{"gene":"CDH23","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2001,"finding":"CDH23 encodes a large single-pass transmembrane protein with 27 extracellular cadherin repeats; null mutations in mouse Cdh23 (waltzer alleles) disrupt stereocilia organization on inner ear hair cells during early hair-cell differentiation, establishing CDH23 as a critical component of hair bundle formation.","method":"Positional cloning, cDNA sequencing, in situ hybridization in mouse inner ear, phenotypic analysis of Cdh23 null alleles (v6J, vAlb, v2J) by scanning electron microscopy","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple null alleles characterized, replicated across two simultaneous papers (PMID 11138008, 11138009), direct demonstration of stereocilia disorganization in loss-of-function mutants","pmids":["11138008","11138009","11386759"],"is_preprint":false},{"year":2009,"finding":"CDH23 null alleles (waltzer mice modeling USH1D) cause complete loss of tip links and disrupted stereocilia bundle development, whereas a missense Cdh23 mutation (salsa mice modeling DFNB12) leaves hair cell development intact but results in progressive loss of tip links, demonstrating that CDH23 is a structural component of tip links required for mechanoelectrical transduction.","method":"Forward genetic screen, scanning electron microscopy of hair bundles, electrophysiology of hair cell mechanotransduction in Cdh23 missense vs null mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD/KO vs missense comparison with defined cellular phenotype (tip-link loss), multiple orthogonal methods in one rigorous study","pmids":["19270079"],"is_preprint":false},{"year":2002,"finding":"DFNB12-causing CDH23 missense mutations (D2148N, D1341N) substitute highly conserved aspartic acid residues in the calcium-binding sites of the extracellular cadherin (EC) domains; molecular modeling based on E-cadherin structure predicts these substitutions impair calcium binding, which normally provides rigidity to the elongated cadherin structure enabling homophilic interactions.","method":"Mutation analysis, molecular modeling of EC domains based on E-cadherin crystal structure, calcium-binding motif conservation analysis","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural modeling with conservation analysis, single lab, no in vitro calcium-binding assay performed","pmids":["12522556"],"is_preprint":false},{"year":2009,"finding":"EHD4, a member of the C-terminal EH domain protein family involved in endocytic recycling, co-localizes and co-immunoprecipitates with CDH23 in mammalian cells; the interaction is calcium-sensitive, suggesting EHD4 regulates CDH23 trafficking/localization in a calcium-dependent manner.","method":"Membrane-based yeast two-hybrid screen of outer hair cell cDNA library, in situ hybridization, co-immunoprecipitation in mammalian cells, EHD4 knockout mouse auditory phenotyping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus yeast two-hybrid plus KO mouse phenotype, single lab","pmids":["19487694"],"is_preprint":false},{"year":2020,"finding":"Alternative splicing of Cdh23 exon 68 is positively regulated by RBM24 and RBM38 and negatively regulated by PTBP1; knockdown or knockout of Rbm24 in cells reduces exon 68 inclusion, demonstrating these splicing factors control production of the hair-cell-specific CDH23 isoform.","method":"Cell-based splicing reporter screen, Rbm24 knockdown and knockout cell experiments, minigene assays","journal":"Neural plasticity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assays with KO validation, single lab, two orthogonal methods","pmids":["32774357"],"is_preprint":false},{"year":2024,"finding":"Cdh23 exon 68 is subject to hair-cell-specific alternative splicing; mice lacking exon 68 show normal tip-link formation but progressive loss of tip-link stability and progressive/noise-induced hearing loss. The cytoplasmic tail of CDH23(+68) but not CDH23(−68) cooperates with harmonin to form phase separation-mediated condensates at the upper tip-link density (UTLD), explaining how exon 68 inclusion stabilizes tip links.","method":"Genetically modified mice (exon 68 deletion), scanning electron microscopy, electrophysiology, phase separation/condensate assays with harmonin in cells, ABR/noise-exposure hearing tests","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo mouse model with defined structural and functional phenotype, in vitro reconstitution of phase separation with harmonin, multiple orthogonal methods in single rigorous study","pmids":["38408254"],"is_preprint":false},{"year":2006,"finding":"The cytoplasmic/transmembrane region of CDH23 isoforms including exon 68 (CDH23+68) localizes to filamentous actin-rich protrusions and the plasma membrane in transfected cultured cells, whereas the BUS mouse mutant splice-site allele (Cdh23:c.9633+1G>A) produces a highly insoluble protein retained in the cytoplasm, leading to lysosomal bulk degradation (accumulation of autophagosomes/autolysosomes) in vivo.","method":"Immunofluorescence in transfected cells, immunochemistry with anti-Cdh23 antibodies in mouse inner ear, transmission electron microscopy of mutant inner ear","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization in transfected cells with functional consequence (protein degradation), in vivo EM, single lab","pmids":["16281288"],"is_preprint":false},{"year":2002,"finding":"Cdh23 and Myo7a do not genetically interact to affect stereocilia bundle organization or age-related hearing loss in mice: Myo7a is expressed normally in Cdh23 null mutant hair cells, and double heterozygotes (Cdh23v/+; Myo7a4626SB/+) show no stereocilia defects or greater hearing loss than single heterozygotes.","method":"Epistasis analysis in double heterozygote and double homozygote mice, immunofluorescence for Myo7a expression, scanning electron microscopy of hair bundles, ABR measurements","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with multiple genotypes, direct localization of Myo7a in Cdh23 mutant; negative result for genetic interaction is itself mechanistically informative","pmids":["12121736"],"is_preprint":false},{"year":2016,"finding":"Early-onset progressive hearing loss caused by heterozygous Ush1g/Sans mutation in C57BL/6J mice requires the co-presence of the hypomorphic Cdh23c.753A allele; CRISPR/Cas9 knock-in of the protective Cdh23c.753A>G substitution completely rescued hearing loss and stereocilia degeneration, indicating that SANS and CDH23 proteins interact in stereocilia and their co-function is required for stereocilia maintenance.","method":"Classical genetic analysis, CRISPR/Cas9 knock-in mice, ABR audiometry, scanning electron microscopy of stereocilia","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue by precise allele replacement confirms functional interaction; two orthogonal methods (genetics + structural analysis)","pmids":["26936824"],"is_preprint":false},{"year":2010,"finding":"CDH23 localizes to the tip links of stereocilia in hair cells; compound heterozygosity of a Cdh23 null allele with the hypomorphic Cdh23ahl allele leads to normal stereocilia development but progressive stereocilia disruption and age-dependent tip-link loss, indicating CDH23 plays an essential role in maintaining tip-link integrity during aging.","method":"Immunolocalization of CDH23 at tip links, ABR audiometry, scanning electron microscopy in compound heterozygous mice","journal":"Experimental animals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunolocalization tied to functional consequence, single lab","pmids":["24172198"],"is_preprint":false},{"year":2010,"finding":"In Cdh23erl/erl mice carrying a missense Cdh23 mutation, hair cell death and hearing loss occur through apoptosis (upregulation of caspase activity); pan-caspase inhibitor Z-VAD-FMK preserves hearing and reduces outer hair cell loss, establishing an apoptotic pathway downstream of Cdh23 dysfunction.","method":"Mouse model with missense Cdh23 mutation, caspase expression analysis, pharmacological inhibition with Z-VAD-FMK, ABR audiometry, hair cell counting","journal":"The pharmacogenomics journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue experiment with defined molecular pathway, single lab","pmids":["20644563"],"is_preprint":false},{"year":2016,"finding":"Endoplasmic reticulum (ER) stress is the earliest molecular event upstream of apoptosis in Cdh23erl/erl hair cells; ER stress inhibitor Salubrinal delays hearing loss and preserves hair cells, placing ER stress upstream of tip-link degeneration and caspase activation in the CDH23 mutation-induced cell death pathway.","method":"ER stress marker analysis in Cdh23erl/erl cochleae, pharmacological treatment with Salubrinal, ABR audiometry, hair cell viability assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue with pathway marker analysis, single lab, two methods","pmids":["27882946"],"is_preprint":false},{"year":2003,"finding":"Cdh23 mutations in waltzer mice cause retinal dysfunction (abnormal ERG a- and b-waves or implicit times) without anatomical retinal degeneration detectable by light microscopy; no functional interaction between Cdh23 and Myo7a was detected in the retina by ERG or microscopy in double mutant mice.","method":"Electroretinography (ERG) of three Cdh23 mutant alleles, light microscopy histology, generation of Cdh23/Myo7a double mutant mice","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (ERG) with multiple alleles and epistasis test; negative genetic interaction is informative","pmids":["14609561"],"is_preprint":false},{"year":2025,"finding":"In cdh23-knockout zebrafish, YO-PRO-1 signal (indicator of MET channel activity) in inner ear and lateral line neuromast hair cells is completely lost, confirming CDH23 is required for mechanosensory transduction. Transcriptomics revealed dysregulation of purine metabolism genes (atp1b2b, myof), and ATP treatment partially rescued the cdh23-null hearing phenotype, suggesting CDH23 function is linked to purine/ATP metabolism in hair cells.","method":"CRISPR/Cas9 cdh23 knockout zebrafish, YO-PRO-1 MET channel assay, startle response behavioral test, comparative transcriptomics, RT-qPCR, ATP supplementation rescue experiment","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MET assay, transcriptomics, pharmacological rescue) in zebrafish model, single lab","pmids":["37575969"],"is_preprint":false},{"year":2025,"finding":"In cdh23-knockout zebrafish, rod photoreceptor degeneration is associated with increased Ca2+ and activation of the MAPK signaling pathway; TUNEL staining confirmed increased apoptosis in the cdh23-null retina, indicating CDH23 loss in the retina triggers cell death through Ca2+–MAPK interaction.","method":"CRISPR/Cas9 cdh23 zebrafish knockout, comparative transcriptomics, TUNEL staining, H&E histology, RT-qPCR","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcriptomics-based pathway inference with TUNEL validation, no direct mechanistic dissection of Ca2+/MAPK link","pmids":["40429749"],"is_preprint":false},{"year":2025,"finding":"In silico molecular dynamics analysis of the CDH23 p.C1717R variant predicts that the mutation abolishes the interaction interface with PCDH15, completely eliminating CDH23–PCDH15 complex formation in the region surrounding the mutation and significantly reducing complex stability, while paradoxically enhancing CDH23 monomer stability.","method":"In silico molecular dynamics simulation and protein–protein interaction modeling","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation of CDH23–PCDH15 interaction disruption in this paper","pmids":["40047980"],"is_preprint":false},{"year":2008,"finding":"CDH23 missense mutation p.R1746Q causes aberrant splicing (exon skipping) as revealed by minigene assay, explaining why this apparent missense mutation causes the syndromic USH1D phenotype rather than the nonsyndromic DFNB12 phenotype, while three other missense mutations (p.A484P, p.T1209A, p.R1507Q) showed normal splicing.","method":"Minigene splicing assay in cultured cells, in silico splicing prediction","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro splicing assay demonstrating aberrant transcript from an apparent missense mutation, single lab","pmids":["18273900"],"is_preprint":false},{"year":2021,"finding":"The Cdh23 c.753G>A variant in mice influences prepulse inhibition (PPI), an endophenotype of schizophrenia; engineering the c.753G allele (from C3H strain) into the C57BL/6N background dampens PPI, and the variant has an eQTL effect on Cdh23 brain expression, suggesting CDH23 function extends to auditory sensory gating in the brain.","method":"QTL mapping with increased marker density, CRISPR/Cas9 knock-in of Cdh23c.753G allele into B6 background, PPI behavioral testing, eQTL analysis of brain expression","journal":"Schizophrenia bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knock-in with behavioral phenotype, eQTL data supporting brain expression role, single lab","pmids":["33595068"],"is_preprint":false},{"year":2002,"finding":"In vitro expression (exon trapping) of two CDH23 splice-site mutations showed: a synonymous c.5712G>A transition at the last base of exon 42 causes exon 42 skipping, and an intronic IVS45-9G>A mutation creates a novel splice acceptor site causing insertion of 7 intronic bp, demonstrating these variants produce premature truncations rather than simple missense/silent changes.","method":"Exon trapping/minigene in vitro splicing assay","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional splicing assay in vitro, single lab, two variants tested","pmids":["11857743"],"is_preprint":false}],"current_model":"CDH23 encodes a large single-pass transmembrane cadherin that forms the upper strand of stereocilia tip links in inner ear hair cells, where its extracellular cadherin repeats bind calcium to maintain structural rigidity; at the cytoplasmic face, the CDH23(+68) isoform (containing exon 68, regulated by RBM24/RBM38/PTBP1 splicing factors) cooperates with harmonin through phase separation to stabilize the upper tip-link density, while CDH23 trafficking/localization is modulated by the endocytic recycling protein EHD4 in a calcium-sensitive manner; null mutations abolish tip links and stereocilia bundle organization during development (USH1D), missense mutations in conserved calcium-binding motifs impair tip-link stability causing progressive loss without developmental defect (DFNB12), and downstream of CDH23 dysfunction hair cells die via ER stress followed by caspase-mediated apoptosis."},"narrative":{"mechanistic_narrative":"CDH23 encodes a large single-pass transmembrane cadherin with 27 extracellular cadherin (EC) repeats that is a structural component of the stereocilia tip links in inner ear hair cells, where it is required both for the developmental organization of the hair bundle and for the maintenance of mechanoelectrical transduction [PMID:11138008, PMID:11138009, PMID:11386759, PMID:19270079, PMID:24172198]. Its EC domains bind calcium at conserved aspartate-containing motifs that confer rigidity to the elongated extracellular structure, and DFNB12-causing missense substitutions in these calcium-binding sites impair tip-link stability and cause progressive hearing loss without disrupting hair-cell development, whereas null mutations abolish tip links and disorganize the bundle during development (USH1D) [PMID:19270079, PMID:12522556]. In zebrafish, loss of cdh23 eliminates MET channel activity, confirming the cadherin's role in mechanosensory transduction [PMID:37575969]. At the cytoplasmic face, the hair-cell-specific CDH23(+68) isoform—whose exon 68 inclusion is positively controlled by the splicing factors RBM24/RBM38 and antagonized by PTBP1—cooperates with harmonin to form phase-separated condensates at the upper tip-link density, and loss of exon 68 leaves tip links forming normally but progressively unstable [PMID:32774357, PMID:38408254]. CDH23 additionally interacts genetically and functionally with the USH1 scaffold protein SANS in stereocilia maintenance, its trafficking is modulated in a calcium-sensitive manner by the endocytic recycling protein EHD4, and dysfunction of CDH23 triggers hair-cell death through ER stress followed by caspase-mediated apoptosis [PMID:26936824, PMID:19487694, PMID:27882946, PMID:20644563]. Several apparent missense or synonymous CDH23 variants instead act by disrupting splicing, accounting for genotype-phenotype relationships across the USH1D/DFNB12 spectrum [PMID:18273900, PMID:11857743].","teleology":[{"year":2001,"claim":"Established CDH23 as an essential hair-bundle protein by showing that null mutations disorganize stereocilia during early hair-cell differentiation, defining its developmental role before any tip-link function was known.","evidence":"Positional cloning and SEM phenotyping of multiple Cdh23 null alleles in mouse inner ear","pmids":["11138008","11138009","11386759"],"confidence":"High","gaps":["Did not localize CDH23 to a specific bundle structure","Molecular partners and biochemical activity unresolved"]},{"year":2002,"claim":"Connected DFNB12 missense mutations to disrupted calcium binding by showing that disease substitutions hit conserved aspartates in EC calcium-binding motifs, providing a structural rationale for how missense alleles impair cadherin rigidity.","evidence":"Mutation analysis and molecular modeling of EC domains on the E-cadherin template","pmids":["12522556"],"confidence":"Medium","gaps":["No in vitro calcium-binding assay performed","Homophilic interaction prediction not experimentally tested"]},{"year":2002,"claim":"Demonstrated that several apparent missense/synonymous CDH23 variants act via aberrant splicing producing premature truncations, refining how genotype maps to phenotype.","evidence":"Exon trapping/minigene assays of splice-site mutations","pmids":["11857743"],"confidence":"Medium","gaps":["Limited to two variants","In vitro splicing may not reflect cochlear transcripts"]},{"year":2002,"claim":"Tested whether CDH23 and MYO7A act in a common genetic pathway in stereocilia and found no genetic interaction, narrowing the network of CDH23-dependent maintenance.","evidence":"Epistasis analysis in double mutant mice with Myo7a immunofluorescence and ABR","pmids":["12121736"],"confidence":"Medium","gaps":["Negative result does not exclude indirect or context-specific interaction","Did not address physical association"]},{"year":2003,"claim":"Extended CDH23 function beyond the ear by showing retinal electrophysiological dysfunction in null mice, indicating a sensory role outside the cochlea.","evidence":"ERG and light microscopy across multiple Cdh23 alleles plus Cdh23/Myo7a double mutants","pmids":["14609561"],"confidence":"Medium","gaps":["No anatomical degeneration detected","Molecular basis of retinal dysfunction unresolved"]},{"year":2006,"claim":"Localized the CDH23(+68) cytoplasmic/transmembrane region to actin-rich protrusions and showed that a splice-site mutant yields insoluble protein cleared by lysosomal degradation, linking aberrant splicing to protein mislocalization and turnover.","evidence":"Immunofluorescence in transfected cells and TEM of mutant mouse inner ear","pmids":["16281288"],"confidence":"Medium","gaps":["Single lab","Did not establish the trafficking machinery responsible"]},{"year":2008,"claim":"Explained why an apparent missense mutation produces the syndromic USH1D rather than nonsyndromic phenotype by showing it causes exon skipping, distinguishing splicing-disrupting from true missense alleles.","evidence":"Minigene splicing assay of four missense variants","pmids":["18273900"],"confidence":"Medium","gaps":["In vitro minigene context","Protein-level consequence not directly measured"]},{"year":2009,"claim":"Resolved CDH23's role as a structural tip-link component by contrasting null (tip-link loss, developmental disruption) with missense (intact development, progressive tip-link loss) models, dissociating developmental from maintenance functions.","evidence":"Forward genetics, SEM, and mechanotransduction electrophysiology in mouse models","pmids":["19270079"],"confidence":"High","gaps":["Did not define the cytoplasmic stabilization machinery","Molecular partner at the tip link not identified here"]},{"year":2009,"claim":"Identified EHD4 as a calcium-sensitive CDH23 interactor, providing a candidate mechanism for regulating CDH23 trafficking and localization.","evidence":"Membrane yeast two-hybrid, reciprocal co-IP, and EHD4 knockout auditory phenotyping","pmids":["19487694"],"confidence":"Medium","gaps":["Single lab","Direct effect on CDH23 trafficking in hair cells not shown"]},{"year":2010,"claim":"Established CDH23 as essential for tip-link maintenance during aging by showing hypomorphic compound heterozygotes develop normally then progressively lose tip links, separating maintenance from formation.","evidence":"CDH23 immunolocalization at tip links, ABR, and SEM in compound heterozygous mice","pmids":["24172198"],"confidence":"Medium","gaps":["Mechanism of age-dependent destabilization unresolved","Single lab"]},{"year":2010,"claim":"Defined an apoptotic, caspase-mediated cell-death pathway downstream of CDH23 dysfunction, identifying a druggable node for hair-cell survival.","evidence":"Caspase analysis and Z-VAD-FMK pharmacological rescue in Cdh23 missense mice","pmids":["20644563"],"confidence":"Medium","gaps":["Upstream trigger of apoptosis not defined here","Single lab"]},{"year":2016,"claim":"Placed ER stress upstream of apoptosis in CDH23-mutant hair cells, ordering the cell-death cascade triggered by tip-link dysfunction.","evidence":"ER stress marker analysis and Salubrinal rescue in Cdh23erl/erl cochleae","pmids":["27882946"],"confidence":"Medium","gaps":["Link between tip-link loss and ER stress induction not mechanistically defined","Single lab"]},{"year":2016,"claim":"Demonstrated a functional CDH23-SANS interaction required for stereocilia maintenance through precise allele rescue, identifying a genetic modifier relationship within the USH1 network.","evidence":"CRISPR knock-in rescue of the protective Cdh23 allele with ABR and SEM","pmids":["26936824"],"confidence":"High","gaps":["Direct physical CDH23-SANS binding not demonstrated here","Stoichiometry and localization of interaction unresolved"]},{"year":2020,"claim":"Identified the splicing regulators controlling the hair-cell-specific CDH23 isoform, showing RBM24/RBM38 promote and PTBP1 represses exon 68 inclusion.","evidence":"Splicing reporter screen, Rbm24 knockdown/knockout, and minigene assays in cells","pmids":["32774357"],"confidence":"Medium","gaps":["In vivo cochlear requirement of these factors not tested here","Single lab"]},{"year":2024,"claim":"Explained the molecular function of exon 68 by showing the CDH23(+68) cytoplasmic tail cooperates with harmonin via phase separation at the upper tip-link density, with exon 68 loss causing progressive tip-link instability.","evidence":"Exon 68 deletion mice, SEM, electrophysiology, and harmonin condensate assays","pmids":["38408254"],"confidence":"High","gaps":["In vivo demonstration of condensates at the UTLD not directly imaged","Regulation of condensate dynamics by calcium not addressed"]},{"year":2025,"claim":"Confirmed CDH23 is required for MET channel activity across vertebrate hair cells and linked its loss to dysregulated purine/ATP metabolism with partial ATP rescue.","evidence":"cdh23-knockout zebrafish, YO-PRO-1 MET assay, transcriptomics, and ATP supplementation","pmids":["37575969"],"confidence":"Medium","gaps":["Mechanism linking CDH23 to purine metabolism unclear","Partial rescue not mechanistically explained"]},{"year":2025,"claim":"Associated retinal CDH23 loss with Ca2+-MAPK-driven apoptosis in zebrafish, proposing a death pathway for photoreceptor degeneration.","evidence":"cdh23-knockout zebrafish transcriptomics with TUNEL and histology","pmids":["40429749"],"confidence":"Low","gaps":["Transcriptomics-based pathway inference without direct mechanistic dissection","Ca2+-MAPK causal link not validated"]},{"year":2025,"claim":"Computationally modeled how a CDH23 variant disrupts the CDH23-PCDH15 interface, proposing a structural basis for tip-link complex destabilization.","evidence":"In silico molecular dynamics and protein-protein interaction modeling","pmids":["40047980"],"confidence":"Low","gaps":["Computational prediction only, no experimental validation","CDH23-PCDH15 binding disruption not measured"]},{"year":2021,"claim":"Extended CDH23 function to central auditory sensory gating by linking a hypomorphic allele to prepulse inhibition and brain eQTL effects.","evidence":"QTL mapping, CRISPR knock-in into B6 background, PPI testing, and eQTL analysis","pmids":["33595068"],"confidence":"Medium","gaps":["Whether the PPI effect reflects peripheral hearing or central role unresolved","Brain CDH23 function mechanism unknown"]},{"year":null,"claim":"How CDH23 phase-separated condensates, calcium-dependent trafficking, and the ER-stress-to-apoptosis cascade are mechanistically coupled to tip-link turnover in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural reconstitution of the full CDH23-PCDH15-harmonin-SANS upper tip-link complex","Trigger linking mechanical tip-link loss to ER stress not identified","Calcium regulation of condensate dynamics uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,11]}],"complexes":["stereocilia tip link","upper tip-link density"],"partners":["HARS/HARMONIN","EHD4","SANS/USH1G","PCDH15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H251","full_name":"Cadherin-23","aliases":["Otocadherin"],"length_aa":3354,"mass_kda":369.5,"function":"Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells. CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle of hair cells in the cochlea and the vestibule during late embryonic/early postnatal development. It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A that mediates mechanotransduction in cochlear hair cells. Required for normal hearing","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H251/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDH23","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CDH23","total_profiled":1310},"omim":[{"mim_id":"619804","title":"DEAFNESS, AUTOSOMAL DOMINANT 82; DFNA82","url":"https://www.omim.org/entry/619804"},{"mim_id":"617540","title":"PITUITARY ADENOMA 5, MULTIPLE TYPES; PITA5","url":"https://www.omim.org/entry/617540"},{"mim_id":"607696","title":"USH1 PROTEIN NETWORK COMPONENT SANS; USH1G","url":"https://www.omim.org/entry/607696"},{"mim_id":"605516","title":"CADHERIN 23; CDH23","url":"https://www.omim.org/entry/605516"},{"mim_id":"605514","title":"PROTOCADHERIN 15; PCDH15","url":"https://www.omim.org/entry/605514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"ovary","ntpm":34.8}],"url":"https://www.proteinatlas.org/search/CDH23"},"hgnc":{"alias_symbol":["CDHR23"],"prev_symbol":["DFNB12","USH1D"]},"alphafold":{"accession":"Q9H251","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H251","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H251-9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H251-9-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDH23","jax_strain_url":"https://www.jax.org/strain/search?query=CDH23"},"sequence":{"accession":"Q9H251","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H251.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H251/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H251"}},"corpus_meta":[{"pmid":"11090341","id":"PMC_11090341","title":"Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by 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gene].","date":"2020","source":"Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery","url":"https://pubmed.ncbi.nlm.nih.gov/32911884","citation_count":1,"is_preprint":false},{"pmid":"40429749","id":"PMC_40429749","title":"Zebrafish cdh23 Affects Rod Cell Phototransduction Through Regulating Ca2+ Transport and MAPK Signaling Pathway.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40429749","citation_count":0,"is_preprint":false},{"pmid":"38878669","id":"PMC_38878669","title":"Generation of an induced pluripotent stem cell line from a late-onset, progressive high frequency hearing loss patient due to mutation in CDH23.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38878669","citation_count":0,"is_preprint":false},{"pmid":"39596651","id":"PMC_39596651","title":"Segregation of Trans Mutations in the CDH23 Gene in an Emirati Family with Sensorineural Hearing Loss.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39596651","citation_count":0,"is_preprint":false},{"pmid":"39966205","id":"PMC_39966205","title":"Cdh23 Gene Mutation-Induced Vestibular Dysfunction in Mice: Abnormal Stereocilia Bundle and Otolith Development and Activation of p53/FoxO Signaling Pathway.","date":"2025","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/39966205","citation_count":0,"is_preprint":false},{"pmid":"41067752","id":"PMC_41067752","title":"Do variants in the CDH23 gene cause non-syndromic retinitis pigmentosa? Dual validation using whole exome sequencing and a zebrafish model.","date":"2025","source":"BMJ open ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/41067752","citation_count":0,"is_preprint":false},{"pmid":"39480672","id":"PMC_39480672","title":"Protective Efficacy of T-type, Calcium Channel Antagonist on Auditory Function in Cdh23 Erl/Erl Mice.","date":"2025","source":"Alternative therapies in health and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39480672","citation_count":0,"is_preprint":false},{"pmid":"40184886","id":"PMC_40184886","title":"Generation of two induced pluripotent stem cell lines carrying the CDH23 c.1515-12G > A variant.","date":"2025","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40184886","citation_count":0,"is_preprint":false},{"pmid":"41230578","id":"PMC_41230578","title":"[Analysis of pathogenic variant carriage for MYO7A, PCDH15, and CDH23 genes among newborns based on high-throughput sequencing technique].","date":"2025","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41230578","citation_count":0,"is_preprint":false},{"pmid":"41612354","id":"PMC_41612354","title":"A novel germline CDH23 variant as a likely cause of an ultra-giant prolactinoma.","date":"2026","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41612354","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.27.667071","title":"Expression of the naked mole-rat transgene for  <i>Has2</i>  improved health span in C57Bl/6 mice, but it did not attenuate age-related hearing loss","date":"2025-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.27.667071","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.21.639406","title":"An integrated system for comprehensive mouse peripheral vestibular function evaluation based on Vestibulo-ocular Reflex","date":"2025-02-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.639406","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.14.618265","title":"KLHDC7B, a novel gene associated with age-related hearing loss in humans, is required for the maintenance of hearing in mice","date":"2024-10-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.14.618265","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.03.616327","title":"Limiting hearing loss in transgenic mouse models","date":"2024-10-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.03.616327","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.28.635338","title":"TadA-Derived Cytosine Base Editor for Precise Genome Editing in Zebrafish","date":"2025-01-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.28.635338","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52410,"output_tokens":4857,"usd":0.115043,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13155,"output_tokens":5047,"usd":0.095975,"stage2_stop_reason":"end_turn"},"total_usd":0.211018,"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\": 2001,\n      \"finding\": \"CDH23 encodes a large single-pass transmembrane protein with 27 extracellular cadherin repeats; null mutations in mouse Cdh23 (waltzer alleles) disrupt stereocilia organization on inner ear hair cells during early hair-cell differentiation, establishing CDH23 as a critical component of hair bundle formation.\",\n      \"method\": \"Positional cloning, cDNA sequencing, in situ hybridization in mouse inner ear, phenotypic analysis of Cdh23 null alleles (v6J, vAlb, v2J) by scanning electron microscopy\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple null alleles characterized, replicated across two simultaneous papers (PMID 11138008, 11138009), direct demonstration of stereocilia disorganization in loss-of-function mutants\",\n      \"pmids\": [\"11138008\", \"11138009\", \"11386759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CDH23 null alleles (waltzer mice modeling USH1D) cause complete loss of tip links and disrupted stereocilia bundle development, whereas a missense Cdh23 mutation (salsa mice modeling DFNB12) leaves hair cell development intact but results in progressive loss of tip links, demonstrating that CDH23 is a structural component of tip links required for mechanoelectrical transduction.\",\n      \"method\": \"Forward genetic screen, scanning electron microscopy of hair bundles, electrophysiology of hair cell mechanotransduction in Cdh23 missense vs null mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KD/KO vs missense comparison with defined cellular phenotype (tip-link loss), multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"19270079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DFNB12-causing CDH23 missense mutations (D2148N, D1341N) substitute highly conserved aspartic acid residues in the calcium-binding sites of the extracellular cadherin (EC) domains; molecular modeling based on E-cadherin structure predicts these substitutions impair calcium binding, which normally provides rigidity to the elongated cadherin structure enabling homophilic interactions.\",\n      \"method\": \"Mutation analysis, molecular modeling of EC domains based on E-cadherin crystal structure, calcium-binding motif conservation analysis\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural modeling with conservation analysis, single lab, no in vitro calcium-binding assay performed\",\n      \"pmids\": [\"12522556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EHD4, a member of the C-terminal EH domain protein family involved in endocytic recycling, co-localizes and co-immunoprecipitates with CDH23 in mammalian cells; the interaction is calcium-sensitive, suggesting EHD4 regulates CDH23 trafficking/localization in a calcium-dependent manner.\",\n      \"method\": \"Membrane-based yeast two-hybrid screen of outer hair cell cDNA library, in situ hybridization, co-immunoprecipitation in mammalian cells, EHD4 knockout mouse auditory phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus yeast two-hybrid plus KO mouse phenotype, single lab\",\n      \"pmids\": [\"19487694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Alternative splicing of Cdh23 exon 68 is positively regulated by RBM24 and RBM38 and negatively regulated by PTBP1; knockdown or knockout of Rbm24 in cells reduces exon 68 inclusion, demonstrating these splicing factors control production of the hair-cell-specific CDH23 isoform.\",\n      \"method\": \"Cell-based splicing reporter screen, Rbm24 knockdown and knockout cell experiments, minigene assays\",\n      \"journal\": \"Neural plasticity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assays with KO validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"32774357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cdh23 exon 68 is subject to hair-cell-specific alternative splicing; mice lacking exon 68 show normal tip-link formation but progressive loss of tip-link stability and progressive/noise-induced hearing loss. The cytoplasmic tail of CDH23(+68) but not CDH23(−68) cooperates with harmonin to form phase separation-mediated condensates at the upper tip-link density (UTLD), explaining how exon 68 inclusion stabilizes tip links.\",\n      \"method\": \"Genetically modified mice (exon 68 deletion), scanning electron microscopy, electrophysiology, phase separation/condensate assays with harmonin in cells, ABR/noise-exposure hearing tests\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo mouse model with defined structural and functional phenotype, in vitro reconstitution of phase separation with harmonin, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38408254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The cytoplasmic/transmembrane region of CDH23 isoforms including exon 68 (CDH23+68) localizes to filamentous actin-rich protrusions and the plasma membrane in transfected cultured cells, whereas the BUS mouse mutant splice-site allele (Cdh23:c.9633+1G>A) produces a highly insoluble protein retained in the cytoplasm, leading to lysosomal bulk degradation (accumulation of autophagosomes/autolysosomes) in vivo.\",\n      \"method\": \"Immunofluorescence in transfected cells, immunochemistry with anti-Cdh23 antibodies in mouse inner ear, transmission electron microscopy of mutant inner ear\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization in transfected cells with functional consequence (protein degradation), in vivo EM, single lab\",\n      \"pmids\": [\"16281288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cdh23 and Myo7a do not genetically interact to affect stereocilia bundle organization or age-related hearing loss in mice: Myo7a is expressed normally in Cdh23 null mutant hair cells, and double heterozygotes (Cdh23v/+; Myo7a4626SB/+) show no stereocilia defects or greater hearing loss than single heterozygotes.\",\n      \"method\": \"Epistasis analysis in double heterozygote and double homozygote mice, immunofluorescence for Myo7a expression, scanning electron microscopy of hair bundles, ABR measurements\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with multiple genotypes, direct localization of Myo7a in Cdh23 mutant; negative result for genetic interaction is itself mechanistically informative\",\n      \"pmids\": [\"12121736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Early-onset progressive hearing loss caused by heterozygous Ush1g/Sans mutation in C57BL/6J mice requires the co-presence of the hypomorphic Cdh23c.753A allele; CRISPR/Cas9 knock-in of the protective Cdh23c.753A>G substitution completely rescued hearing loss and stereocilia degeneration, indicating that SANS and CDH23 proteins interact in stereocilia and their co-function is required for stereocilia maintenance.\",\n      \"method\": \"Classical genetic analysis, CRISPR/Cas9 knock-in mice, ABR audiometry, scanning electron microscopy of stereocilia\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue by precise allele replacement confirms functional interaction; two orthogonal methods (genetics + structural analysis)\",\n      \"pmids\": [\"26936824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDH23 localizes to the tip links of stereocilia in hair cells; compound heterozygosity of a Cdh23 null allele with the hypomorphic Cdh23ahl allele leads to normal stereocilia development but progressive stereocilia disruption and age-dependent tip-link loss, indicating CDH23 plays an essential role in maintaining tip-link integrity during aging.\",\n      \"method\": \"Immunolocalization of CDH23 at tip links, ABR audiometry, scanning electron microscopy in compound heterozygous mice\",\n      \"journal\": \"Experimental animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunolocalization tied to functional consequence, single lab\",\n      \"pmids\": [\"24172198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Cdh23erl/erl mice carrying a missense Cdh23 mutation, hair cell death and hearing loss occur through apoptosis (upregulation of caspase activity); pan-caspase inhibitor Z-VAD-FMK preserves hearing and reduces outer hair cell loss, establishing an apoptotic pathway downstream of Cdh23 dysfunction.\",\n      \"method\": \"Mouse model with missense Cdh23 mutation, caspase expression analysis, pharmacological inhibition with Z-VAD-FMK, ABR audiometry, hair cell counting\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue experiment with defined molecular pathway, single lab\",\n      \"pmids\": [\"20644563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Endoplasmic reticulum (ER) stress is the earliest molecular event upstream of apoptosis in Cdh23erl/erl hair cells; ER stress inhibitor Salubrinal delays hearing loss and preserves hair cells, placing ER stress upstream of tip-link degeneration and caspase activation in the CDH23 mutation-induced cell death pathway.\",\n      \"method\": \"ER stress marker analysis in Cdh23erl/erl cochleae, pharmacological treatment with Salubrinal, ABR audiometry, hair cell viability assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue with pathway marker analysis, single lab, two methods\",\n      \"pmids\": [\"27882946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cdh23 mutations in waltzer mice cause retinal dysfunction (abnormal ERG a- and b-waves or implicit times) without anatomical retinal degeneration detectable by light microscopy; no functional interaction between Cdh23 and Myo7a was detected in the retina by ERG or microscopy in double mutant mice.\",\n      \"method\": \"Electroretinography (ERG) of three Cdh23 mutant alleles, light microscopy histology, generation of Cdh23/Myo7a double mutant mice\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (ERG) with multiple alleles and epistasis test; negative genetic interaction is informative\",\n      \"pmids\": [\"14609561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cdh23-knockout zebrafish, YO-PRO-1 signal (indicator of MET channel activity) in inner ear and lateral line neuromast hair cells is completely lost, confirming CDH23 is required for mechanosensory transduction. Transcriptomics revealed dysregulation of purine metabolism genes (atp1b2b, myof), and ATP treatment partially rescued the cdh23-null hearing phenotype, suggesting CDH23 function is linked to purine/ATP metabolism in hair cells.\",\n      \"method\": \"CRISPR/Cas9 cdh23 knockout zebrafish, YO-PRO-1 MET channel assay, startle response behavioral test, comparative transcriptomics, RT-qPCR, ATP supplementation rescue experiment\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MET assay, transcriptomics, pharmacological rescue) in zebrafish model, single lab\",\n      \"pmids\": [\"37575969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cdh23-knockout zebrafish, rod photoreceptor degeneration is associated with increased Ca2+ and activation of the MAPK signaling pathway; TUNEL staining confirmed increased apoptosis in the cdh23-null retina, indicating CDH23 loss in the retina triggers cell death through Ca2+–MAPK interaction.\",\n      \"method\": \"CRISPR/Cas9 cdh23 zebrafish knockout, comparative transcriptomics, TUNEL staining, H&E histology, RT-qPCR\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcriptomics-based pathway inference with TUNEL validation, no direct mechanistic dissection of Ca2+/MAPK link\",\n      \"pmids\": [\"40429749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In silico molecular dynamics analysis of the CDH23 p.C1717R variant predicts that the mutation abolishes the interaction interface with PCDH15, completely eliminating CDH23–PCDH15 complex formation in the region surrounding the mutation and significantly reducing complex stability, while paradoxically enhancing CDH23 monomer stability.\",\n      \"method\": \"In silico molecular dynamics simulation and protein–protein interaction modeling\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation of CDH23–PCDH15 interaction disruption in this paper\",\n      \"pmids\": [\"40047980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDH23 missense mutation p.R1746Q causes aberrant splicing (exon skipping) as revealed by minigene assay, explaining why this apparent missense mutation causes the syndromic USH1D phenotype rather than the nonsyndromic DFNB12 phenotype, while three other missense mutations (p.A484P, p.T1209A, p.R1507Q) showed normal splicing.\",\n      \"method\": \"Minigene splicing assay in cultured cells, in silico splicing prediction\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro splicing assay demonstrating aberrant transcript from an apparent missense mutation, single lab\",\n      \"pmids\": [\"18273900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Cdh23 c.753G>A variant in mice influences prepulse inhibition (PPI), an endophenotype of schizophrenia; engineering the c.753G allele (from C3H strain) into the C57BL/6N background dampens PPI, and the variant has an eQTL effect on Cdh23 brain expression, suggesting CDH23 function extends to auditory sensory gating in the brain.\",\n      \"method\": \"QTL mapping with increased marker density, CRISPR/Cas9 knock-in of Cdh23c.753G allele into B6 background, PPI behavioral testing, eQTL analysis of brain expression\",\n      \"journal\": \"Schizophrenia bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knock-in with behavioral phenotype, eQTL data supporting brain expression role, single lab\",\n      \"pmids\": [\"33595068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In vitro expression (exon trapping) of two CDH23 splice-site mutations showed: a synonymous c.5712G>A transition at the last base of exon 42 causes exon 42 skipping, and an intronic IVS45-9G>A mutation creates a novel splice acceptor site causing insertion of 7 intronic bp, demonstrating these variants produce premature truncations rather than simple missense/silent changes.\",\n      \"method\": \"Exon trapping/minigene in vitro splicing assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional splicing assay in vitro, single lab, two variants tested\",\n      \"pmids\": [\"11857743\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDH23 encodes a large single-pass transmembrane cadherin that forms the upper strand of stereocilia tip links in inner ear hair cells, where its extracellular cadherin repeats bind calcium to maintain structural rigidity; at the cytoplasmic face, the CDH23(+68) isoform (containing exon 68, regulated by RBM24/RBM38/PTBP1 splicing factors) cooperates with harmonin through phase separation to stabilize the upper tip-link density, while CDH23 trafficking/localization is modulated by the endocytic recycling protein EHD4 in a calcium-sensitive manner; null mutations abolish tip links and stereocilia bundle organization during development (USH1D), missense mutations in conserved calcium-binding motifs impair tip-link stability causing progressive loss without developmental defect (DFNB12), and downstream of CDH23 dysfunction hair cells die via ER stress followed by caspase-mediated apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDH23 encodes a large single-pass transmembrane cadherin with 27 extracellular cadherin (EC) repeats that is a structural component of the stereocilia tip links in inner ear hair cells, where it is required both for the developmental organization of the hair bundle and for the maintenance of mechanoelectrical transduction [#0, #1, #9]. Its EC domains bind calcium at conserved aspartate-containing motifs that confer rigidity to the elongated extracellular structure, and DFNB12-causing missense substitutions in these calcium-binding sites impair tip-link stability and cause progressive hearing loss without disrupting hair-cell development, whereas null mutations abolish tip links and disorganize the bundle during development (USH1D) [#1, #2]. In zebrafish, loss of cdh23 eliminates MET channel activity, confirming the cadherin's role in mechanosensory transduction [#13]. At the cytoplasmic face, the hair-cell-specific CDH23(+68) isoform—whose exon 68 inclusion is positively controlled by the splicing factors RBM24/RBM38 and antagonized by PTBP1—cooperates with harmonin to form phase-separated condensates at the upper tip-link density, and loss of exon 68 leaves tip links forming normally but progressively unstable [#4, #5]. CDH23 additionally interacts genetically and functionally with the USH1 scaffold protein SANS in stereocilia maintenance, its trafficking is modulated in a calcium-sensitive manner by the endocytic recycling protein EHD4, and dysfunction of CDH23 triggers hair-cell death through ER stress followed by caspase-mediated apoptosis [#8, #3, #11, #10]. Several apparent missense or synonymous CDH23 variants instead act by disrupting splicing, accounting for genotype-phenotype relationships across the USH1D/DFNB12 spectrum [#16, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established CDH23 as an essential hair-bundle protein by showing that null mutations disorganize stereocilia during early hair-cell differentiation, defining its developmental role before any tip-link function was known.\",\n      \"evidence\": \"Positional cloning and SEM phenotyping of multiple Cdh23 null alleles in mouse inner ear\",\n      \"pmids\": [\"11138008\", \"11138009\", \"11386759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not localize CDH23 to a specific bundle structure\", \"Molecular partners and biochemical activity unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected DFNB12 missense mutations to disrupted calcium binding by showing that disease substitutions hit conserved aspartates in EC calcium-binding motifs, providing a structural rationale for how missense alleles impair cadherin rigidity.\",\n      \"evidence\": \"Mutation analysis and molecular modeling of EC domains on the E-cadherin template\",\n      \"pmids\": [\"12522556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro calcium-binding assay performed\", \"Homophilic interaction prediction not experimentally tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that several apparent missense/synonymous CDH23 variants act via aberrant splicing producing premature truncations, refining how genotype maps to phenotype.\",\n      \"evidence\": \"Exon trapping/minigene assays of splice-site mutations\",\n      \"pmids\": [\"11857743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to two variants\", \"In vitro splicing may not reflect cochlear transcripts\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Tested whether CDH23 and MYO7A act in a common genetic pathway in stereocilia and found no genetic interaction, narrowing the network of CDH23-dependent maintenance.\",\n      \"evidence\": \"Epistasis analysis in double mutant mice with Myo7a immunofluorescence and ABR\",\n      \"pmids\": [\"12121736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result does not exclude indirect or context-specific interaction\", \"Did not address physical association\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended CDH23 function beyond the ear by showing retinal electrophysiological dysfunction in null mice, indicating a sensory role outside the cochlea.\",\n      \"evidence\": \"ERG and light microscopy across multiple Cdh23 alleles plus Cdh23/Myo7a double mutants\",\n      \"pmids\": [\"14609561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No anatomical degeneration detected\", \"Molecular basis of retinal dysfunction unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localized the CDH23(+68) cytoplasmic/transmembrane region to actin-rich protrusions and showed that a splice-site mutant yields insoluble protein cleared by lysosomal degradation, linking aberrant splicing to protein mislocalization and turnover.\",\n      \"evidence\": \"Immunofluorescence in transfected cells and TEM of mutant mouse inner ear\",\n      \"pmids\": [\"16281288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not establish the trafficking machinery responsible\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Explained why an apparent missense mutation produces the syndromic USH1D rather than nonsyndromic phenotype by showing it causes exon skipping, distinguishing splicing-disrupting from true missense alleles.\",\n      \"evidence\": \"Minigene splicing assay of four missense variants\",\n      \"pmids\": [\"18273900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro minigene context\", \"Protein-level consequence not directly measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved CDH23's role as a structural tip-link component by contrasting null (tip-link loss, developmental disruption) with missense (intact development, progressive tip-link loss) models, dissociating developmental from maintenance functions.\",\n      \"evidence\": \"Forward genetics, SEM, and mechanotransduction electrophysiology in mouse models\",\n      \"pmids\": [\"19270079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the cytoplasmic stabilization machinery\", \"Molecular partner at the tip link not identified here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified EHD4 as a calcium-sensitive CDH23 interactor, providing a candidate mechanism for regulating CDH23 trafficking and localization.\",\n      \"evidence\": \"Membrane yeast two-hybrid, reciprocal co-IP, and EHD4 knockout auditory phenotyping\",\n      \"pmids\": [\"19487694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct effect on CDH23 trafficking in hair cells not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established CDH23 as essential for tip-link maintenance during aging by showing hypomorphic compound heterozygotes develop normally then progressively lose tip links, separating maintenance from formation.\",\n      \"evidence\": \"CDH23 immunolocalization at tip links, ABR, and SEM in compound heterozygous mice\",\n      \"pmids\": [\"24172198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of age-dependent destabilization unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined an apoptotic, caspase-mediated cell-death pathway downstream of CDH23 dysfunction, identifying a druggable node for hair-cell survival.\",\n      \"evidence\": \"Caspase analysis and Z-VAD-FMK pharmacological rescue in Cdh23 missense mice\",\n      \"pmids\": [\"20644563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream trigger of apoptosis not defined here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed ER stress upstream of apoptosis in CDH23-mutant hair cells, ordering the cell-death cascade triggered by tip-link dysfunction.\",\n      \"evidence\": \"ER stress marker analysis and Salubrinal rescue in Cdh23erl/erl cochleae\",\n      \"pmids\": [\"27882946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between tip-link loss and ER stress induction not mechanistically defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a functional CDH23-SANS interaction required for stereocilia maintenance through precise allele rescue, identifying a genetic modifier relationship within the USH1 network.\",\n      \"evidence\": \"CRISPR knock-in rescue of the protective Cdh23 allele with ABR and SEM\",\n      \"pmids\": [\"26936824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical CDH23-SANS binding not demonstrated here\", \"Stoichiometry and localization of interaction unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified the splicing regulators controlling the hair-cell-specific CDH23 isoform, showing RBM24/RBM38 promote and PTBP1 represses exon 68 inclusion.\",\n      \"evidence\": \"Splicing reporter screen, Rbm24 knockdown/knockout, and minigene assays in cells\",\n      \"pmids\": [\"32774357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo cochlear requirement of these factors not tested here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Explained the molecular function of exon 68 by showing the CDH23(+68) cytoplasmic tail cooperates with harmonin via phase separation at the upper tip-link density, with exon 68 loss causing progressive tip-link instability.\",\n      \"evidence\": \"Exon 68 deletion mice, SEM, electrophysiology, and harmonin condensate assays\",\n      \"pmids\": [\"38408254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of condensates at the UTLD not directly imaged\", \"Regulation of condensate dynamics by calcium not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed CDH23 is required for MET channel activity across vertebrate hair cells and linked its loss to dysregulated purine/ATP metabolism with partial ATP rescue.\",\n      \"evidence\": \"cdh23-knockout zebrafish, YO-PRO-1 MET assay, transcriptomics, and ATP supplementation\",\n      \"pmids\": [\"37575969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CDH23 to purine metabolism unclear\", \"Partial rescue not mechanistically explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Associated retinal CDH23 loss with Ca2+-MAPK-driven apoptosis in zebrafish, proposing a death pathway for photoreceptor degeneration.\",\n      \"evidence\": \"cdh23-knockout zebrafish transcriptomics with TUNEL and histology\",\n      \"pmids\": [\"40429749\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Transcriptomics-based pathway inference without direct mechanistic dissection\", \"Ca2+-MAPK causal link not validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Computationally modeled how a CDH23 variant disrupts the CDH23-PCDH15 interface, proposing a structural basis for tip-link complex destabilization.\",\n      \"evidence\": \"In silico molecular dynamics and protein-protein interaction modeling\",\n      \"pmids\": [\"40047980\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no experimental validation\", \"CDH23-PCDH15 binding disruption not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended CDH23 function to central auditory sensory gating by linking a hypomorphic allele to prepulse inhibition and brain eQTL effects.\",\n      \"evidence\": \"QTL mapping, CRISPR knock-in into B6 background, PPI testing, and eQTL analysis\",\n      \"pmids\": [\"33595068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the PPI effect reflects peripheral hearing or central role unresolved\", \"Brain CDH23 function mechanism unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDH23 phase-separated condensates, calcium-dependent trafficking, and the ER-stress-to-apoptosis cascade are mechanistically coupled to tip-link turnover in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural reconstitution of the full CDH23-PCDH15-harmonin-SANS upper tip-link complex\", \"Trigger linking mechanical tip-link loss to ER stress not identified\", \"Calcium regulation of condensate dynamics uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\"stereocilia tip link\", \"upper tip-link density\"],\n    \"partners\": [\"HARS/harmonin\", \"EHD4\", \"SANS/USH1G\", \"PCDH15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}