CDH23 encodes cadherin-23, a large calcium-dependent cadherin family cell-adhesion protein. In sensory hair cells, CDH23 contributes to the upper part of the stereocilia tip-link apparatus and interacts with harmonin and related Usher syndrome proteins to maintain hair-bundle cohesion and mechanotransduction. CDH23 is also expressed in retina, and pathogenic variants cause Usher syndrome and nonsyndromic hearing loss; germline variants have additionally been associated with pituitary adenoma predisposition, but the best-supported normal molecular role remains cadherin-mediated stereocilium adhesion and organization.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0098609
cell-cell adhesion
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin interactions supporting stereocilia cohesion and tip-link anchoring.
Reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization; the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most informative framing.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
Cadherins are calcium-dependent cell adhesion proteins.
PMID:12485990
cadherin 23 are both present in the growing stereocilia and that they bind to each other
|
|
GO:0016477
cell migration
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Cell migration is a generic cadherin-family propagation and is not a well-supported core CDH23 function.
Reason: The direct CDH23 evidence in this review supports stereocilium adhesion/organization, hearing, vestibular function, and retinal maintenance rather than cell migration.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
CDH23 is required for establishing and/or maintaining the proper organization of the stereocilia bundle
|
|
GO:0008013
beta-catenin binding
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Beta-catenin/catenin-complex annotations appear to be over-propagated from classical cadherin biology and are not central to CDH23 hair-bundle function.
Reason: The reviewed CDH23 evidence emphasizes PCDH15, harmonin/USH1C, USH1G, and MYO7A in stereocilia rather than beta-catenin complex function.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A
|
|
GO:0016342
catenin complex
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Beta-catenin/catenin-complex annotations appear to be over-propagated from classical cadherin biology and are not central to CDH23 hair-bundle function.
Reason: The reviewed CDH23 evidence emphasizes PCDH15, harmonin/USH1C, USH1G, and MYO7A in stereocilia rather than beta-catenin complex function.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
It is part of the functional network formed by USH1C, USH1G, CDH23 and MYO7A
|
|
GO:0031175
neuron projection development
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Neuron projection development is too broad and not the right cellular context for the best-supported CDH23 function.
Reason: CDH23 acts in sensory hair-cell stereocilia bundles, not generic neuron projection development.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
proper organization of the stereocilia bundle of hair cells
|
|
GO:0045296
cadherin binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Cadherin binding is appropriate because CDH23 participates in cadherin-mediated tip-link/adhesion assemblies, including heterophilic PCDH15 interaction by similarity and related cadherin-family interactions.
Reason: This term captures a real molecular interaction mode better than generic protein binding.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction with PCDH15.
|
|
GO:0005509
calcium ion binding
|
IEA
GO_REF:0000002 |
ACCEPT |
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.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
Three calcium ions are usually bound at the interface of each cadherin domain
|
|
GO:0005886
plasma membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
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.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
SUBCELLULAR LOCATION: Cell membrane
file:human/CDH23/CDH23-uniprot.txt
Single-pass type I membrane protein
|
|
GO:0007155
cell adhesion
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin interactions supporting stereocilia cohesion and tip-link anchoring.
Reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization; the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most informative framing.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
Cadherins are calcium-dependent cell adhesion proteins.
PMID:12485990
cadherin 23 are both present in the growing stereocilia and that they bind to each other
|
|
GO:0007156
homophilic cell-cell adhesion
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: CDH23 mediates heterophilic, not homophilic, cell-cell adhesion. The functional tip-link is a CDH23-PCDH15 heterodimer, so the InterPro-propagated homophilic annotation from the generic cadherin domain is an over-annotation for this paralog.
Reason: The InterPro2GO mapping propagated a generic cadherin-family homophilic adhesion term, but CDH23 specifically forms an antiparallel heterodimer with PCDH15 via cadherin repeats 1-2, defining the upper part of the stereocilia tip link. The broader cell adhesion term (GO:0007155) and stereocilium-specific terms are retained as accurate; homophilic adhesion is not supported for this gene.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
SUBUNIT: antiparallel heterodimer with PCDH15
file:human/CDH23/CDH23-uniprot.txt
Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction with PCDH15.
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000002 |
ACCEPT |
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.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
SUBCELLULAR LOCATION: Cell membrane
file:human/CDH23/CDH23-uniprot.txt
Single-pass type I membrane protein
|
|
GO:0005515
protein binding
|
IPI
PMID:22879593 Large protein assemblies formed by multivalent interactions ... |
MARK AS OVER ANNOTATED |
Summary: The cited interaction evidence is meaningful but generic protein binding is too vague for CDH23 curation.
Reason: The interaction should be interpreted as harmonin/USH protein binding and stereocilium tip-link anchoring rather than generic protein binding.
Supporting Evidence:
PMID:22879593
cadherin23/harmonin complexes
|
|
GO:0042802
identical protein binding
|
IPI
PMID:22879593 Large protein assemblies formed by multivalent interactions ... |
KEEP AS NON CORE |
Summary: Identical protein binding is supported by evidence that an exon68-encoded CDH23 peptide can self-dimerize.
Reason: Self-dimerization contributes to polymeric CDH23-harmonin assemblies but is not the whole gene-level core function.
Supporting Evidence:
PMID:22879593
the exon68-encoded peptide of cadherin23 can either interact with the N-terminal domain (NTD) of harmonin or form a homodimer
|
|
GO:0006816
calcium ion transport
|
IMP
PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... |
REMOVE |
Summary: CDH23 is not a calcium transporter; the cited calcium-transport study centers on PMCA2/ATP2B2 with CDH23 as a hearing modifier.
Reason: The annotation conflates hair-cell calcium physiology with CDH23 cadherin function.
Supporting Evidence:
PMID:17234811
Ca2+ enters the stereocilia of hair cells through mechanoelectrical transduction channels
PMID:17234811
exported back to endolymph by an unusual splicing isoform
|
|
GO:0007605
sensory perception of sound
|
IMP
PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... |
ACCEPT |
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.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
GO:0051480
regulation of cytosolic calcium ion concentration
|
IMP
PMID:17234811 A functional study of plasma-membrane calcium-pump isoform 2... |
MARK AS OVER ANNOTATED |
Summary: Regulation of cytosolic calcium concentration is an indirect hearing-physiology consequence rather than a direct CDH23 function.
Reason: The direct molecular role of CDH23 is cadherin-mediated stereocilium adhesion; PMCA2 is the calcium pump in the cited work.
Supporting Evidence:
PMID:17234811
stereociliary Ca2+ transients induced by Ca2+ uncaging was compromised
|
|
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: This phenotype-level sensory annotation is supported but should be kept as non-core relative to the molecular cadherin/stereocilium function.
Reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product role is stereocilium adhesion and hair-bundle organization.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
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: This phenotype-level sensory annotation is supported but should be kept as non-core relative to the molecular cadherin/stereocilium function.
Reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product role is stereocilium adhesion and hair-bundle organization.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
GO:0005515
protein binding
|
IPI
PMID:12485990 Myosin VIIa, harmonin and cadherin 23, three Usher I gene pr... |
MARK AS OVER ANNOTATED |
Summary: The cited interaction evidence is meaningful but generic protein binding is too vague for CDH23 curation.
Reason: The interaction should be interpreted as harmonin/USH protein binding and stereocilium tip-link anchoring rather than generic protein binding.
Supporting Evidence:
PMID:12485990
cadherin 23 are both present in the growing stereocilia and that they bind to each other
|
|
GO:0007605
sensory perception of sound
|
IMP
PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... |
ACCEPT |
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.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
GO:0032420
stereocilium
|
ISS
PMID:12485990 Myosin VIIa, harmonin and cadherin 23, three Usher I gene pr... |
ACCEPT |
Summary: Stereocilium localization is directly supported and central to CDH23 function in hair cells.
Reason: CDH23 is present in developing stereocilia and participates in tip-link/hair-bundle architecture.
Supporting Evidence:
PMID:12485990
cadherin 23 are both present in the growing stereocilia
|
|
GO:0050957
equilibrioception
|
IMP
PMID:16679490 Survey of the frequency of USH1 gene mutations in a cohort o... |
KEEP AS NON CORE |
Summary: This phenotype-level sensory annotation is supported but should be kept as non-core relative to the molecular cadherin/stereocilium function.
Reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product role is stereocilium adhesion and hair-bundle organization.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
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: 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.
Supporting Evidence:
PMID:15537665
CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle
file:human/CDH23/CDH23-uniprot.txt
Required for normal hearing.
|
|
GO:0016020
membrane
|
NAS
PMID:11138009 Mutation of CDH23, encoding a new member of the cadherin gen... |
ACCEPT |
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.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
SUBCELLULAR LOCATION: Cell membrane
file:human/CDH23/CDH23-uniprot.txt
Single-pass type I membrane protein
|
|
GO:0016339
calcium-dependent cell-cell adhesion
|
NAS
PMID:11138009 Mutation of CDH23, encoding a new member of the cadherin gen... |
ACCEPT |
Summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin interactions supporting stereocilia cohesion and tip-link anchoring.
Reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization; the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most informative framing.
Supporting Evidence:
file:human/CDH23/CDH23-uniprot.txt
Cadherins are calcium-dependent cell adhesion proteins.
PMID:12485990
cadherin 23 are both present in the growing stereocilia and that they bind to each other
|
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.
PITA context: CDH23 corresponds to PITA5 / pituitary adenoma 5, multiple types. UniProt notes that PITA5 includes GH-, PRL-, ACTH-, TSH-secreting and plurihormonal tumors and that familial transmission is consistent with autosomal dominant inheritance with reduced penetrance [file:human/CDH23/CDH23-uniprot.txt "PITA5 is consistent with autosomal dominant inheritance with reduced penetrance"].
Deep research status: just deep-research-falcon human CDH23 --fallback perplexity-lite timed out on Falcon after 600 seconds, and the fallback failed with a Perplexity quota error. I proceeded using fetched UniProt, GOA, and cached publications.
Functional summary: CDH23 is a cadherin-family adhesion protein whose best-supported normal function is in stereocilia/hair-bundle architecture. UniProt states that "Cadherins are calcium-dependent cell adhesion proteins" and that CDH23 is required for "proper organization of the stereocilia bundle" [file:human/CDH23/CDH23-uniprot.txt "Cadherins are calcium-dependent cell adhesion proteins."; file:human/CDH23/CDH23-uniprot.txt "proper organization of the stereocilia bundle of hair cells"]. Experimental evidence shows cadherin 23 is present in growing stereocilia and binds harmonin PMID:12485990, and CDH23/PCDH15 maintain normal stereocilia bundle organization PMID:15537665.
Annotation decisions: I accepted cadherin adhesion, calcium binding, membrane/stereocilium localization, and sensory phenotypes as supported, with sensory phenotypes kept non-core where they are phenotype-level consequences. I removed the calcium ion transport annotation because the cited PMCA2 paper describes stereociliary calcium entry/export biology rather than CDH23 transporter activity [PMID:17234811 "Ca2+ enters the stereocilia of hair cells through mechanoelectrical transduction channels"; PMID:17234811 "exported back to endolymph by an unusual splicing isoform"].
id: Q9H251
gene_symbol: CDH23
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: CDH23 encodes cadherin-23, a large calcium-dependent cadherin family cell-adhesion
protein. In sensory hair cells, CDH23 contributes to the upper part of the stereocilia tip-link
apparatus and interacts with harmonin and related Usher syndrome proteins to maintain hair-bundle
cohesion and mechanotransduction. CDH23 is also expressed in retina, and pathogenic variants
cause Usher syndrome and nonsyndromic hearing loss; germline variants have additionally been
associated with pituitary adenoma predisposition, but the best-supported normal molecular role
remains cadherin-mediated stereocilium adhesion and organization.
alternative_products:
- name: '1'
id: Q9H251-1
- name: '2'
id: Q9H251-2
sequence_note: VSP_000645
- name: '3'
id: Q9H251-3
sequence_note: VSP_000646
- name: '4'
id: Q9H251-4
sequence_note: VSP_000647
- name: '5'
id: Q9H251-5
sequence_note: VSP_013268, VSP_013269
- name: '6'
id: Q9H251-6
sequence_note: VSP_035289, VSP_035290
- name: 7 (B1)
id: Q9H251-7
sequence_note: VSP_044260
- name: '8'
id: Q9H251-8
sequence_note: VSP_044261, VSP_000645
- name: 9 (B2)
id: Q9H251-9
sequence_note: VSP_044260, VSP_000647
- name: 10 (C1)
id: Q9H251-10
sequence_note: VSP_047923, VSP_047924
- name: 11 (C2)
id: Q9H251-11
sequence_note: VSP_047923, VSP_047924, VSP_000647
existing_annotations:
- term:
id: GO:0098609
label: cell-cell adhesion
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin
interactions supporting stereocilia cohesion and tip-link anchoring.
action: ACCEPT
reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization;
the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most
informative framing.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Cadherins are calcium-dependent cell adhesion proteins.
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia and that they bind
to each other
- term:
id: GO:0016477
label: cell migration
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Cell migration is a generic cadherin-family propagation and is not a well-supported
core CDH23 function.
action: MARK_AS_OVER_ANNOTATED
reason: The direct CDH23 evidence in this review supports stereocilium adhesion/organization,
hearing, vestibular function, and retinal maintenance rather than cell migration.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: CDH23 is required for establishing and/or maintaining the proper organization
of the stereocilia bundle
- term:
id: GO:0008013
label: beta-catenin binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Beta-catenin/catenin-complex annotations appear to be over-propagated from classical
cadherin biology and are not central to CDH23 hair-bundle function.
action: MARK_AS_OVER_ANNOTATED
reason: The reviewed CDH23 evidence emphasizes PCDH15, harmonin/USH1C, USH1G, and MYO7A in
stereocilia rather than beta-catenin complex function.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: It is part of the functional network formed by USH1C, USH1G, CDH23 and
MYO7A
- term:
id: GO:0016342
label: catenin complex
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: part_of
review:
summary: Beta-catenin/catenin-complex annotations appear to be over-propagated from classical
cadherin biology and are not central to CDH23 hair-bundle function.
action: MARK_AS_OVER_ANNOTATED
reason: The reviewed CDH23 evidence emphasizes PCDH15, harmonin/USH1C, USH1G, and MYO7A in
stereocilia rather than beta-catenin complex function.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: It is part of the functional network formed by USH1C, USH1G, CDH23 and
MYO7A
- term:
id: GO:0031175
label: neuron projection development
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Neuron projection development is too broad and not the right cellular context for
the best-supported CDH23 function.
action: MARK_AS_OVER_ANNOTATED
reason: CDH23 acts in sensory hair-cell stereocilia bundles, not generic neuron projection
development.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: proper organization of the stereocilia bundle of hair cells
- term:
id: GO:0045296
label: cadherin binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Cadherin binding is appropriate because CDH23 participates in cadherin-mediated tip-link/adhesion
assemblies, including heterophilic PCDH15 interaction by similarity and related cadherin-family
interactions.
action: ACCEPT
reason: This term captures a real molecular interaction mode better than generic protein binding.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction
with PCDH15.
- term:
id: GO:0005509
label: calcium ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: Calcium ion binding is appropriate for the extracellular cadherin repeats of CDH23.
action: ACCEPT
reason: Cadherin repeats use calcium to rigidify extracellular-domain interfaces and support
adhesion.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Three calcium ions are usually bound at the interface of each cadherin
domain
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization
is appropriate.
action: ACCEPT
reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization
being more informative.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Single-pass type I membrane protein
- term:
id: GO:0007155
label: cell adhesion
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin
interactions supporting stereocilia cohesion and tip-link anchoring.
action: ACCEPT
reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization;
the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most
informative framing.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Cadherins are calcium-dependent cell adhesion proteins.
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia and that they bind
to each other
- term:
id: GO:0007156
label: homophilic cell-cell adhesion
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: CDH23 mediates heterophilic, not homophilic, cell-cell adhesion. The functional
tip-link is a CDH23-PCDH15 heterodimer, so the InterPro-propagated homophilic annotation
from the generic cadherin domain is an over-annotation for this paralog.
action: MARK_AS_OVER_ANNOTATED
reason: The InterPro2GO mapping propagated a generic cadherin-family homophilic adhesion term,
but CDH23 specifically forms an antiparallel heterodimer with PCDH15 via cadherin repeats
1-2, defining the upper part of the stereocilia tip link. The broader cell adhesion term
(GO:0007155) and stereocilium-specific terms are retained as accurate; homophilic adhesion
is not supported for this gene.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: 'SUBUNIT: antiparallel heterodimer with PCDH15'
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Cadherin repeats 1 and 2 mediate calcium-dependent heterophilic interaction
with PCDH15.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: located_in
review:
summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization
is appropriate.
action: ACCEPT
reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization
being more informative.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Single-pass type I membrane protein
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22879593
qualifier: enables
review:
summary: The cited interaction evidence is meaningful but generic protein binding is too vague
for CDH23 curation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction should be interpreted as harmonin/USH protein binding and stereocilium
tip-link anchoring rather than generic protein binding.
supported_by:
- reference_id: PMID:22879593
supporting_text: cadherin23/harmonin complexes
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22879593
qualifier: enables
review:
summary: Identical protein binding is supported by evidence that an exon68-encoded CDH23 peptide
can self-dimerize.
action: KEEP_AS_NON_CORE
reason: Self-dimerization contributes to polymeric CDH23-harmonin assemblies but is not the
whole gene-level core function.
supported_by:
- reference_id: PMID:22879593
supporting_text: the exon68-encoded peptide of cadherin23 can either interact with the N-terminal
domain (NTD) of harmonin or form a homodimer
- term:
id: GO:0006816
label: calcium ion transport
evidence_type: IMP
original_reference_id: PMID:17234811
qualifier: involved_in
review:
summary: CDH23 is not a calcium transporter; the cited calcium-transport study centers on
PMCA2/ATP2B2 with CDH23 as a hearing modifier.
action: REMOVE
reason: The annotation conflates hair-cell calcium physiology with CDH23 cadherin function.
supported_by:
- reference_id: PMID:17234811
supporting_text: Ca2+ enters the stereocilia of hair cells through mechanoelectrical transduction
channels
- reference_id: PMID:17234811
supporting_text: exported back to endolymph by an unusual splicing isoform
- term:
id: GO:0007605
label: sensory perception of sound
evidence_type: IMP
original_reference_id: PMID:17234811
qualifier: involved_in
review:
summary: Sensory perception of sound is a core physiological process supported by CDH23 stereocilium/hair-bundle
function and hearing-loss genetics.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0051480
label: regulation of cytosolic calcium ion concentration
evidence_type: IMP
original_reference_id: PMID:17234811
qualifier: involved_in
review:
summary: Regulation of cytosolic calcium concentration is an indirect hearing-physiology consequence
rather than a direct CDH23 function.
action: MARK_AS_OVER_ANNOTATED
reason: The direct molecular role of CDH23 is cadherin-mediated stereocilium adhesion; PMCA2
is the calcium pump in the cited work.
supported_by:
- reference_id: PMID:17234811
supporting_text: stereociliary Ca2+ transients induced by Ca2+ uncaging was compromised
- term:
id: GO:0045494
label: photoreceptor cell maintenance
evidence_type: IMP
original_reference_id: PMID:16679490
qualifier: involved_in
review:
summary: This phenotype-level sensory annotation is supported but should be kept as non-core
relative to the molecular cadherin/stereocilium function.
action: KEEP_AS_NON_CORE
reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product
role is stereocilium adhesion and hair-bundle organization.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0050953
label: sensory perception of light stimulus
evidence_type: IMP
original_reference_id: PMID:16679490
qualifier: involved_in
review:
summary: This phenotype-level sensory annotation is supported but should be kept as non-core
relative to the molecular cadherin/stereocilium function.
action: KEEP_AS_NON_CORE
reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product
role is stereocilium adhesion and hair-bundle organization.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12485990
qualifier: enables
review:
summary: The cited interaction evidence is meaningful but generic protein binding is too vague
for CDH23 curation.
action: MARK_AS_OVER_ANNOTATED
reason: The interaction should be interpreted as harmonin/USH protein binding and stereocilium
tip-link anchoring rather than generic protein binding.
supported_by:
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia and that they bind
to each other
- term:
id: GO:0007605
label: sensory perception of sound
evidence_type: IMP
original_reference_id: PMID:16679490
qualifier: involved_in
review:
summary: Sensory perception of sound is a core physiological process supported by CDH23 stereocilium/hair-bundle
function and hearing-loss genetics.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0032420
label: stereocilium
evidence_type: ISS
original_reference_id: PMID:12485990
qualifier: located_in
review:
summary: Stereocilium localization is directly supported and central to CDH23 function in
hair cells.
action: ACCEPT
reason: CDH23 is present in developing stereocilia and participates in tip-link/hair-bundle
architecture.
supported_by:
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia
- term:
id: GO:0050957
label: equilibrioception
evidence_type: IMP
original_reference_id: PMID:16679490
qualifier: involved_in
review:
summary: This phenotype-level sensory annotation is supported but should be kept as non-core
relative to the molecular cadherin/stereocilium function.
action: KEEP_AS_NON_CORE
reason: CDH23 mutations cause hearing/vestibular/retinal phenotypes, but the core gene product
role is stereocilium adhesion and hair-bundle organization.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0007605
label: sensory perception of sound
evidence_type: IMP
original_reference_id: PMID:15537665
qualifier: acts_upstream_of_or_within
review:
summary: Sensory perception of sound is a core physiological process supported by CDH23 stereocilium/hair-bundle
function and hearing-loss genetics.
action: ACCEPT
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.
supported_by:
- reference_id: PMID:15537665
supporting_text: CDH23 and PCDH15 play an essential long-term role in maintaining the normal
organization of the stereocilia bundle
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Required for normal hearing.
- term:
id: GO:0016020
label: membrane
evidence_type: NAS
original_reference_id: PMID:11138009
qualifier: located_in
review:
summary: CDH23 is a single-pass type I membrane protein, so membrane/plasma membrane localization
is appropriate.
action: ACCEPT
reason: The broad membrane annotation is true, with stereocilium/hair-bundle membrane localization
being more informative.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Cell membrane'
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Single-pass type I membrane protein
- term:
id: GO:0016339
label: calcium-dependent cell-cell adhesion
evidence_type: NAS
original_reference_id: PMID:11138009
qualifier: involved_in
review:
summary: Cell-cell adhesion is a core cadherin-23 function, with calcium-dependent cadherin
interactions supporting stereocilia cohesion and tip-link anchoring.
action: ACCEPT
reason: CDH23 is a cadherin family adhesion protein required for stereocilia bundle organization;
the broad adhesion terms are appropriate, though stereocilium/tip-link context is the most
informative framing.
supported_by:
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: Cadherins are calcium-dependent cell adhesion proteins.
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia and that they bind
to each other
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:11138009
title: "Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D."
findings: []
- id: PMID:12485990
title: "Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle."
findings: []
- id: PMID:15537665
title: Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and
protocadherin 15 in mice and humans.
findings: []
- id: PMID:16679490
title: Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the
importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above
90%.
findings: []
- id: PMID:17234811
title: A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic
deafness.
findings: []
- id: PMID:22879593
title: "Large protein assemblies formed by multivalent interactions between cadherin23 and harmonin suggest a stable anchorage structure at the tip link of stereocilia."
findings: []
- id: file:human/CDH23/CDH23-uniprot.txt
title: UniProt record for CDH23
findings: []
core_functions:
- molecular_function:
id: GO:0045296
label: cadherin binding
description: CDH23 mediates calcium-dependent cadherin interactions in the stereocilium tip-link/hair-bundle
apparatus, anchoring CDH23-harmonin and related Usher protein assemblies needed for stereocilia
cohesion and mechanotransduction.
directly_involved_in:
- id: GO:0007605
label: sensory perception of sound
locations:
- id: GO:0032420
label: stereocilium
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: PMID:12485990
supporting_text: cadherin 23 are both present in the growing stereocilia and that they bind
to each other
- reference_id: PMID:22879593
supporting_text: cadherin23/harmonin complexes
- reference_id: file:human/CDH23/CDH23-uniprot.txt
supporting_text: CDH23 is required for establishing and/or maintaining the proper organization
of the stereocilia bundle
proposed_new_terms: []
suggested_questions:
- question: Which CDH23 domains or isoforms, if any, are mechanistically relevant to pituitary
adenoma predisposition rather than hearing/retinal biology?
- question: Can PITA5-associated CDH23 variants be shown to perturb cadherin adhesion, mechanotransduction-related
assemblies, or a pituitary-specific interaction network?
suggested_experiments:
- description: 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.
- description: 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.