data\",\n      \"pmids\": [\"9503015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TECTA mRNA expression in mouse cochlea peaks at postnatal day 3 and dramatically decreases by P15, indicating TECTA is transcribed at particularly high levels during tectorial membrane morphogenesis.\",\n      \"method\": \"Quantitative non-radioactive RT-PCR across developmental time points (E15 through adulthood) in mouse cochlea\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct quantitative expression assay with temporal resolution, single lab, single method\",\n      \"pmids\": [\"11711860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Tecta(deltaENT/deltaENT) mice with detached tectorial membranes (TM) show markedly reduced distortion product otoacoustic emissions only detectable above 65 dB SPL and loss of normal TM-dependent hair cell excitation, demonstrating that TECTA-dependent TM attachment is required for normal outer hair cell mechanotransduction via the TM.\",\n      \"method\": \"DPOAE recording in wild-type vs. Tecta(deltaENT/deltaENT) mutant mice with detached TMs; electrophysiological comparison\",\n      \"journal\": \"Journal of neurophysiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional comparison in genetic mouse model with well-defined TM detachment phenotype; multiple DPOAE parameters measured\",\n      \"pmids\": [\"14523068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation in the Tecta gene (c.1046C>A, p.A349D) in mouse is recessive and causes tectorial membrane (TM) detachment, loss of striated-sheet matrix, and deficiency of beta-tectorin and otogelin in the TM. Mutated Tecta (A349D) protein is incorporated into the TM but is unable to interact with beta-tectorin or otogelin, identifying these as functional binding partners of alpha-tectorin in TM assembly.\",\n      \"method\": \"Characterization of spontaneous mouse Tecta missense mutant; immunolabeling for Tecta, Tectb (beta-tectorin), and otogelin; electron microscopy of TM structure; comparison with Tecta(deltaENT/deltaENT) mouse\",\n      \"journal\": \"Journal of the Association for Research in Otolaryngology : JARO\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with direct protein localization by immunolabeling and ultrastructural analysis; multiple orthogonal methods (EM, immunolabeling, phenotype comparison)\",\n      \"pmids\": [\"18452040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Tecta(Y1870C/+) heterozygous missense mutation reduces tectorin content and glycoconjugate content of the tectorial membrane (TM), decreases fixed charge concentration, reduces osmotic pressure response, and decreases both radial and longitudinal TM shear impedance by ~10 dB, consistent with increased TM porosity; these mechanical changes underlie the 60-dB hearing threshold shift in these mice.\",\n      \"method\": \"Force spectroscopy, osmotic pressure response measurement, fixed charge concentration measurement, lectin/immunolabeling (wheat germ agglutinin) in TMs from Tecta(Y1870C/+) vs. wild-type mice\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biomechanical measurements combined with molecular labeling in defined genetic mouse model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21081075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Tecta C1509G mutation causes altered collagen architecture and stereocilin-labeling patterns in the TM. Heterozygous TM attaches only to the first row of outer hair cells (OHCs) and homozygous TM does not attach to any OHCs. The axial Young's modulus of the mutant TM is significantly reduced in the basal region, and modeling shows this reduces OHC stereociliary deflection, mechanistically linking alpha-tectorin to TM mechanical coupling with OHC stereocilia.\",\n      \"method\": \"Second- and third-harmonic imaging, scanning electron microscopy, immunolabeling (stereocilin), force spectroscopy with Young's modulus measurements, and mechanical modeling in wild-type, heterozygous, and homozygous Tecta C1509G mice\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (SHG/THG imaging, SEM, immunolabeling, force spectroscopy, modeling) in defined genetic mouse model, single rigorous study\",\n      \"pmids\": [\"21575588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ZP-domain missense mutations in TECTA affect intracellular localization of alpha-tectorin in vitro, suggesting that these mutations impair protein secretion and reduce incorporation of alpha-tectorin into the tectorial membrane.\",\n      \"method\": \"In vitro expression of wild-type and mutant alpha-tectorin; comparison of intracellular localization patterns between wild-type and missense mutants\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro localization study, single lab, single method (cell-based localization assay); no reconstitution or structural validation\",\n      \"pmids\": [\"22718023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZP-domain mutations in Tecta (L1820F/G1824D and C1837G) cause distinct structural TM changes including elevated auditory thresholds of 30–40 dB in 8–40 kHz range, while a ZA-domain mutation (C1619S) elevates thresholds by 20–30 dB, establishing domain-specific structural phenotypes in the TM and an allelic series linking genotype to phenotype and TM structural changes.\",\n      \"method\": \"Creation and characterization of three knock-in mouse models; auditory brainstem response (ABR) threshold measurements; structural analysis of TM in domain-specific mutants\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knock-in mouse models, ABR measurements, TM structural analysis; three independent mutations tested with consistent domain-specific phenotypes\",\n      \"pmids\": [\"24363064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A synonymous TECTA mutation (c.5331G>A; p.L1777L) causes loss of an exonic splice enhancer (ESE), leading to aberrant exon 16 skipping and an in-frame deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin just N-terminal of the ZP domain, demonstrating that the protein deletion likely impairs ZP domain processing and function.\",\n      \"method\": \"RT-PCR of aberrant TECTA transcript from affected individual; splice enhancer prediction; segregation analysis\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RT-PCR directly demonstrates aberrant splicing; single lab with two orthogonal methods (RT-PCR + ESE prediction + segregation)\",\n      \"pmids\": [\"18575463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A splice site mutation (c.6162+3insT) in TECTA causes exon skipping leading to a truncated protein, as demonstrated by exon-trapping analysis in vitro; compound heterozygous mutations (p.C1691F missense + splice mutation) in TECTA cause recessive nonsyndromic hearing loss.\",\n      \"method\": \"Exon-trapping in vitro functional assay for splice site mutation; Sanger sequencing for missense mutation; segregation analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro functional splice assay, single lab, single functional method\",\n      \"pmids\": [\"22037481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tecta(Y1870C/+) heterozygous mice are prolific emitters of spontaneous otoacoustic emissions (SOAEs) despite moderate hearing loss, and Kimura's membrane separates from the main body of the TM except at apical locations. Second-harmonic SOAEs are present and are not spatially separated from their primaries, demonstrating that the alpha-tectorin Y1870C mutation disrupts TM structural integrity in a way that alters how OHC amplification is controlled by the TM.\",\n      \"method\": \"SOAE recording from ear canal in Tecta(Y1870C/+) knock-in mice; suppressor tone experiments; structural analysis of TM\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional OAE measurements in defined genetic mouse model with structural analysis; multiple parameters measured; single lab\",\n      \"pmids\": [\"30627650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel splice-site variant c.5383+6T>A in TECTA causes aberrant splicing with exon 16 skipping, as confirmed by minigene-based splicing analysis and in vivo RNA analysis; quantitative RT-PCR shows no significant reduction in mRNA levels, indicating the dominant-negative effect rather than haploinsufficiency underlies DFNA8/12 in this family.\",\n      \"method\": \"Minigene splicing assay; in vivo RNA analysis from patient samples; quantitative RT-PCR; protein structure prediction by molecular modeling; whole-exome sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional RNA analyses (minigene + in vivo RT-PCR + qPCR), single lab, single study\",\n      \"pmids\": [\"38676628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel TECTA variant c.5999G>A (p.Gly2000Glu) causes aberrant splicing of exon 20, resulting in two in-frame deletions. Quantitative RT-PCR shows no significant reduction in mRNA levels in lymphoblasts from carriers, supporting a dominant-negative rather than haploinsufficiency mechanism for DFNA8/12 caused by splicing variants.\",\n      \"method\": \"In vivo RNA analysis; exome sequencing; qRT-PCR of lymphoblast-derived RNA; pedigree analysis in five-generation Chinese family\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo RNA functional analysis with qRT-PCR, two splice variants compared, single lab\",\n      \"pmids\": [\"40583560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A cysteine-to-glycine substitution in the vWFD4 domain of alpha-tectorin (C1509G) causes progressive high-frequency hearing loss, while mutations outside the vWFD domains cause mid-frequency hearing impairment, establishing a domain-specific genotype-phenotype correlation; the vWFD domain cysteines are proposed to participate in disulfide bonds and protein-protein interactions critical for TM function.\",\n      \"method\": \"TECTA gene sequencing; linkage analysis (LOD 4.6); comparison across three families with conserved cysteine mutations in vWFD domain\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clinical/genetic correlation across multiple families, no direct biochemical validation of disulfide bond or protein interaction\",\n      \"pmids\": [\"15319541\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Alpha-tectorin (TECTA) is the major non-collagenous glycoprotein of the cochlear tectorial membrane (TM), essential for normal hearing; it forms the striated-sheet matrix of the TM where it interacts with beta-tectorin and otogelin, mediates TM attachment to outer hair cell stereocilia, and controls TM mechanical properties (shear impedance, fixed charge, porosity) that couple sound-induced vibration to hair cell mechanotransduction — with domain-specific mutations in the ZP domain causing mid-frequency hearing loss and ZA/vWFD domain mutations causing high-frequency hearing loss, and dominant mutations acting via dominant-negative rather than haploinsufficiency mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TECTA encodes alpha-tectorin, the major non-collagenous glycoprotein of the cochlear tectorial membrane (TM), where it builds the striated-sheet matrix required for normal hearing [#4, #6]. Within the TM, alpha-tectorin interacts with beta-tectorin and otogelin, and a recessive A349D substitution that is incorporated into the TM yet cannot bind these partners abolishes striated-sheet assembly and depletes beta-tectorin and otogelin, identifying them as functional partners in matrix construction [#4]. Tecta is transcribed at high levels during TM morphogenesis, peaking at postnatal day 3 [#2]. Functionally, TECTA-dependent TM attachment mechanically couples sound-induced vibration to outer hair cell mechanotransduction: detachment of the TM abolishes normal TM-dependent hair cell excitation and otoacoustic emissions [#3], and point mutations that alter TM composition reduce fixed charge, raise porosity, lower shear impedance and axial stiffness, and degrade OHC stereociliary coupling and amplification [#5, #6, #11]. Mutations show domain-specific genotype-phenotype relationships, with knock-in alleles in distinct domains producing characteristic threshold and structural phenotypes [#8], and dominant disease alleles act through a dominant-negative mechanism rather than haploinsufficiency, since splicing variants produce altered protein without reducing mRNA levels [#12, #13].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the genomic location of TECTA was needed to test whether this TM glycoprotein underlies an inherited deafness locus.\",\n      \"evidence\": \"YAC-based physical mapping and mouse-human synteny analysis placing TECTA in the DFNA12 candidate interval\",\n      \"pmids\": [\"9503015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping alone does not prove causation\", \"No functional consequence of any allele established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"A recessive splice-site mutation showed TECTA loss can cause deafness and implied alpha-tectorin functions in homo- or heteromeric assemblies.\",\n      \"evidence\": \"Linkage and gene sequencing in a consanguineous family with carrier-versus-dominant phenotype comparison\",\n      \"pmids\": [\"9949200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein truncation inferred, not directly observed\", \"Oligomeric partners not identified at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining when TECTA is expressed clarified its developmental window of action in TM formation.\",\n      \"evidence\": \"Quantitative RT-PCR across mouse cochlear developmental time points\",\n      \"pmids\": [\"11711860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA timing does not establish protein dynamics\", \"No link to specific assembly events\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether TM attachment is required for hair cell function was tested by examining a TM-detached mutant, showing the TM mechanically couples sound to OHC excitation.\",\n      \"evidence\": \"DPOAE recording in Tecta(deltaENT/deltaENT) mice with detached TMs\",\n      \"pmids\": [\"14523068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve which molecular interactions mediate attachment\", \"Mechanism distinct from frank TM absence not dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Cross-family correlation linked vWFD-domain cysteine mutations to high-frequency loss versus mid-frequency loss for other mutations, introducing domain-specific genotype-phenotype mapping.\",\n      \"evidence\": \"TECTA sequencing and linkage across three families with conserved cysteine substitutions\",\n      \"pmids\": [\"15319541\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical validation of proposed disulfide bonds or interactions\", \"Clinical correlation only, no functional assay\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying alpha-tectorin's TM binding partners answered how the matrix is assembled: the A349D protein incorporates but fails to bind beta-tectorin and otogelin, abolishing the striated-sheet matrix.\",\n      \"evidence\": \"Spontaneous mouse missense mutant with immunolabeling for Tectb and otogelin and EM of TM ultrastructure\",\n      \"pmids\": [\"18452040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction surfaces not mapped\", \"Stoichiometry of the matrix network unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A synonymous variant disrupting an exonic splice enhancer showed that splicing defects deleting sequence near the ZP domain impair alpha-tectorin function.\",\n      \"evidence\": \"RT-PCR of aberrant transcript, ESE prediction, and segregation analysis\",\n      \"pmids\": [\"18575463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect on protein folding/secretion inferred, not measured\", \"Mechanism of ZP-domain impairment not shown directly\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"How a dominant mutation degrades hearing was answered biophysically: Y1870C lowers tectorin and glycoconjugate content, fixed charge, and shear impedance, tying TM material properties to threshold shifts.\",\n      \"evidence\": \"Force spectroscopy, osmotic pressure and fixed-charge measurement, and lectin/immunolabeling in Tecta(Y1870C/+) TMs\",\n      \"pmids\": [\"21081075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of porosity increase not resolved at structural level\", \"Heterozygous protein interaction defect not directly visualized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The C1509G allele linked alpha-tectorin directly to OHC mechanical coupling, showing dose-dependent loss of TM-OHC attachment and reduced TM stiffness that lowers stereociliary deflection.\",\n      \"evidence\": \"SHG/THG imaging, SEM, stereocilin immunolabeling, force spectroscopy, and modeling across genotypes\",\n      \"pmids\": [\"21575588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface between TM and stereocilin/stereocilia not defined\", \"Causal link from stiffness to amplification is model-based\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A splice-site variant producing a truncated protein in compound heterozygosity confirmed recessive nonsyndromic hearing loss from TECTA disruption.\",\n      \"evidence\": \"In vitro exon-trapping assay and Sanger sequencing with segregation analysis\",\n      \"pmids\": [\"22037481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Truncated protein not characterized at protein level\", \"TM consequences not examined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Why ZP-domain missense mutations are pathogenic was addressed by showing they alter intracellular localization, implicating impaired secretion and reduced TM incorporation.\",\n      \"evidence\": \"In vitro expression and localization comparison of wild-type versus mutant alpha-tectorin\",\n      \"pmids\": [\"22718023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-based localization assay without reconstitution or structural validation\", \"Secretion defect inferred from localization only\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An allelic series of knock-in mice established that ZP- versus ZA-domain mutations produce distinct TM structural and threshold phenotypes, formalizing domain-specific pathology.\",\n      \"evidence\": \"Three knock-in mouse models with ABR thresholds and TM structural analysis\",\n      \"pmids\": [\"24363064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism distinguishing domain effects not fully resolved\", \"Frequency mapping to TM regions not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How a structural TM defect alters cochlear amplification was probed by showing Y1870C/+ mice over-emit SOAEs with separated Kimura's membrane, indicating dysregulated OHC amplification control.\",\n      \"evidence\": \"SOAE recording, suppressor-tone experiments, and TM structural analysis in knock-in mice\",\n      \"pmids\": [\"30627650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from TM separation to SOAE emission not fully mechanistic\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether dominant splicing variants act by loss of dosage or dominant-negative effect was resolved: aberrant splicing alters protein without reducing mRNA, supporting a dominant-negative mechanism for DFNA8/12.\",\n      \"evidence\": \"Minigene and in vivo RNA analysis with qRT-PCR for two splice variants (c.5383+6T>A and c.5999G>A)\",\n      \"pmids\": [\"38676628\", \"40583560\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of mutant protein poisoning wild-type assembly not shown\", \"Effect on TM not examined in patient tissue\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic-level interaction surfaces by which alpha-tectorin binds beta-tectorin, otogelin, and the OHC stereociliary apparatus, and the molecular basis of dominant-negative interference, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the alpha-tectorin matrix network\", \"Disulfide bonding and ZP-domain processing not biochemically resolved\", \"Mechanism of dominant-negative protein interaction not directly demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"tectorial membrane striated-sheet matrix\"],\n    \"partners\": [\"TECTB\", \"OTOG\", \"STRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}