CDH23 encodes cadherin-23, a large calcium-dependent adhesion protein with multiple splice isoforms. In sensory hair cells, its extracellular region contributes to the upper part of stereociliary tip links and its cytoplasmic tail binds harmonin, supporting hair-bundle organization and mechanotransduction. CDH23 can also form homophilic adhesive contacts; experiments in human epithelial cell lines link its expression to cell aggregation and migration behavior. Pathogenic variants cause nonsyndromic hearing loss or Usher syndrome with auditory, vestibular and retinal involvement.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0098609 cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links. Reason: CDH23 inhibitory antibody and CDH23-directed RNAi reduce homotypic MCF-7 adhesion and MCF-7/fibroblast aggregation in PMID:22413011 Results/Fig. 3. These are genuine contacts between human cells, distinct from links between stereocilia of one hair cell. PMID:30747484 independently measures endogenous CDH23 silencing, aggregation and transwell migration in human HEK293T cells. Mouse EC1-2 homodimer biophysics and adhesion of native-CDH23-expressing human A549 cells in PMID:31729176 provide complementary molecular support; the purified construct is not human. This evidence supports the existing adhesion assertion without assigning a metastatic signaling activity. |
| GO:0016477 cell migration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CDH23-mediated adhesion contributes to cell migration behavior in human cultured cells. Reason: The current-main PAINT table records the migration IBD at PTN008601603 in PTHR24026. PMID:30747484 Results section 3.2/Fig. 2 couples CDH23-specific silencing in human HEK293T cells to reduced aggregation and increased transwell migration; the adhesive protein supplies a physical contribution to that context. Retain the inherited process as a secondary role. The overexpression plasmid is described as a gift without a species/accession in the inspected Methods, so the human target evidence here is anchored to endogenous-protein silencing rather than inferred from host-cell identity. Supporting Evidence: |
| GO:0008013 beta-catenin binding | IBA GO_REF:0000033 | UNDECIDED | Summary: The inherited beta-catenin-binding assertion remains unresolved despite a distinct harmonin linkage and junctional colocalization. Reason: The PAINT IBD is at PTN008601603. PMID:12485990 Discussion reports absent classical R1/R2 beta-catenin-binding motifs and establishes a separate harmonin interface; its statement about absent catenins is limited to developing hair bundles and unpublished observations. PMID:22413011 uses beta-catenin as a junction marker, while PMID:30747484 Results section 3.1/Fig. 1 explicitly reports CDH23/beta-catenin colocalization in native human A549 contacts. Its Discussion proposes MAGI-1 as a possible bridge, without a demonstrated CDH23-beta-catenin binding assay. Thus the targeted human MF remains unresolved: colocalization does not establish it, but motif divergence and another binding partner do not prove universal loss. The preserved OpenScientist report incorrectly denies the catenin passage; it cannot close this evidence gap. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008601603 Β· PTN008601603 UNRESOLVED Classical motif loss is a mechanistic concern; target-cell colocalization supplies context but not a direct interaction assay. Ancestral interaction and complex membership require separate adjudication. Supporting Evidence: PMID:12485990 cadherin 23 lacks the consensus R1 and R2 binding sites for Ξ²-catenin |
| GO:0016342 catenin complex | IBA GO_REF:0000033 | UNDECIDED | Summary: CDH23 localization at beta-catenin-positive contacts does not settle its membership in a catenin complex. Reason: The separate catenin-complex IBD is recorded at PTN008601603. PMID:22413011 and PMID:30747484 show native human cell contacts containing CDH23 and beta-catenin, but the inspected results do not isolate a defined complex containing both. The MAGI-1 bridge discussed in PMID:30747484 is a proposed explanation, not an assayed assembly in that paper. Conversely, lack of a classical direct beta-catenin interface does not itself exclude indirect complex membership. Preserve UNDECIDED for this CC assertion independently of the unresolved beta-catenin-binding MF, without converting sensory specialization into a universal negative. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN008601603 Β· PTN008601603 UNRESOLVED Classical motif loss is a mechanistic concern; target-cell colocalization supplies context but not a direct interaction assay. Ancestral interaction and complex membership require separate adjudication. Supporting Evidence: PMID:30747484 puncta at the cellβcell boundaries that were coβlocalized with Ξ²βcatenin |
| GO:0031175 neuron projection development | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Supporting Evidence: file:interpro/panther/PTHR24026/PTHR24026-paint.tsv PTHR24026 PTN004649584 GO:0031175 P IBD false FB:FBgn0262018|MGI:MGI:1890219|ZFIN:ZDB-GENE-040513-7 taxon:33213 20231129 |
| GO:0045296 cadherin binding | IBA GO_REF:0000033 | ACCEPT | Summary: CDH23 binds cadherin partners through its extracellular adhesion domains. Reason: The PTN008601603 IBD is consistent with CDH23-PCDH15 tip-link binding and extracellular CDH23 homophilic interactions. PMID:31729176 Methods uses mouse NP_075859.2 EC1-2 constructs; Results/Fig. 2 tests adhesion of human A549 cells to immobilized protein and cell aggregation after EC1-2 transfection. PMID:22413011 independently perturbs endogenous CDH23-dependent adhesion between human cells. Retain the broad cadherin-binding MF because it accommodates both sensory contacts between stereocilia of one cell and distinct intercellular contacts. GO:0098641 would describe only the latter and would improperly constrain the principal sensory core if substituted for every cadherin-binding role. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium ion binding is appropriate for the extracellular cadherin repeats of CDH23. Reason: Extracellular cadherin repeats coordinate calcium to stabilize domain interfaces and adhesive interactions, consistent with the InterPro-derived assertion and the calcium-dependent ectodomain experiments in PMID:31729176. This binding/cofactor requirement is distinct from intrinsic calcium pumping or an independently resolved calcium-transport process. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Membrane localization is appropriate for the long transmembrane CDH23 products. Reason: The original human cloning study PMID:11138009 describes a single transmembrane domain; human cell-contact experiments in PMID:22413011 and the intact UniProt topology independently support the source location. This gene-level assertion is not a claim that all eleven alternatively spliced products are membrane-spanning: truncated products are retained separately and no isoform-specific source qualifier is invented. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links. Reason: CDH23 inhibitory antibody and CDH23-directed RNAi reduce homotypic MCF-7 adhesion and MCF-7/fibroblast aggregation in PMID:22413011 Results/Fig. 3. These are genuine contacts between human cells, distinct from links between stereocilia of one hair cell. PMID:30747484 independently measures endogenous CDH23 silencing, aggregation and transwell migration in human HEK293T cells. Mouse EC1-2 homodimer biophysics and adhesion of native-CDH23-expressing human A549 cells in PMID:31729176 provide complementary molecular support; the purified construct is not human. This evidence supports the existing adhesion assertion without assigning a metastatic signaling activity. |
| GO:0007156 homophilic cell-cell adhesion | IEA GO_REF:0000002 | ACCEPT | 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. Supporting Evidence: PMID:22413011 RNAi treatment significantly reduced the ability of MCF-7 cells to participate in homotypic adhesion. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane localization is appropriate for the long transmembrane CDH23 products. Reason: The original human cloning study PMID:11138009 describes a single transmembrane domain; human cell-contact experiments in PMID:22413011 and the intact UniProt topology independently support the source location. This gene-level assertion is not a claim that all eleven alternatively spliced products are membrane-spanning: truncated products are retained separately and no isoform-specific source qualifier is invented. |
| GO:0005515 protein binding | IPI PMID:22879593 Large protein assemblies formed by multivalent interactions ... | MODIFY | Summary: CDH23 binds the PDZ2 domain of harmonin through its cytoplasmic region. Reason: PMID:22879593 was read in the authentic author manuscript at Protein Preparation and Results/Figs. 4-6, and the normal cache refresh has now independently recovered the complete PMC3460447 text. It tests human CDH23 cytoplasmic tails with or without exon68 and human harmonin-a. PBM deletion/NTD-site perturbations and binding/assembly measurements distinguish the C-terminal PDZ-binding motif from the two NTD-binding sites; the PDZ interface is further resolved by the human-CDH23-tail/isolated mouse-harmonin-PDZ2 assay in PMID:12485990 Fig. 6. Retain the supported PDZ-domain-binding refinement for this interface. Do not relabel the exon68/NTD interface or self-association as PDZ binding, or call the recombinant assembly an in-vivo measurement of anchorage strength. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:22879593 exon68 peptide, and the C-terminal PDZ binding motif |
| GO:0042802 identical protein binding | IPI PMID:22879593 Large protein assemblies formed by multivalent interactions ... | ACCEPT | Summary: Exon68-dependent self-association of the CDH23 cytoplasmic tail supports anchoring-assembly formation. Reason: PMID:22879593 author-manuscript Protein Preparation and Results/Fig. 4 test human CDH23 cytoplasmic tails. Analytical ultracentrifugation resolves the +exon68 tail as a dimer and the -exon68 tail as a monomer. The isolated GB1-exon68 construct instead forms nonspecific aggregates; flanking tail sequences help stabilize the dimer. Thus the supported assertion is exon68-dependent self-association of the tested tail, not stable homodimerization by the isolated peptide or every splice product. Results/Figs. 5-6 show that these contacts promote multivalent CDH23/harmonin assembly, a mechanistically relevant part of the sensory anchoring apparatus. Supporting Evidence: PMID:22879593 exon68 can induce dimer formation of the cadherin23 cytoplasmic tail PMID:22879593 The GB1-exon68 protein forms nonspecific aggregates |
| GO:0006816 calcium ion transport | IMP PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... | UNDECIDED | Summary: The calcium-process annotation needs separation of mechanical channel coupling from calcium-pump assays. Reason: The full PMID:17234811 Results, Discussion and Methods were re-read. CDH23 T1999S is a segregating family variant discussed as a hearing-loss modifier and previously reported polymorphism; the healthy father and brother also carry it. The calcium-clearance experiments test PMCA2 splice variants/G283S/G293S in CHO cells, while hair-cell calcium imaging and mechanotransduction-current measurements compare PMCA2-mutant/knockout mice. No CDH23-specific calcium-handling assay is established by those experiments, and the paper leaves an effect of the CDH23-harmonin-myosin complex on PMCA2 open. A tip-link protein can nevertheless participate structurally in channel gating without being a pump. Preserve UNDECIDED for this precise source-linked process; neither pump-activity exclusion nor the broader hearing phenotype settles it. Supporting Evidence: PMID:17234811 Whether the tripolar complex has any role in the function of PMCA2 is an open question. |
| GO:0007605 sensory perception of sound | IMP PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... | ACCEPT | Summary: Human CDH23 variation contributes to a digenic hearing-loss phenotype. Reason: PMID:17234811 reports CDH23 T1999S in the affected son with a PMCA2 variant but also in unaffected father and brother, and discusses it as a genetic modifier rather than an independently sufficient pathogenic allele. Retain the curated hearing-process annotation in the context of that digenic model and independent human CDH23 hearing-loss genetics in PMID:11138009 and PMID:16679490. This does not establish CDH23 calcium-pump activity or resolve the two specific calcium-process assertions. |
| GO:0051480 regulation of cytosolic calcium ion concentration | IMP PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... | UNDECIDED | Summary: The calcium-process annotation needs separation of mechanical channel coupling from calcium-pump assays. Reason: The full PMID:17234811 Results, Discussion and Methods were re-read. CDH23 T1999S is a segregating family variant discussed as a hearing-loss modifier and previously reported polymorphism; the healthy father and brother also carry it. The calcium-clearance experiments test PMCA2 splice variants/G283S/G293S in CHO cells, while hair-cell calcium imaging and mechanotransduction-current measurements compare PMCA2-mutant/knockout mice. No CDH23-specific calcium-handling assay is established by those experiments, and the paper leaves an effect of the CDH23-harmonin-myosin complex on PMCA2 open. A tip-link protein can nevertheless participate structurally in channel gating without being a pump. Preserve UNDECIDED for this precise source-linked process; neither pump-activity exclusion nor the broader hearing phenotype settles it. Supporting Evidence: |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... | KEEP AS NON CORE | 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. Supporting Evidence: |
| GO:0050953 sensory perception of light stimulus | IMP PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... | KEEP AS NON CORE | 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. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:12485990 Myosin VIIa, harmonin and cadherin 23, three Usher I gene pr... | MODIFY | Summary: CDH23 binds the PDZ2 domain of harmonin through its cytoplasmic region. Reason: PMID:12485990 Results/Fig. 6 and Expression constructs explicitly test the human CDH23 cytoplasmic segment 3086-3354 (retinal cDNA NM_022124) against mouse harmonin constructs. Isolated PDZ2 binds immobilized CDH23 cytodomain, while PDZ1 and PDZ3 controls do not; GST/pull-down and yeast-two-hybrid results are concordant. This supports the own human target MF PDZ domain binding with the stated cross-species partner/fragment scope. The later human-tail/human-harmonin study PMID:22879593 distinguishes that C-terminal motif from NTD-binding interfaces. No harmonin actin-binding activity is assigned to CDH23. Proposed replacements: PDZ domain binding |
| GO:0007605 sensory perception of sound | IMP PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... | ACCEPT | 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. Supporting Evidence: PMID:16679490 Mutations found in CDH23 , PCDH15 , and USH1C were overwhelmingly truncation mutations. |
| GO:0032420 stereocilium | ISS PMID:12485990 Myosin VIIa, harmonin and cadherin 23, three Usher I gene pr... | ACCEPT | Summary: The ortholog localization study supports CDH23 in sensory-hair-cell stereocilia. Reason: PMID:12485990 localization experiments examine developing mouse sensory hair bundles, consistent with the original ISS assertion. Read Results and immunofluorescence/immunoelectron-microscopy Methods; this is ortholog localization, not direct human imaging. The study reports a developmental staining pattern, which is not used to deny later mature tip-link localization. Human-CDH23-tail biochemical constructs elsewhere in the same paper do not change the organism of this localization assay. Supporting Evidence: |
| GO:0050957 equilibrioception | IMP PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... | ACCEPT | 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. Supporting Evidence: |
| GO:0007605 sensory perception of sound | IMP PMID:15537665 Digenic inheritance of deafness caused by mutations in genes... | ACCEPT | Summary: Sensory perception of sound is a core physiological process supported by CDH23 stereocilium/hair-bundle function and hearing-loss genetics. Reason: The authentic PMID:15537665 abstract reports hearing loss and stereociliary degeneration in Cdh23/Pcdh15 double-heterozygous mice and a digenic USH1 phenotype in three human families. Preserve the source assertion and its original acts_upstream_of_or_within qualifier; the ortholog morphology experiment is not relabeled as direct human hair-cell imaging. Together with independent human CDH23 genetic evidence and its adhesive tip-link role, sound perception is a core physiological context. |
| GO:0016020 membrane | NAS PMID:11138009 Mutation of CDH23, encoding a new member of the cadherin gen... | ACCEPT | Summary: Membrane localization is appropriate for the long transmembrane CDH23 products. Reason: The original human cloning study PMID:11138009 describes a single transmembrane domain; human cell-contact experiments in PMID:22413011 and the intact UniProt topology independently support the source location. This gene-level assertion is not a claim that all eleven alternatively spliced products are membrane-spanning: truncated products are retained separately and no isoform-specific source qualifier is invented. |
| GO:0016339 calcium-dependent cell-cell adhesion | NAS PMID:11138009 Mutation of CDH23, encoding a new member of the cadherin gen... | ACCEPT | Summary: CDH23 contributes directly to adhesive contacts between cells as well as to stereociliary links. Reason: CDH23 inhibitory antibody and CDH23-directed RNAi reduce homotypic MCF-7 adhesion and MCF-7/fibroblast aggregation in PMID:22413011 Results/Fig. 3. These are genuine contacts between human cells, distinct from links between stereocilia of one hair cell. PMID:30747484 independently measures endogenous CDH23 silencing, aggregation and transwell migration in human HEK293T cells. Mouse EC1-2 homodimer biophysics and adhesion of native-CDH23-expressing human A549 cells in PMID:31729176 provide complementary molecular support; the purified construct is not human. This evidence supports the existing adhesion assertion without assigning a metastatic signaling activity. |
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Download this section (compressed HTML)Q: Which CDH23 domains or isoforms, if any, are mechanistically relevant to pituitary adenoma predisposition rather than hearing/retinal biology?
Q: Can PITA5-associated CDH23 variants be shown to perturb cadherin adhesion, mechanotransduction-related assemblies, or a pituitary-specific interaction network?
Experiment: Test PITA5-associated CDH23 variants in cadherin adhesion and harmonin/PCDH15 interaction assays alongside known hearing-loss variants.
Hypothesis: PITA5-associated variants may perturb CDH23 adhesion or scaffold interactions differently from classic hearing-loss variants.
Experiment: Assess CDH23 isoform expression and subcellular localization in normal pituitary and pituitary adenoma samples.
Hypothesis: Pituitary-relevant isoform expression or localization would explain how CDH23 variation contributes to adenoma predisposition.
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