{"gene":"CABP2","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2012,"finding":"A splice-site mutation (c.637+1G>T) in CABP2 leads to exon 6 skipping and premature truncation (p.Phe164Serfs*4); the truncated CaBP2 showed altered Ca2+ binding by isothermal titration calorimetry and less potent regulation of CaV1.3 Ca2+ channels compared to wild-type CaBP2, establishing that CaBP2 modulates CaV1.3 channels via Ca2+ sensing.","method":"Isothermal titration calorimetry (Ca2+ binding assay) and CaV1.3 channel regulation assay comparing wild-type vs. truncated CaBP2","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro Ca2+ binding assay and channel regulation functional assay with mutant vs. wild-type comparison in a single rigorous study","pmids":["22981119"],"is_preprint":false},{"year":2021,"finding":"AAV-mediated delivery of Cabp2 coding sequence into inner hair cells (IHCs) of Cabp2 knockout mice restored CaV1.3 calcium channel function (reversed enhanced steady-state inactivation) and improved hearing, confirming that CaBP2 suppresses steady-state inactivation of IHC CaV1.3 channels to enable synaptic sound encoding.","method":"AAV2/1 and AAV-PHP.eB gene delivery in Cabp2 KO mice; in vitro patch clamp of IHCs and in vivo auditory brainstem responses (ABRs)","journal":"Frontiers in molecular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function rescue with defined cellular phenotype (CaV1.3 inactivation and ABR recovery), two orthogonal methods (patch clamp + ABR), single lab","pmids":["34489639"],"is_preprint":false},{"year":2018,"finding":"CaBP2 KO mice exhibit significant ABR threshold elevations and reduced DPOAEs by 9 weeks, demonstrating that CaBP2 is required for normal peripheral auditory function, particularly in the mid-frequency range, and that loss of CaBP2 impairs both inner and outer hair cell-dependent hearing.","method":"Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Cabp2 KO mice","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined auditory phenotype using two orthogonal functional assays, single lab","pmids":["29661613"],"is_preprint":false},{"year":2016,"finding":"CaBP2 KO mice show altered retinal ganglion cell light response amplitude and kinetics compared to wild-type, while gross retinal and synapse morphology (including ribbon synapses) remain normal, indicating CaBP2 is required for proper transmission of light responses through the retina via presynaptic Ca2+-dependent signaling, but not for synapse structural integrity.","method":"Whole-cell patch clamp recordings of retinal ganglion cells in Cabp2 KO mice; immunohistochemistry and transmission electron microscopy for morphology","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined electrophysiological phenotype and structural controls, multiple methods, single lab","pmids":["27822497"],"is_preprint":false},{"year":2025,"finding":"CaBP2 modulates presynaptic CaV1.3 Ca2+ channel function in IHCs; lack of CaBP2 causes enhanced steady-state inactivation of CaV1.3 channels, impairing synaptic sound encoding (auditory synaptopathy), consistent with its role as a required modulator of IHC presynaptic calcium channel availability.","method":"Review/perspective synthesizing DFNB93 mouse model electrophysiology and gene therapy preclinical data","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — mechanistic conclusion replicated across multiple independent studies cited; this paper synthesizes replicated findings from mouse models and gene therapy rescue experiments","pmids":["40927552"],"is_preprint":false}],"current_model":"CaBP2 is a calmodulin-related Ca2+-binding protein expressed in cochlear inner hair cells (IHCs) and retinal neurons that directly binds Ca2+ and suppresses steady-state inactivation of presynaptic CaV1.3 voltage-gated calcium channels, thereby sustaining calcium channel availability required for indefatigable synaptic sound encoding; loss of CaBP2 causes enhanced CaV1.3 inactivation leading to auditory synaptopathy (DFNB93), and AAV-mediated gene replacement restores IHC CaV1.3 function and hearing in mouse models."},"narrative":{"mechanistic_narrative":"CABP2 encodes a calmodulin-related Ca2+-binding protein that serves as a presynaptic modulator of CaV1.3 voltage-gated calcium channels required for synaptic signal encoding in cochlear inner hair cells and retinal neurons [PMID:22981119, PMID:34489639]. CaBP2 directly binds Ca2+ and, through this Ca2+ sensing, suppresses steady-state inactivation of CaV1.3 channels, thereby sustaining calcium channel availability for indefatigable synaptic transmission [PMID:22981119, PMID:34489639]. A truncating splice-site mutation that disrupts Ca2+ binding weakens CaV1.3 regulation, linking CaBP2 loss of function to autosomal-recessive deafness (DFNB93) [PMID:22981119]. In Cabp2 knockout mice, loss of CaBP2 produces enhanced CaV1.3 inactivation, elevated auditory brainstem response thresholds, and reduced otoacoustic emissions, while AAV-mediated re-expression of Cabp2 in inner hair cells reverses the enhanced channel inactivation and restores hearing [PMID:34489639, PMID:29661613]. CaBP2 additionally shapes retinal ganglion cell light-response amplitude and kinetics through presynaptic Ca2+-dependent signaling without being required for ribbon synapse structural integrity [PMID:27822497].","teleology":[{"year":2012,"claim":"Established that CaBP2 regulates CaV1.3 channels through its Ca2+-binding capacity by showing a disease-associated truncation impairs both Ca2+ binding and channel modulation.","evidence":"Isothermal titration calorimetry and CaV1.3 channel regulation assays comparing wild-type and truncated CaBP2 from a DFNB93 family","pmids":["22981119"],"confidence":"High","gaps":["Did not define which structural region of CaBP2 contacts CaV1.3","Channel regulation assessed in vitro, not in native hair cells"]},{"year":2016,"claim":"Demonstrated that CaBP2 is required for proper presynaptic Ca2+-dependent transmission of light responses in the retina, distinguishing a functional role from a structural one.","evidence":"Whole-cell patch clamp of retinal ganglion cells plus immunohistochemistry and electron microscopy in Cabp2 KO mice","pmids":["27822497"],"confidence":"Medium","gaps":["Did not identify the specific channel CaBP2 modulates in retinal neurons","Mechanism of altered response kinetics not resolved at the molecular level"]},{"year":2018,"claim":"Showed CaBP2 is required for normal peripheral auditory function across both inner and outer hair cell-dependent measures, defining the in vivo deafness phenotype.","evidence":"Auditory brainstem responses and distortion product otoacoustic emissions in Cabp2 KO mice","pmids":["29661613"],"confidence":"Medium","gaps":["DPOAE deficit implicates outer hair cells but the molecular basis there was not established","Frequency-specific vulnerability not mechanistically explained"]},{"year":2021,"claim":"Established causality and therapeutic reversibility by showing AAV-delivered Cabp2 restores CaV1.3 channel availability and hearing in knockout mice.","evidence":"AAV2/1 and AAV-PHP.eB gene delivery in Cabp2 KO mice with IHC patch clamp and in vivo ABR readouts","pmids":["34489639"],"confidence":"High","gaps":["Durability of rescue and human translatability not addressed","Did not resolve stoichiometry of CaBP2:CaV1.3 interaction"]},{"year":2025,"claim":"Consolidated the mechanistic model that CaBP2 suppresses CaV1.3 steady-state inactivation to maintain presynaptic Ca2+ channel availability for fatigue-resistant sound encoding.","evidence":"Review synthesizing DFNB93 mouse electrophysiology and gene therapy preclinical data","pmids":["40927552"],"confidence":"Medium","gaps":["No new primary data","Structural basis of channel modulation still undefined"]},{"year":null,"claim":"The structural mechanism by which CaBP2 binds and modulates CaV1.3, and whether it acts on additional channel targets in retinal neurons, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of a CaBP2–CaV1.3 complex","Identity of the retinal channel target not established","Interactome beyond CaV1.3 uncharacterized in the available corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":[],"partners":["CACNA1D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPB3","full_name":"Calcium-binding protein 2","aliases":[],"length_aa":220,"mass_kda":24.5,"function":"Required for sound encoding at inner hair cells (IHCs) synapses, likely via inhibition of the inactivation of voltage-gated calcium channel of type 1.3 (Cav1.3) in the IHCs (PubMed:28183797). Required for the normal transfer of light signals through the retina (By similarity)","subcellular_location":"Cytoplasm, perinuclear region; Cell membrane; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q9NPB3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CABP2","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/CABP2","total_profiled":1310},"omim":[{"mim_id":"614899","title":"DEAFNESS, AUTOSOMAL RECESSIVE 93; DFNB93","url":"https://www.omim.org/entry/614899"},{"mim_id":"608965","title":"CALCIUM-BINDING PROTEIN 4; CABP4","url":"https://www.omim.org/entry/608965"},{"mim_id":"607314","title":"CALCIUM-BINDING PROTEIN 2; CABP2","url":"https://www.omim.org/entry/607314"},{"mim_id":"600982","title":"MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 1; MAP3K1","url":"https://www.omim.org/entry/600982"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"retina","ntpm":6.8}],"url":"https://www.proteinatlas.org/search/CABP2"},"hgnc":{"alias_symbol":[],"prev_symbol":["DFNB93"]},"alphafold":{"accession":"Q9NPB3","domains":[{"cath_id":"1.10.238.10","chopping":"78-149","consensus_level":"high","plddt":84.8006,"start":78,"end":149},{"cath_id":"1.10.238.10","chopping":"153-220","consensus_level":"high","plddt":83.7529,"start":153,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPB3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPB3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPB3-F1-predicted_aligned_error_v6.png","plddt_mean":68.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CABP2","jax_strain_url":"https://www.jax.org/strain/search?query=CABP2"},"sequence":{"accession":"Q9NPB3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPB3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPB3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPB3"}},"corpus_meta":[{"pmid":"22981119","id":"PMC_22981119","title":"A mutation in CABP2, expressed in cochlear hair cells, causes autosomal-recessive hearing impairment.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22981119","citation_count":84,"is_preprint":false},{"pmid":"8300576","id":"PMC_8300576","title":"Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8300576","citation_count":77,"is_preprint":false},{"pmid":"7835433","id":"PMC_7835433","title":"Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7835433","citation_count":73,"is_preprint":false},{"pmid":"8477750","id":"PMC_8477750","title":"CaBP2 is a rat homolog of ERp72 with proteindisulfide isomerase activity.","date":"1993","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8477750","citation_count":57,"is_preprint":false},{"pmid":"29661613","id":"PMC_29661613","title":"Functions of CaBP1 and CaBP2 in the peripheral auditory system.","date":"2018","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/29661613","citation_count":21,"is_preprint":false},{"pmid":"34489639","id":"PMC_34489639","title":"Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.","date":"2021","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34489639","citation_count":21,"is_preprint":false},{"pmid":"27822497","id":"PMC_27822497","title":"Lack of CaBP1/Caldendrin or CaBP2 Leads to Altered Ganglion Cell Responses.","date":"2016","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/27822497","citation_count":13,"is_preprint":false},{"pmid":"9058200","id":"PMC_9058200","title":"Phosphorylation of CaBP1 and CaBP2 by protein kinase CK2.","date":"1997","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9058200","citation_count":10,"is_preprint":false},{"pmid":"31661684","id":"PMC_31661684","title":"A Novel Pathogenic Variant in the CABP2 Gene Causes Severe Nonsyndromic Hearing Loss in a Consanguineous Iranian Family.","date":"2019","source":"Audiology & neuro-otology","url":"https://pubmed.ncbi.nlm.nih.gov/31661684","citation_count":10,"is_preprint":false},{"pmid":"29318123","id":"PMC_29318123","title":"Genetic Linkage Analysis of DFNB4, DFNB28, DFNB93 Loci in Autosomal Recessive Non-syndromic Hearing Loss: Evidence for Digenic Inheritance in GJB2 and GJB3 Mutations.","date":"2018","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/29318123","citation_count":8,"is_preprint":false},{"pmid":"33666369","id":"PMC_33666369","title":"First reported CABP2-related non-syndromic hearing loss in Northern Europe.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33666369","citation_count":6,"is_preprint":false},{"pmid":"40927552","id":"PMC_40927552","title":"Is CABP2-Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry.","date":"2025","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/40927552","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8170,"output_tokens":1403,"usd":0.022777,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8095,"output_tokens":1933,"usd":0.0444,"stage2_stop_reason":"end_turn"},"total_usd":0.067177,"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\": 2012,\n      \"finding\": \"A splice-site mutation (c.637+1G>T) in CABP2 leads to exon 6 skipping and premature truncation (p.Phe164Serfs*4); the truncated CaBP2 showed altered Ca2+ binding by isothermal titration calorimetry and less potent regulation of CaV1.3 Ca2+ channels compared to wild-type CaBP2, establishing that CaBP2 modulates CaV1.3 channels via Ca2+ sensing.\",\n      \"method\": \"Isothermal titration calorimetry (Ca2+ binding assay) and CaV1.3 channel regulation assay comparing wild-type vs. truncated CaBP2\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro Ca2+ binding assay and channel regulation functional assay with mutant vs. wild-type comparison in a single rigorous study\",\n      \"pmids\": [\"22981119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AAV-mediated delivery of Cabp2 coding sequence into inner hair cells (IHCs) of Cabp2 knockout mice restored CaV1.3 calcium channel function (reversed enhanced steady-state inactivation) and improved hearing, confirming that CaBP2 suppresses steady-state inactivation of IHC CaV1.3 channels to enable synaptic sound encoding.\",\n      \"method\": \"AAV2/1 and AAV-PHP.eB gene delivery in Cabp2 KO mice; in vitro patch clamp of IHCs and in vivo auditory brainstem responses (ABRs)\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function rescue with defined cellular phenotype (CaV1.3 inactivation and ABR recovery), two orthogonal methods (patch clamp + ABR), single lab\",\n      \"pmids\": [\"34489639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CaBP2 KO mice exhibit significant ABR threshold elevations and reduced DPOAEs by 9 weeks, demonstrating that CaBP2 is required for normal peripheral auditory function, particularly in the mid-frequency range, and that loss of CaBP2 impairs both inner and outer hair cell-dependent hearing.\",\n      \"method\": \"Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Cabp2 KO mice\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined auditory phenotype using two orthogonal functional assays, single lab\",\n      \"pmids\": [\"29661613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaBP2 KO mice show altered retinal ganglion cell light response amplitude and kinetics compared to wild-type, while gross retinal and synapse morphology (including ribbon synapses) remain normal, indicating CaBP2 is required for proper transmission of light responses through the retina via presynaptic Ca2+-dependent signaling, but not for synapse structural integrity.\",\n      \"method\": \"Whole-cell patch clamp recordings of retinal ganglion cells in Cabp2 KO mice; immunohistochemistry and transmission electron microscopy for morphology\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined electrophysiological phenotype and structural controls, multiple methods, single lab\",\n      \"pmids\": [\"27822497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CaBP2 modulates presynaptic CaV1.3 Ca2+ channel function in IHCs; lack of CaBP2 causes enhanced steady-state inactivation of CaV1.3 channels, impairing synaptic sound encoding (auditory synaptopathy), consistent with its role as a required modulator of IHC presynaptic calcium channel availability.\",\n      \"method\": \"Review/perspective synthesizing DFNB93 mouse model electrophysiology and gene therapy preclinical data\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic conclusion replicated across multiple independent studies cited; this paper synthesizes replicated findings from mouse models and gene therapy rescue experiments\",\n      \"pmids\": [\"40927552\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CaBP2 is a calmodulin-related Ca2+-binding protein expressed in cochlear inner hair cells (IHCs) and retinal neurons that directly binds Ca2+ and suppresses steady-state inactivation of presynaptic CaV1.3 voltage-gated calcium channels, thereby sustaining calcium channel availability required for indefatigable synaptic sound encoding; loss of CaBP2 causes enhanced CaV1.3 inactivation leading to auditory synaptopathy (DFNB93), and AAV-mediated gene replacement restores IHC CaV1.3 function and hearing in mouse models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CABP2 encodes a calmodulin-related Ca2+-binding protein that serves as a presynaptic modulator of CaV1.3 voltage-gated calcium channels required for synaptic signal encoding in cochlear inner hair cells and retinal neurons [#0, #1]. CaBP2 directly binds Ca2+ and, through this Ca2+ sensing, suppresses steady-state inactivation of CaV1.3 channels, thereby sustaining calcium channel availability for indefatigable synaptic transmission [#0, #1]. A truncating splice-site mutation that disrupts Ca2+ binding weakens CaV1.3 regulation, linking CaBP2 loss of function to autosomal-recessive deafness (DFNB93) [#0]. In Cabp2 knockout mice, loss of CaBP2 produces enhanced CaV1.3 inactivation, elevated auditory brainstem response thresholds, and reduced otoacoustic emissions, while AAV-mediated re-expression of Cabp2 in inner hair cells reverses the enhanced channel inactivation and restores hearing [#1, #2]. CaBP2 additionally shapes retinal ganglion cell light-response amplitude and kinetics through presynaptic Ca2+-dependent signaling without being required for ribbon synapse structural integrity [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that CaBP2 regulates CaV1.3 channels through its Ca2+-binding capacity by showing a disease-associated truncation impairs both Ca2+ binding and channel modulation.\",\n      \"evidence\": \"Isothermal titration calorimetry and CaV1.3 channel regulation assays comparing wild-type and truncated CaBP2 from a DFNB93 family\",\n      \"pmids\": [\"22981119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which structural region of CaBP2 contacts CaV1.3\", \"Channel regulation assessed in vitro, not in native hair cells\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that CaBP2 is required for proper presynaptic Ca2+-dependent transmission of light responses in the retina, distinguishing a functional role from a structural one.\",\n      \"evidence\": \"Whole-cell patch clamp of retinal ganglion cells plus immunohistochemistry and electron microscopy in Cabp2 KO mice\",\n      \"pmids\": [\"27822497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the specific channel CaBP2 modulates in retinal neurons\", \"Mechanism of altered response kinetics not resolved at the molecular level\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CaBP2 is required for normal peripheral auditory function across both inner and outer hair cell-dependent measures, defining the in vivo deafness phenotype.\",\n      \"evidence\": \"Auditory brainstem responses and distortion product otoacoustic emissions in Cabp2 KO mice\",\n      \"pmids\": [\"29661613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DPOAE deficit implicates outer hair cells but the molecular basis there was not established\", \"Frequency-specific vulnerability not mechanistically explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established causality and therapeutic reversibility by showing AAV-delivered Cabp2 restores CaV1.3 channel availability and hearing in knockout mice.\",\n      \"evidence\": \"AAV2/1 and AAV-PHP.eB gene delivery in Cabp2 KO mice with IHC patch clamp and in vivo ABR readouts\",\n      \"pmids\": [\"34489639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability of rescue and human translatability not addressed\", \"Did not resolve stoichiometry of CaBP2:CaV1.3 interaction\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated the mechanistic model that CaBP2 suppresses CaV1.3 steady-state inactivation to maintain presynaptic Ca2+ channel availability for fatigue-resistant sound encoding.\",\n      \"evidence\": \"Review synthesizing DFNB93 mouse electrophysiology and gene therapy preclinical data\",\n      \"pmids\": [\"40927552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No new primary data\", \"Structural basis of channel modulation still undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural mechanism by which CaBP2 binds and modulates CaV1.3, and whether it acts on additional channel targets in retinal neurons, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of a CaBP2–CaV1.3 complex\", \"Identity of the retinal channel target not established\", \"Interactome beyond CaV1.3 uncharacterized in the available corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007268\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CACNA1D\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}