{"gene":"CEACAM16","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2014,"finding":"CEACAM16 interacts with both α-tectorin (TECTA) and β-tectorin (TECTB) in the tectorial membrane; loss of CEACAM16 reduces TECTB levels, abolishes the striated-sheet matrix, and eliminates Hensen's stripe, suggesting CEACAM16 stabilizes TECTA–TECTB interactions.","method":"Ceacam16-null mutant mouse; immunohistochemistry and electron microscopy of tectorial membrane structure; Co-immunoprecipitation/interaction assays confirming binding to TECTA and TECTB","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mutant mouse with defined structural phenotypes, protein interaction data, replicated across two independent null-mouse studies (PMIDs 25080593 and 22544735)","pmids":["25080593"],"is_preprint":false},{"year":2012,"finding":"CEACAM16 can engage in homotypic trans interactions via its C-terminal immunoglobulin variable-like N2 domain (demonstrated by cell-sorting assay), and forms oligomers through unpaired cysteines (demonstrated by Western blot under reducing vs. non-reducing conditions).","method":"Ectopic cell-surface expression of the N2 domain of CEACAM16 followed by homotypic cell-sorting assay; Western blot under reducing and non-reducing conditions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (cell-sorting and redox Western blot) in a single study","pmids":["22544735"],"is_preprint":false},{"year":2012,"finding":"CEACAM16 is secreted and deposited into the tectorial membrane between postnatal days 12–15 (onset of hearing in mice), originating from interdental and Deiters cells; its loss alters tectorial membrane physical properties (more often stretched out rather than contracted and detached from outer hair cells).","method":"Immunohistochemistry of cochlear sections from wild-type and Ceacam16−/− mice at multiple postnatal ages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (TM morphology change) in null mutant, single lab","pmids":["22544735"],"is_preprint":false},{"year":2015,"finding":"CEACAM16 is a secreted protein; a missense mutation p.G169R in exon 3 significantly reduces secretion efficiency of the mutant protein compared to wild-type, as demonstrated in transfected HEK293T cells.","method":"Immunofluorescence staining and Western blot of HEK293T cells transfected with wild-type vs. mutant CEACAM16; secretion assay comparing conditioned medium protein levels","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct secretion assay with mutant vs. wild-type comparison using two orthogonal detection methods, single lab","pmids":["25589040"],"is_preprint":false},{"year":2018,"finding":"Loss-of-function splice-altering variants in CEACAM16 (c.37G>T causing complete skipping of exon 2 and loss of AUG start site; c.662-1G>C activating a cryptic splice site causing frameshift) cause recessive hearing loss, establishing that biallelic loss of CEACAM16 function is sufficient to produce deafness.","method":"Minigene splicing assays for both variants; next-generation sequencing with OtoSCOPE panel; Sanger sequencing for segregation","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional minigene splicing assays validating molecular mechanism, single lab","pmids":["29703829"],"is_preprint":false},{"year":2019,"finding":"Loss of CEACAM16 accelerates age-related degradation of the tectorial membrane core matrix, with apically-biased (low-frequency region) progression, leading to progressive late-onset hearing loss in aged null-mutant mice.","method":"Longitudinal analysis of Ceacam16 null mutant mice at 1, 6, and 12 months; ABR, DPOAE, and SOAE measurements; histological analysis of tectorial membrane structure","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — longitudinal in vivo null-mutant study with multiple functional and structural readouts, single lab","pmids":["31249509"],"is_preprint":false},{"year":2021,"finding":"CEACAM16 is required for maintaining tectorial membrane stiffness and viscosity in adult mice; TMs from adult Ceacam16 null mice show significantly reduced stiffness and viscosity relative to wild-type controls, while juvenile null mice have TM mechanical properties more similar to wild-type.","method":"Direct mechanical measurements (stiffness and viscosity) of isolated tectorial membranes from Ceacam16 null and wild-type mice at juvenile and adult ages using biophysical assays","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro biophysical measurement with age-matched controls, single lab, multiple age timepoints","pmids":["34555361"],"is_preprint":false},{"year":2014,"finding":"Loss of CEACAM16 leads to increased spontaneous otoacoustic emissions (SOAEs) in 70% of null mice vs. <3% in wild-type, with SOAEs predominantly >15 kHz correlating with loss of Hensen's stripe, indicating CEACAM16-dependent tectorial membrane structure balances cochlear amplifier gain against instability.","method":"In vivo SOAE, stimulus-frequency OAE, transiently evoked OAE, and ABR measurements in Ceacam16-null mutant vs. wild-type mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined functional phenotype in null mutant with multiple electrophysiological readouts, replicated across labs in follow-up studies","pmids":["25080593"],"is_preprint":false}],"current_model":"CEACAM16 is a secreted glycoprotein deposited into the tectorial membrane of the cochlea from interdental and Deiters cells at hearing onset; it forms oligomers via unpaired cysteines and engages in homotypic trans-interactions through its N2 domain, and interacts with both α-tectorin (TECTA) and β-tectorin (TECTB) to stabilize the striated-sheet matrix, maintain tectorial membrane stiffness and viscosity, and balance cochlear amplifier gain—loss of CEACAM16 disrupts tectorial membrane structure and mechanics, leading to progressive age-related hearing loss, while dominant missense mutations reduce secretion efficiency and recessive loss-of-function alleles cause postlingual progressive deafness."},"narrative":{"mechanistic_narrative":"CEACAM16 is a secreted glycoprotein that builds and maintains the structural and mechanical integrity of the cochlear tectorial membrane, where it functions as an essential matrix-organizing factor for hearing [PMID:25080593, PMID:22544735]. It is deposited into the tectorial membrane from interdental and Deiters cells around the onset of hearing (postnatal days 12–15) and physically interacts with both α-tectorin (TECTA) and β-tectorin (TECTB); its loss reduces TECTB levels, abolishes the striated-sheet matrix, and eliminates Hensen's stripe, indicating that CEACAM16 stabilizes the TECTA–TECTB matrix [PMID:25080593, PMID:22544735]. CEACAM16 forms oligomers through unpaired cysteines and mediates homotypic trans-interactions via its C-terminal N2 immunoglobulin variable-like domain, providing a molecular basis for its matrix-crosslinking role [PMID:22544735]. Functionally, CEACAM16 is required to maintain tectorial membrane stiffness and viscosity in adult animals and to balance cochlear amplifier gain against instability, as its loss produces aberrant spontaneous otoacoustic emissions and progressive, apically-biased age-related degradation of the tectorial membrane core [PMID:31249509, PMID:34555361, PMID:25080593]. Recessive loss-of-function splice variants cause progressive deafness, while a dominant missense allele (p.G169R) impairs secretion of the protein, directly linking CEACAM16 dysfunction to hereditary hearing loss [PMID:25589040, PMID:29703829].","teleology":[{"year":2012,"claim":"Established the molecular basis for how CEACAM16 could organize an extracellular matrix by showing it self-associates, defining oligomerization and trans-interaction as its core biochemical activities.","evidence":"Ectopic N2-domain cell-surface expression with homotypic cell-sorting assay and reducing vs. non-reducing Western blots","pmids":["22544735"],"confidence":"Medium","gaps":["Structural basis of N2-domain trans-interaction not resolved","Which cysteines mediate oligomerization not mapped","Stoichiometry of oligomers undefined"]},{"year":2012,"claim":"Defined the spatial and temporal context of CEACAM16 function, showing it is secreted into the tectorial membrane at hearing onset and that its loss alters membrane morphology.","evidence":"Immunohistochemistry of cochlear sections from wild-type and Ceacam16-null mice across postnatal ages","pmids":["22544735"],"confidence":"Medium","gaps":["Mechanism coupling secretion timing to hearing onset unknown","Single-lab localization data"]},{"year":2014,"claim":"Resolved how CEACAM16 contributes to matrix architecture by identifying TECTA and TECTB as binding partners and linking its loss to collapse of the striated-sheet matrix and Hensen's stripe.","evidence":"Ceacam16-null mouse with IHC and EM of tectorial membrane plus Co-IP/interaction assays for TECTA and TECTB","pmids":["25080593"],"confidence":"High","gaps":["Binding interfaces with TECTA/TECTB not mapped","Whether interactions are direct or matrix-mediated not fully distinguished","Stoichiometry within the striated sheet unknown"]},{"year":2014,"claim":"Connected CEACAM16-dependent matrix structure to cochlear amplifier function, showing its loss causes aberrant spontaneous otoacoustic emissions correlated with loss of Hensen's stripe.","evidence":"In vivo SOAE, SFOAE, TEOAE, and ABR measurements in Ceacam16-null vs. wild-type mice","pmids":["25080593"],"confidence":"High","gaps":["Quantitative link between matrix mechanics and amplifier gain not established","Frequency-dependence mechanism unresolved"]},{"year":2015,"claim":"Provided a disease-relevant mechanism by showing the p.G169R missense mutation reduces secretion efficiency, explaining how a dominant allele impairs CEACAM16 deposition.","evidence":"Immunofluorescence, Western blot, and conditioned-medium secretion assay in transfected HEK293T cells comparing wild-type and mutant","pmids":["25589040"],"confidence":"Medium","gaps":["Cellular fate of retained mutant protein not determined","In vivo consequence in cochlea not tested","Single-lab heterologous system"]},{"year":2018,"claim":"Established that biallelic loss of CEACAM16 function is sufficient to cause deafness, defining a recessive loss-of-function disease mechanism distinct from the dominant secretion-defect allele.","evidence":"Minigene splicing assays for two splice-altering variants, OtoSCOPE NGS, and Sanger segregation","pmids":["29703829"],"confidence":"Medium","gaps":["Residual protein levels in patients not quantified","Genotype–phenotype severity correlation limited","Single-lab functional validation"]},{"year":2019,"claim":"Demonstrated that CEACAM16 maintains tectorial membrane integrity over the lifespan, with its loss accelerating apically-biased matrix degradation and producing progressive late-onset hearing loss.","evidence":"Longitudinal ABR, DPOAE, SOAE, and histology in null mice at 1, 6, and 12 months","pmids":["31249509"],"confidence":"Medium","gaps":["Molecular cause of apical-to-basal gradient unknown","Whether degradation is degradative vs. failure-to-maintain not distinguished"]},{"year":2021,"claim":"Directly quantified the mechanical role of CEACAM16, showing it is required to maintain adult tectorial membrane stiffness and viscosity while being dispensable for juvenile mechanics.","evidence":"Direct biophysical stiffness and viscosity measurements of isolated tectorial membranes from null and wild-type mice at juvenile and adult ages","pmids":["34555361"],"confidence":"Medium","gaps":["Molecular basis for age-dependent mechanical decline unresolved","Link between measured mechanics and amplifier gain not directly tested","Single-lab measurement"]},{"year":null,"claim":"How CEACAM16 oligomerization and trans-interaction are structurally coordinated with TECTA/TECTB binding to assemble the striated-sheet matrix, and how this assembly sets frequency-dependent mechanical properties, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the CEACAM16–tectorin complex","Binding interfaces unmapped","Mechanism linking matrix architecture to amplifier gain undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[0,2]}],"pathway":[],"complexes":[],"partners":["TECTA","TECTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2WEN9","full_name":"Cell adhesion molecule CEACAM16","aliases":["Carcinoembryonic antigen-like 2","Carcinoembryonic antigen-related cell adhesion molecule 16","CEA cell adhesion molecule 16"],"length_aa":425,"mass_kda":45.9,"function":"Required for proper hearing, plays a role in maintaining the integrity of the tectorial membrane","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q2WEN9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEACAM16","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEACAM16","total_profiled":1310},"omim":[{"mim_id":"618410","title":"DEAFNESS, AUTOSOMAL RECESSIVE 113; DFNB113","url":"https://www.omim.org/entry/618410"},{"mim_id":"614614","title":"DEAFNESS, AUTOSOMAL DOMINANT 4B; DFNA4B","url":"https://www.omim.org/entry/614614"},{"mim_id":"614591","title":"CEA CELL ADHESION MOLECULE 16; CEACAM16","url":"https://www.omim.org/entry/614591"},{"mim_id":"600652","title":"DEAFNESS, AUTOSOMAL DOMINANT 4A; DFNA4A","url":"https://www.omim.org/entry/600652"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"pancreas","ntpm":1.9}],"url":"https://www.proteinatlas.org/search/CEACAM16"},"hgnc":{"alias_symbol":["DFNA4B"],"prev_symbol":[]},"alphafold":{"accession":"Q2WEN9","domains":[{"cath_id":"2.60.40.10","chopping":"24-125","consensus_level":"high","plddt":94.7609,"start":24,"end":125},{"cath_id":"2.60.40.10","chopping":"135-214","consensus_level":"high","plddt":95.7236,"start":135,"end":214},{"cath_id":"2.60.40.10","chopping":"227-313","consensus_level":"high","plddt":90.287,"start":227,"end":313},{"cath_id":"2.60.40.10","chopping":"321-420","consensus_level":"high","plddt":93.9095,"start":321,"end":420}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2WEN9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2WEN9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2WEN9-F1-predicted_aligned_error_v6.png","plddt_mean":90.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEACAM16","jax_strain_url":"https://www.jax.org/strain/search?query=CEACAM16"},"sequence":{"accession":"Q2WEN9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2WEN9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2WEN9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2WEN9"}},"corpus_meta":[{"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":"22544735","id":"PMC_22544735","title":"Loss of mammal-specific tectorial membrane component carcinoembryonic antigen cell adhesion molecule 16 (CEACAM16) leads to hearing impairment at low and high frequencies.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22544735","citation_count":41,"is_preprint":false},{"pmid":"29703829","id":"PMC_29703829","title":"Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29703829","citation_count":26,"is_preprint":false},{"pmid":"25589040","id":"PMC_25589040","title":"Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family.","date":"2015","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25589040","citation_count":20,"is_preprint":false},{"pmid":"31249509","id":"PMC_31249509","title":"Accelerated Age-Related Degradation of the Tectorial Membrane in the Ceacam16 Null Mutant Mouse, a Model for Late-Onset Human Hereditary Deafness DFNB113.","date":"2019","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31249509","citation_count":19,"is_preprint":false},{"pmid":"26648831","id":"PMC_26648831","title":"A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment.","date":"2015","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/26648831","citation_count":11,"is_preprint":false},{"pmid":"30514912","id":"PMC_30514912","title":"Further evidence for loss-of-function mutations in the CEACAM16 gene causing nonsyndromic autosomal recessive hearing loss in humans.","date":"2018","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30514912","citation_count":9,"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":"33040498","id":"PMC_33040498","title":"[Identification of a novel mutation of CEACAM16 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss].","date":"2020","source":"Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/33040498","citation_count":2,"is_preprint":false},{"pmid":"39157884","id":"PMC_39157884","title":"Auditory Phenotype of a Novel Missense Variant in the CEACAM16 Gene in a Large Russian Family With Autosomal Dominant Nonsyndromic Hearing Loss.","date":"2024","source":"The journal of international advanced otology","url":"https://pubmed.ncbi.nlm.nih.gov/39157884","citation_count":1,"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":7547,"output_tokens":2013,"usd":0.026418,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9008,"output_tokens":2938,"usd":0.059245,"stage2_stop_reason":"end_turn"},"total_usd":0.085663,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"CEACAM16 interacts with both α-tectorin (TECTA) and β-tectorin (TECTB) in the tectorial membrane; loss of CEACAM16 reduces TECTB levels, abolishes the striated-sheet matrix, and eliminates Hensen's stripe, suggesting CEACAM16 stabilizes TECTA–TECTB interactions.\",\n      \"method\": \"Ceacam16-null mutant mouse; immunohistochemistry and electron microscopy of tectorial membrane structure; Co-immunoprecipitation/interaction assays confirming binding to TECTA and TECTB\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mutant mouse with defined structural phenotypes, protein interaction data, replicated across two independent null-mouse studies (PMIDs 25080593 and 22544735)\",\n      \"pmids\": [\"25080593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEACAM16 can engage in homotypic trans interactions via its C-terminal immunoglobulin variable-like N2 domain (demonstrated by cell-sorting assay), and forms oligomers through unpaired cysteines (demonstrated by Western blot under reducing vs. non-reducing conditions).\",\n      \"method\": \"Ectopic cell-surface expression of the N2 domain of CEACAM16 followed by homotypic cell-sorting assay; Western blot under reducing and non-reducing conditions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (cell-sorting and redox Western blot) in a single study\",\n      \"pmids\": [\"22544735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CEACAM16 is secreted and deposited into the tectorial membrane between postnatal days 12–15 (onset of hearing in mice), originating from interdental and Deiters cells; its loss alters tectorial membrane physical properties (more often stretched out rather than contracted and detached from outer hair cells).\",\n      \"method\": \"Immunohistochemistry of cochlear sections from wild-type and Ceacam16−/− mice at multiple postnatal ages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (TM morphology change) in null mutant, single lab\",\n      \"pmids\": [\"22544735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEACAM16 is a secreted protein; a missense mutation p.G169R in exon 3 significantly reduces secretion efficiency of the mutant protein compared to wild-type, as demonstrated in transfected HEK293T cells.\",\n      \"method\": \"Immunofluorescence staining and Western blot of HEK293T cells transfected with wild-type vs. mutant CEACAM16; secretion assay comparing conditioned medium protein levels\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct secretion assay with mutant vs. wild-type comparison using two orthogonal detection methods, single lab\",\n      \"pmids\": [\"25589040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss-of-function splice-altering variants in CEACAM16 (c.37G>T causing complete skipping of exon 2 and loss of AUG start site; c.662-1G>C activating a cryptic splice site causing frameshift) cause recessive hearing loss, establishing that biallelic loss of CEACAM16 function is sufficient to produce deafness.\",\n      \"method\": \"Minigene splicing assays for both variants; next-generation sequencing with OtoSCOPE panel; Sanger sequencing for segregation\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional minigene splicing assays validating molecular mechanism, single lab\",\n      \"pmids\": [\"29703829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of CEACAM16 accelerates age-related degradation of the tectorial membrane core matrix, with apically-biased (low-frequency region) progression, leading to progressive late-onset hearing loss in aged null-mutant mice.\",\n      \"method\": \"Longitudinal analysis of Ceacam16 null mutant mice at 1, 6, and 12 months; ABR, DPOAE, and SOAE measurements; histological analysis of tectorial membrane structure\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — longitudinal in vivo null-mutant study with multiple functional and structural readouts, single lab\",\n      \"pmids\": [\"31249509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEACAM16 is required for maintaining tectorial membrane stiffness and viscosity in adult mice; TMs from adult Ceacam16 null mice show significantly reduced stiffness and viscosity relative to wild-type controls, while juvenile null mice have TM mechanical properties more similar to wild-type.\",\n      \"method\": \"Direct mechanical measurements (stiffness and viscosity) of isolated tectorial membranes from Ceacam16 null and wild-type mice at juvenile and adult ages using biophysical assays\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biophysical measurement with age-matched controls, single lab, multiple age timepoints\",\n      \"pmids\": [\"34555361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of CEACAM16 leads to increased spontaneous otoacoustic emissions (SOAEs) in 70% of null mice vs. <3% in wild-type, with SOAEs predominantly >15 kHz correlating with loss of Hensen's stripe, indicating CEACAM16-dependent tectorial membrane structure balances cochlear amplifier gain against instability.\",\n      \"method\": \"In vivo SOAE, stimulus-frequency OAE, transiently evoked OAE, and ABR measurements in Ceacam16-null mutant vs. wild-type mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined functional phenotype in null mutant with multiple electrophysiological readouts, replicated across labs in follow-up studies\",\n      \"pmids\": [\"25080593\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEACAM16 is a secreted glycoprotein deposited into the tectorial membrane of the cochlea from interdental and Deiters cells at hearing onset; it forms oligomers via unpaired cysteines and engages in homotypic trans-interactions through its N2 domain, and interacts with both α-tectorin (TECTA) and β-tectorin (TECTB) to stabilize the striated-sheet matrix, maintain tectorial membrane stiffness and viscosity, and balance cochlear amplifier gain—loss of CEACAM16 disrupts tectorial membrane structure and mechanics, leading to progressive age-related hearing loss, while dominant missense mutations reduce secretion efficiency and recessive loss-of-function alleles cause postlingual progressive deafness.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEACAM16 is a secreted glycoprotein that builds and maintains the structural and mechanical integrity of the cochlear tectorial membrane, where it functions as an essential matrix-organizing factor for hearing [#0, #2]. It is deposited into the tectorial membrane from interdental and Deiters cells around the onset of hearing (postnatal days 12–15) and physically interacts with both α-tectorin (TECTA) and β-tectorin (TECTB); its loss reduces TECTB levels, abolishes the striated-sheet matrix, and eliminates Hensen's stripe, indicating that CEACAM16 stabilizes the TECTA–TECTB matrix [#0, #2]. CEACAM16 forms oligomers through unpaired cysteines and mediates homotypic trans-interactions via its C-terminal N2 immunoglobulin variable-like domain, providing a molecular basis for its matrix-crosslinking role [#1]. Functionally, CEACAM16 is required to maintain tectorial membrane stiffness and viscosity in adult animals and to balance cochlear amplifier gain against instability, as its loss produces aberrant spontaneous otoacoustic emissions and progressive, apically-biased age-related degradation of the tectorial membrane core [#5, #6, #7]. Recessive loss-of-function splice variants cause progressive deafness, while a dominant missense allele (p.G169R) impairs secretion of the protein, directly linking CEACAM16 dysfunction to hereditary hearing loss [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the molecular basis for how CEACAM16 could organize an extracellular matrix by showing it self-associates, defining oligomerization and trans-interaction as its core biochemical activities.\",\n      \"evidence\": \"Ectopic N2-domain cell-surface expression with homotypic cell-sorting assay and reducing vs. non-reducing Western blots\",\n      \"pmids\": [\"22544735\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of N2-domain trans-interaction not resolved\", \"Which cysteines mediate oligomerization not mapped\", \"Stoichiometry of oligomers undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the spatial and temporal context of CEACAM16 function, showing it is secreted into the tectorial membrane at hearing onset and that its loss alters membrane morphology.\",\n      \"evidence\": \"Immunohistochemistry of cochlear sections from wild-type and Ceacam16-null mice across postnatal ages\",\n      \"pmids\": [\"22544735\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism coupling secretion timing to hearing onset unknown\", \"Single-lab localization data\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how CEACAM16 contributes to matrix architecture by identifying TECTA and TECTB as binding partners and linking its loss to collapse of the striated-sheet matrix and Hensen's stripe.\",\n      \"evidence\": \"Ceacam16-null mouse with IHC and EM of tectorial membrane plus Co-IP/interaction assays for TECTA and TECTB\",\n      \"pmids\": [\"25080593\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Binding interfaces with TECTA/TECTB not mapped\", \"Whether interactions are direct or matrix-mediated not fully distinguished\", \"Stoichiometry within the striated sheet unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected CEACAM16-dependent matrix structure to cochlear amplifier function, showing its loss causes aberrant spontaneous otoacoustic emissions correlated with loss of Hensen's stripe.\",\n      \"evidence\": \"In vivo SOAE, SFOAE, TEOAE, and ABR measurements in Ceacam16-null vs. wild-type mice\",\n      \"pmids\": [\"25080593\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Quantitative link between matrix mechanics and amplifier gain not established\", \"Frequency-dependence mechanism unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided a disease-relevant mechanism by showing the p.G169R missense mutation reduces secretion efficiency, explaining how a dominant allele impairs CEACAM16 deposition.\",\n      \"evidence\": \"Immunofluorescence, Western blot, and conditioned-medium secretion assay in transfected HEK293T cells comparing wild-type and mutant\",\n      \"pmids\": [\"25589040\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cellular fate of retained mutant protein not determined\", \"In vivo consequence in cochlea not tested\", \"Single-lab heterologous system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that biallelic loss of CEACAM16 function is sufficient to cause deafness, defining a recessive loss-of-function disease mechanism distinct from the dominant secretion-defect allele.\",\n      \"evidence\": \"Minigene splicing assays for two splice-altering variants, OtoSCOPE NGS, and Sanger segregation\",\n      \"pmids\": [\"29703829\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Residual protein levels in patients not quantified\", \"Genotype–phenotype severity correlation limited\", \"Single-lab functional validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that CEACAM16 maintains tectorial membrane integrity over the lifespan, with its loss accelerating apically-biased matrix degradation and producing progressive late-onset hearing loss.\",\n      \"evidence\": \"Longitudinal ABR, DPOAE, SOAE, and histology in null mice at 1, 6, and 12 months\",\n      \"pmids\": [\"31249509\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular cause of apical-to-basal gradient unknown\", \"Whether degradation is degradative vs. failure-to-maintain not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Directly quantified the mechanical role of CEACAM16, showing it is required to maintain adult tectorial membrane stiffness and viscosity while being dispensable for juvenile mechanics.\",\n      \"evidence\": \"Direct biophysical stiffness and viscosity measurements of isolated tectorial membranes from null and wild-type mice at juvenile and adult ages\",\n      \"pmids\": [\"34555361\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular basis for age-dependent mechanical decline unresolved\", \"Link between measured mechanics and amplifier gain not directly tested\", \"Single-lab measurement\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEACAM16 oligomerization and trans-interaction are structurally coordinated with TECTA/TECTB binding to assemble the striated-sheet matrix, and how this assembly sets frequency-dependent mechanical properties, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the CEACAM16–tectorin complex\", \"Binding interfaces unmapped\", \"Mechanism linking matrix architecture to amplifier gain undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:9709957\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TECTA\", \"TECTB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}