CDHR1 (photoreceptor cadherin, formerly PCDH21) is an atypical cadherin with six extracellular cadherin repeats and a single transmembrane segment in its canonical 859-amino-acid product. It is concentrated near the base of photoreceptor outer segments and contributes to outer-segment membrane organization and photoreceptor survival. Human biallelic variants cause retinal dystrophy. Mouse ultrastructure places its ortholog at contacts between nascent outer-segment membranes and the inner segment of the same photoreceptor. Zebrafish Cdhr1a associates with Pcdh15b and supports heterotypic adhesion in cell assays, suggesting a conserved cadherin-based connection between outer segments and calyceal processes; the precise human molecular complex remains unresolved. Ectodomain shedding and association with prominin-1 have been demonstrated in mammalian ortholog systems.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Conserved cadherin repeats support calcium binding as a structural property. Reason: The InterPro inference is compatible with the extracellular cadherin-repeat architecture of Q96JP9. Retain this supportive biochemical property without treating the 2026 aggregation assay as a calcium-binding or calcium-dependence measurement: that study did not titrate calcium or measure affinity. The cadherin interaction and outer-segment role define the functional synthesis. Supporting Evidence: GO_REF:0000002 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The plasma membrane is a site of the conserved cadherin activity. Reason: The PAINT activity-location inference is consistent with transmembrane CDHR1 topology and the ortholog surface-interaction assays, not merely intracellular staining. Mouse ultrastructure places PCDH21 at outer-segment/inner-segment membrane contacts, and human retinal staining corroborates the conserved distribution. The historical PTN001932250 ancestral reconstruction was not independently re-read; no incorrect node placement or evolutionary loss is asserted. Supporting Evidence: GO_REF:0000033 PMID:15284225 prCAD localizes to the site of the future outer segment |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The canonical product localizes to the photoreceptor plasma membrane. Reason: The combined electronic assertion agrees with the source protein topology and experimental mouse membrane localization. Current mouse Q8VHP6 GOA contains plasma-membrane IDA evidence from PMID:11738025. This is a conserved localization inference, not a claim that that mouse experiment used human CDHR1 or that both human splice products have identical membrane behavior. Supporting Evidence: GO_REF:0000120 PMID:11738025 the prCAD protein is localized to the base of the outer segment of both rods and cones |
| GO:0007155 cell adhesion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain a broad inherited adhesion capability outside the principal same-cell retinal role. Reason: The PAINT assertion is biologically compatible with positive heterotypic trans-aggregation by zebrafish Cdhr1a/Pcdh15b in separately transfected K562 populations. That ortholog experiment supports adhesive capability; it does not demonstrate adhesion between neighboring human photoreceptors. The native outer-segment/inner-segment geometry examined in mouse is within one cell. This qualified retention does not reconstruct or challenge the historical PTN001932250 node. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: The broad domain-based adhesion assignment is consistent with ortholog trans-adhesive capability. Reason: The 2026 mixed-cell assay supplies independent functional support beyond the cadherin signature alone. Retain the broad electronic term as a non-core capability, while distinguishing zebrafish constructs in human host cells from native human-protein evidence and from the proposed intraphotoreceptor tether. |
| GO:0007156 homophilic cell-cell adhesion | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: A cadherin domain does not establish homophilic intercellular adhesion for CDHR1. Reason: GO:0007156 requires identical adhesion molecules on adjacent cells. The directly inspected Cdhr1a/Pcdh15b assay supports a heterotypic pair; each singly transfected population showed minimal aggregation compared with the mixed populations. This makes the domain-derived homophilic specificity insufficiently supported. It is not a universal negative claim about human CDHR1, and no negative self-association experiment is attributed to the older ectodomain-shedding paper. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR002126 UNRESOLVED Original cadherin-like-domain mapping retained. A conserved domain alone does not resolve homophilic specificity; the selected ortholog assay instead supports heterotypic association. This is an assessment of term specificity, not a claim that the InterPro entry or domain assignment is wrong. Supporting Evidence: GO_REF:0000002 PMID:41995082 Introduction of either cadherin alone resulted in minimal aggregation |
| GO:0008594 photoreceptor cell morphogenesis | IMP PMID:23044944 Identification of a novel mutation in the CDHR1 gene in a fa... | MODIFY | Summary: Refine the broad morphogenesis assertion to outer-segment organization. Reason: The original human IMP study uses SD-OCT and AOSLO to characterize outer-retinal abnormalities in adults with a segregating truncating allele; the authors interpret the structural lesions as possible disorganized outer segments. It does not directly assay the acquisition of specialized photoreceptor features described by GO:0008594. The replacement GO:0035845 therefore captures the anatomical scope of this human evidence as a lateral semantic refinement, not an ontology-descendant narrowing. Independent fish work supports the outer-segment structural role and shows early changes at 5 and 15 dpf; those findings are a caveat against excluding developmental biology, not the justification for this source-specific replacement. The original source and evidence code remain unchanged. The replacement already has another source row, so no NEW assertion is added. Proposed replacements: photoreceptor cell outer segment organization Supporting Evidence: PMID:23044944 CDHR1 is important for normal photoreceptor structure and survival |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: The canonical CDHR1 product is an integral membrane protein. Reason: The broad membrane term is consistent with the preserved single-pass canonical sequence and the photoreceptor membrane localization. It describes the same core cellular setting as the more specific plasma-membrane and outer-segment-membrane assertions, without adding a distinct compartment or extending the conclusion to the uncharacterized alternative product. |
| GO:0035845 photoreceptor cell outer segment organization | IMP PMID:23044944 Identification of a novel mutation in the CDHR1 gene in a fa... | ACCEPT | Summary: Outer-segment organization is a central CDHR1 function. Reason: The full human study links a segregating CDHR1 truncation to altered outer retinal structure measured by SD-OCT and AOSLO. These observations agree with mouse membrane-contact ultrastructure and fish Cdhr1a-dependent outer-segment architecture. The proposed tether supplies a structural contribution; no phototransduction catalysis or membrane-fusion enzyme activity is inferred. Supporting Evidence: PMID:23044944 thinning and loss of the outer nuclear, IS, and OS layers |
| GO:0042622 photoreceptor outer segment membrane | IEA GO_REF:0000107 | ACCEPT | Summary: CDHR1 acts at the outer-segment membrane, especially near developing discs. Reason: The preserved mouse-donor transfer is supported by current Q8VHP6 GOA IDA from PMID:18654668. Selected full JCI methods identify mouse PCDH21 constructs and mouse retinal assays, with human PROM1 transgenes. Independent mouse immunogold tomography places PCDH21 at the nascent outer-segment membrane contacts. These are ortholog localization data, not human-protein interaction assays. |
| GO:0045494 photoreceptor cell maintenance | IEA GO_REF:0000117 | ACCEPT | Summary: Photoreceptor maintenance is independently supported beyond the ARBA rule. Reason: Human recessive disease with progressive photoreceptor loss and ortholog loss-of-function studies establish the maintenance role. Retain the correct ARBA-derived assertion on that independent grounding; the exact historical rule antecedents were not reconstructed. This does not imply that every retinal-disease protein has the same molecular activity. |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:20805371 Mutations in PCDH21 cause autosomal recessive cone-rod dystr... | ACCEPT | Summary: The human frameshift-associated retinal degeneration supports photoreceptor maintenance. Reason: The full original study reports six affected relatives homozygous for c.524dupA, verifies the frameshift in patient fibroblast cDNA, and documents progressive cone-rod disease. This supports the curated maintenance assertion and is corroborated by ortholog degeneration phenotypes. It does not by itself identify a binding partner or demonstrate a calcium-binding mechanism. Supporting Evidence: PMID:20805371 All patients were homozygous for a 1-bp duplication in PCDH21, c.524dupA |
| GO:0050839 cell adhesion molecule binding | IBA GO_REF:0000033 | MODIFY | Summary: Refine cell adhesion molecule binding to cadherin binding. Reason: The inherited molecular-function assertion is retained and made more informative using the independently inspected Cdhr1a/Pcdh15b association and mixed-cell aggregation assays. Both proteins in those assays are zebrafish constructs; human tissue staining supports conservation but is not a human binary-binding experiment. Unconstrained cadherin binding captures the supported molecular role without requiring the proposed native outer-segment/calyceal-process connection to join different cells. No redundant NEW molecular-function row is needed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN009075544 UNRESOLVED The original ancestral-node identifier is preserved; its historical IBD/tree/MSA was not re-read. The narrower molecular function is justified by independent ortholog experiments, not donor counting or an asserted error in ancestral placement. Proposed replacements: cadherin binding |
| GO:0098609 cell-cell adhesion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retain cell-cell adhesion as an ortholog-supported experimental capability. Reason: Mixed K562 populations bearing zebrafish Cdhr1a or Pcdh15b form aggregates, providing a direct trans-adhesion capability beyond the original general cadherin-domain inference. Native mouse outer-segment/inner-segment contacts and the proposed human retinal mechanism involve parts of one photoreceptor, so intercellular adhesion is not presented as the defining physiological role. The assay does not establish native human neighboring-cell adhesion. |
Loading supporting content…
Download this section (compressed HTML)Q: Does native human CDHR1 directly bind PCDH15, and what stoichiometry and geometry connect the outer-segment membrane to calyceal processes in rods versus cones?
Q: Which calcium sites and affinities govern human CDHR1 ectodomain structure and partner binding? The inspected ortholog aggregation study did not measure calcium dependence.
Q: How does the preserved alternative product Q96JP9-2, whose sequence differs around the canonical transmembrane region and lacks the canonical distal tail, localize and function relative to Q96JP9-1?
Q: Which protease cleaves CDHR1, and how is ectodomain shedding coupled to disc formation and release in rods versus cones? CDHR1 is the cleaved substrate, not an established protease.
Q: Is the CDHR1-PROM1 association a direct molecular interaction, and how does it relate to the PCDH15-associated outer-segment connection? Existing mouse PCDH21 co-immunoprecipitation does not resolve a purified binary interface or the native human complex.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)