CDH23

Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links.

Reason: Human MCF-7 cell adhesion is reduced by CDH23 inhibitory antibody and RNAi (PMID:22413011); human HEK293T perturbations independently support an aggregation function (PMID:30747484). Thus cell-cell adhesion is not justified solely by tip links between stereocilia of one cell. Calcium-dependent extracellular homophilic binding is supported by ortholog ectodomain experiments (PMID:31729176). The IBA at PTN008601603 in PTHR24026 is compatible with these target-cell findings.

Summary: CDH23-mediated adhesion contributes to cell migration behavior in human cultured cells.

Reason: The cell-migration IBD is at PTN008601603 in PTHR24026. PMID:30747484 directly tests CDH23 expression and silencing in human HEK293T cells: silencing decreases aggregation and increases transwell migration. Its adhesive activity supplies a physical contribution to the migratory context. Retain this inherited process as a secondary role; the prominent sensory tip-link function does not establish loss of migration-related function.

Summary: Classical catenin-binding motifs are absent, but the scope of the inherited catenin interaction remains unresolved.

Reason: The relevant IBD is at PTN008601603 in PTHR24026. PMID:12485990 reports absence of consensus R1/R2 beta-catenin-binding sites and an alternative harmonin linkage; its absence-of-catenin observation is limited to growing hair bundles and is described as unpublished. PMID:30747484 and PMID:22413011 instead show CDH23 at beta-catenin-positive human cell contacts. Colocalization does not establish direct binding or membership of a catenin complex, but sensory specialization and motif differences alone do not adjudicate every isoform or tissue. Leave the distinct molecular-function and complex-membership assertions unresolved after the focused review. The OpenScientist report incorrectly states that PMID:30747484 never mentions catenin; its full text expressly reports colocalization and proposes MAGI-1 as a possible bridge. This is not direct binding evidence, but it prevents adopting the report's categorical exclusion. Direct binding and indirect complex membership remain separate human follow-up questions.

Summary: Classical catenin-binding motifs are absent, but the scope of the inherited catenin interaction remains unresolved.

Reason: The relevant IBD is at PTN008601603 in PTHR24026. PMID:12485990 reports absence of consensus R1/R2 beta-catenin-binding sites and an alternative harmonin linkage; its absence-of-catenin observation is limited to growing hair bundles and is described as unpublished. PMID:30747484 and PMID:22413011 instead show CDH23 at beta-catenin-positive human cell contacts. Colocalization does not establish direct binding or membership of a catenin complex, but sensory specialization and motif differences alone do not adjudicate every isoform or tissue. Leave the distinct molecular-function and complex-membership assertions unresolved after the focused review. The OpenScientist report incorrectly states that PMID:30747484 never mentions catenin; its full text expressly reports colocalization and proposes MAGI-1 as a possible bridge. This is not direct binding evidence, but it prevents adopting the report's categorical exclusion. Direct binding and indirect complex membership remain separate human follow-up questions.

Summary: Retain the inherited neuron-projection-development role as a secondary, phylogenetically inferred process.

Reason: PTHR24026 places this process at PTN004649584. CDH23 is a multidomain adhesion protein with multiple isoforms and expression outside hair cells. The reviewed sources do not demonstrate loss of the inherited developmental function. Lack of a target-neuron experiment and predominance of the hair-bundle literature are not sufficient grounds to reject the IBD. The specific human neuronal mechanism remains unresolved after the focused report. The report's zebrafish retinal morphology and optokinetic results are limited to those assays and do not establish loss of every human neuron-projection role; its lack-of-target-experiment objection does not overturn the IBD.

Summary: CDH23 binds cadherin partners through its extracellular adhesion domains.

Reason: The PTN008601603 inference is consistent with the established CDH23-PCDH15 tip-link partnership and with homophilic ectodomain interactions. PMID:31729176 uses mouse EC1-2 constructs and human A549-cell adhesion, with conserved interacting residues; this is ortholog biochemical support rather than a purified-human-ectodomain assay. Harmonin binding is a separate intracellular PDZ-domain interaction, not itself cadherin binding.

Summary: Calcium ion binding is appropriate for the extracellular cadherin repeats of CDH23.

Reason: Cadherin repeats use calcium to rigidify extracellular-domain interfaces and support adhesion.

Summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization is appropriate.

Reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization being more informative.

Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links.

Reason: Human MCF-7 cell adhesion is reduced by CDH23 inhibitory antibody and RNAi (PMID:22413011); human HEK293T perturbations independently support an aggregation function (PMID:30747484). Thus cell-cell adhesion is not justified solely by tip links between stereocilia of one cell. Calcium-dependent extracellular homophilic binding is supported by ortholog ectodomain experiments (PMID:31729176). The IBA at PTN008601603 in PTHR24026 is compatible with these target-cell findings.

Summary: CDH23 can mediate homophilic adhesion in addition to its heterophilic tip-link interaction.

Reason: PMID:22413011 demonstrates CDH23-dependent homotypic adhesion in human MCF-7 cells, and PMID:31729176 resolves a trans-homodimer mechanism using mouse EC1-2 proteins and tests adhesion of human A549 cells. The interacting residues are conserved between human and mouse. Heterophilic binding to PCDH15 in hair cells therefore does not exclude homophilic capacity in other contexts.

Summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization is appropriate.

Reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization being more informative.

Summary: CDH23 binds the PDZ2 domain of harmonin through its cytoplasmic region.

Reason: The original interaction studies support a more informative molecular function than generic protein binding. PMID:12485990 directly tests isolated harmonin PDZ domains in binding assays, and PMID:22879593 describes the C-terminal PDZ-binding motif within multivalent CDH23-harmonin assemblies. Use PDZ domain binding for this specific interface; other N-terminal-domain interactions and self-association are not being relabeled as PDZ binding.

Proposed replacements: PDZ domain binding

Summary: Self-association of CDH23 contributes to adhesive and anchoring assemblies.

Reason: PMID:22879593 explicitly reports homodimerization of the exon68-encoded cytoplasmic peptide and its contribution to CDH23-harmonin polymer formation. This is functionally relevant to the stereociliary anchoring apparatus, rather than incidental binding. The result is construct/isoform dependent; retain the original source fields without implying that every splice isoform contains exon68.

Summary: The calcium-process annotation needs separation of mechanical channel coupling from calcium-pump assays.

Reason: PMID:17234811 studies CDH23 genetic variation in a family with PMCA2-associated deafness, but its calcium-clearance and current assays test PMCA2 variants and PMCA2-mutant mice. The paper explicitly leaves CDH23-harmonin involvement in PMCA2 function open. CDH23 need not itself be a pump to participate structurally in calcium entry through mechanotransduction, so the previous categorical exclusion on that basis was invalid. The cited IMP process and broader mechanotransduction evidence require adjudication before accepting or rejecting this precise calcium claim. The focused report correctly assigns the pump assays to PMCA2 but again treats absence of pump activity as excluding structural participation in a transport process. It does not resolve the specific IMP source claim, so human follow-up remains necessary.

Summary: Human CDH23 variation contributes to a digenic hearing-loss phenotype.

Reason: The full original study identifies the CDH23 variant in the affected son carrying a PMCA2 mutation; its inheritance pattern supports the reported auditory contribution. This hearing phenotype does not, by itself, establish CDH23 calcium-pump activity.

Summary: The calcium-process annotation needs separation of mechanical channel coupling from calcium-pump assays.

Reason: PMID:17234811 studies CDH23 genetic variation in a family with PMCA2-associated deafness, but its calcium-clearance and current assays test PMCA2 variants and PMCA2-mutant mice. The paper explicitly leaves CDH23-harmonin involvement in PMCA2 function open. CDH23 need not itself be a pump to participate structurally in calcium entry through mechanotransduction, so the previous categorical exclusion on that basis was invalid. The cited IMP process and broader mechanotransduction evidence require adjudication before accepting or rejecting this precise calcium claim. The focused report correctly assigns the pump assays to PMCA2 but again treats absence of pump activity as excluding structural participation in a transport process. It does not resolve the specific IMP source claim, so human follow-up remains necessary.

Summary: The Usher syndrome cohort supports CDH23 contributions to auditory, vestibular and retinal function.

Reason: PMID:16679490 directly sequences CDH23 among the five USH1 genes and identifies pathogenic genotypes in patients selected for the combined deafness, vestibular dysfunction and retinal-degeneration phenotype. Retain the sensory annotation from this curated human genetic evidence. Hearing and balance fit the established sensory-hair-cell adhesion mechanism; the retinal phenotypes remain secondary roles here, with their exact cellular mechanism less resolved.

Summary: The Usher syndrome cohort supports CDH23 contributions to auditory, vestibular and retinal function.

Reason: PMID:16679490 directly sequences CDH23 among the five USH1 genes and identifies pathogenic genotypes in patients selected for the combined deafness, vestibular dysfunction and retinal-degeneration phenotype. Retain the sensory annotation from this curated human genetic evidence. Hearing and balance fit the established sensory-hair-cell adhesion mechanism; the retinal phenotypes remain secondary roles here, with their exact cellular mechanism less resolved.

Summary: CDH23 binds the PDZ2 domain of harmonin through its cytoplasmic region.

Reason: The original interaction studies support a more informative molecular function than generic protein binding. PMID:12485990 directly tests isolated harmonin PDZ domains in binding assays, and PMID:22879593 describes the C-terminal PDZ-binding motif within multivalent CDH23-harmonin assemblies. Use PDZ domain binding for this specific interface; other N-terminal-domain interactions and self-association are not being relabeled as PDZ binding.

Proposed replacements: PDZ domain binding

Summary: The Usher syndrome cohort supports CDH23 contributions to auditory, vestibular and retinal function.

Reason: PMID:16679490 directly sequences CDH23 among the five USH1 genes and identifies pathogenic genotypes in patients selected for the combined deafness, vestibular dysfunction and retinal-degeneration phenotype. Retain the sensory annotation from this curated human genetic evidence. Hearing and balance fit the established sensory-hair-cell adhesion mechanism; the retinal phenotypes remain secondary roles here, with their exact cellular mechanism less resolved.

Summary: The ortholog localization study supports CDH23 in sensory-hair-cell stereocilia.

Reason: PMID:12485990 examines developing mouse hair bundles and detects cadherin 23 in stereocilia, consistent with the original ISS evidence. The study is not a direct human localization experiment. Its developmental staining pattern does not negate later evidence for mature tip-link localization.

Summary: The Usher syndrome cohort supports CDH23 contributions to auditory, vestibular and retinal function.

Reason: PMID:16679490 directly sequences CDH23 among the five USH1 genes and identifies pathogenic genotypes in patients selected for the combined deafness, vestibular dysfunction and retinal-degeneration phenotype. Retain the sensory annotation from this curated human genetic evidence. Hearing and balance fit the established sensory-hair-cell adhesion mechanism; the retinal phenotypes remain secondary roles here, with their exact cellular mechanism less resolved.

Summary: Sensory perception of sound is a core physiological process supported by CDH23 stereocilium/hair-bundle function and hearing-loss genetics.

Reason: CDH23 is required for normal hearing through its role in stereocilia bundle organization, so sound perception should be treated as the core biological-process context for the cadherin/tip-link function.

Summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization is appropriate.

Reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization being more informative.

Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links.

Reason: Human MCF-7 cell adhesion is reduced by CDH23 inhibitory antibody and RNAi (PMID:22413011); human HEK293T perturbations independently support an aggregation function (PMID:30747484). Thus cell-cell adhesion is not justified solely by tip links between stereocilia of one cell. Calcium-dependent extracellular homophilic binding is supported by ortholog ectodomain experiments (PMID:31729176). The IBA at PTN008601603 in PTHR24026 is compatible with these target-cell findings.