ADGRV1 (VLGR1, GPR98 or MASS1) is a large adhesion G protein-coupled receptor whose longest human isoform has approximately 6,300 residues. Its extracellular region contains 35 Calx-beta repeats, EAR/EPTP repeats and a pentraxin-like domain, followed by a GAIN/GPS region and seven transmembrane helices. Isolated Calx-beta repeat fragments bind calcium. The receptor supplies an extracellular structural component of transient ankle links between neighboring stereocilia in developing cochlear hair bundles. Its C-terminal PDZ-binding motif docks onto whirlin and PDZD7 in the USH2 protein network, organizing sensory-cell membrane complexes with usherin. In photoreceptors, ADGRV1 localizes around the connecting cilium and supports photoreceptor maintenance. Reported Gs/Gq/Gi coupling is established mainly for the shorter VLGR1a isoform and C-terminal fragments; coupling of intact VLGR1b in native sensory cells remains unresolved. Intracellular ER-associated pools and roles in calcium homeostasis have also been reported. Biallelic pathogenic variants cause Usher syndrome type 2C, with congenital sensorineural hearing loss and progressive retinal degeneration. Neural expression and reported seizure-associated variants provide additional disease context, with less established human causal mechanisms than for Usher syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007601 visual perception | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically propagated annotation consistent with strong human genetic and animal-model evidence: ADGRV1 is the USH2C gene, and its loss causes progressive retinitis pigmentosa; ADGRV1 is part of the photoreceptor periciliary membrane complex with usherin and whirlin. Reason: The inherited visual-perception annotation is retained as physiological involvement in retinal function. Human USH2C genetics and rod/cone dysfunction support that scope (PMID:14740321; PMID:15671307), while the PDZ-linked periciliary complex supports photoreceptor maintenance (PMID:20440071). The mechanistic core is maintenance of photoreceptor integrity, GO:0045494; these experiments do not resolve an additional ADGRV1-specific step in receiving or converting a light stimulus. Classify the broader perception annotation as non-core without asserting an erroneous PAINT node placement or absence of a signaling role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002928249 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. Supporting Evidence: PMID:15671307 The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. |
| GO:0001965 G-protein alpha-subunit binding | IBA GO_REF:0000033 | ACCEPT | Summary: ADGRV1 associates with G-alpha subunits and supports G protein signaling. Reason: Mouse intracellular-domain pull-downs in PMID:24191038 identify Gs/Gq association, while human VLGR1a/CTF affinity proteomics and signaling assays in PMID:35630584 identify context-dependent G-alpha interactions. Mouse beta-subunit Gi signaling in PMID:24962568 provides complementary functional evidence. These data support the specific binding function without implying that Gs or Gq inhibits adenylate cyclase. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928248 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. Supporting Evidence: PMID:24191038 MASS1 interacts with GΞ±s/GΞ±q and activates PKA and PKC in response to extracellular calcium. PMID:35630584 we found the association of a full-length VLGR1a with GΞ±i and GΞ±s |
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: ADGRV1 has experimentally supported G protein-coupled receptor activity, with construct-dependent coupling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928248 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ADGRV1 has documented intracellular membrane-associated pools within the cytoplasm. Reason: GO:0005737 includes subcellular structures outside the nucleus and plasma membrane; it does not mean soluble cytosol. PMID:36139365 localizes human VLGR1 C-terminal constructs to ER/MAM-enriched fractions in HEK293T cells and ER-associated regions in HeLa cells, with endogenous photoreceptor immunoelectron microscopy in pig and zebrafish. PMID:35630584 also reports perinuclear cytoplasmic staining in mouse astrocytes. Retain this broader contextual localization as non-core; the best-established sensory structural functions occur at specialized cell-surface membranes. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002928248 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. The human target among descendant evidence is legitimate experimental grounding, not circular support. Supporting Evidence: PMID:36139365 VLGR1_CTF was detected together with the MAM core proteins S1R and ACSL4 in crude mitochondria fraction, the ER and more importantly also in the fraction enriched for MAMs. |
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation consistent with human USH2C congenital hearing loss and mouse Vlgr1 mutant hair-bundle defects; ADGRV1 forms the stereociliary ankle links required for normal hair-bundle development and hearing. Reason: Core function. Biallelic ADGRV1 mutations cause the congenital hearing loss of Usher syndrome type 2C [PMID:14740321], and the mouse ortholog is required for ankle-link formation and hair-bundle integrity (basis of the USH2/ankle-link complex literature) [PMID:25406310]. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928249 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. The human target among descendant evidence is legitimate experimental grounding, not circular support. Supporting Evidence: PMID:14740321 is classified phenotypically as congenital hearing loss and progressive retinitis pigmentosa |
| GO:0010855 adenylate cyclase inhibitor activity | IBA GO_REF:0000033 | MODIFY | Summary: Gi-coupled ADGRV1 signaling suppresses cAMP in cell assays; a pathway term captures the demonstrated mechanism. Reason: The live GO:0010855 definition requires binding to and decreasing the activity of adenylate cyclase. PMID:24962568 establishes Gi-dependent signaling using mouse Vgain and beta-subunit constructs, PTX sensitivity and G protein chimeras, rather than a direct receptor-cyclase inhibitory interaction. Replace with GO:0007193 while retaining the separate GPCR molecular-function annotations. This is a mechanistic scope correction, not a claim that every possible physical contact with cyclase has been excluded. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002928248 UNRESOLVED PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. The specific inhibitor MF needs a mechanistic scope correction despite conserved receptor signaling. Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0032420 stereocilium | IBA GO_REF:0000033 | ACCEPT | Summary: ADGRV1 localizes to the base (ankle region) of stereocilia in developing hair bundles, where its ectodomain forms the ankle links. Core cellular component. Reason: Well supported: ADGRV1/GPR98 colocalizes with usherin, whirlin and PDZD7 at the ankle-link region of the developing hair bundle [PMID:25406310]; UniProt notes localization at the ankle region of stereocilia (stereocilium membrane). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002928249 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. Supporting Evidence: PMID:25406310 In hair cells, proteins encoded by the four genes are colocalized at the ankle link region of the mechanosensitive structure, the hair bundle, during development |
| GO:0071277 cellular response to calcium ion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Extracellular calcium-dependent ADGRV1 signaling regulates MAG abundance in the studied myelin-forming-cell context. Reason: PMID:24191038 combines Frings mouse oligodendrocyte findings with mini-MASS1 constructs, calcium manipulation and signaling perturbations. The shortened construct requires its Calx-beta domains to enhance MAG abundance through Gs/Gq-associated PKA/PKC signaling. This supports the mouse-derived calcium-response annotation as a context-specific role. The separate ER-to-mitochondria calcium-homeostasis experiments do not substitute for this extracellular-calcium response. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002928248 SUPPORTS TRANSFER PAINT ancestral assertion assessed against the primary evidence described above. The tree/alignment was not reconstructed; no target-specific loss is inferred from donor count. Supporting Evidence: PMID:24191038 MASS1 interacts with GΞ±s/GΞ±q and activates PKA and PKC in response to extracellular calcium. |
| GO:0001917 photoreceptor inner segment | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping. ADGRV1 localizes to the apical inner segment/periciliary membrane surrounding the photoreceptor connecting cilium, together with usherin and whirlin. Reason: Consistent with immunolocalization of GPR98/Vlgr1 at the photoreceptor connecting cilium region in zebrafish and mammals [PMID:20440071, PMID:16434480] and with the periciliary membrane complex literature. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0457 SUPPORTS TRANSFER Seeded UniProt subcellular-location mapping assessed against the relevant primary localization evidence and intact membrane architecture. Supporting Evidence: PMID:20440071 Both proteins were found at the connecting cilium and at the photoreceptor synapse, consistent with reports in mammals |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-derived parent-level receptor activity annotation; correct, though the more specific GPCR activity term (also annotated) is preferable. Reason: True and consistent with the 7TM receptor architecture; acceptable as a broader IEA alongside the more specific GO:0004930 annotations. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR017981 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: ADGRV1 has experimentally supported G protein-coupled receptor activity, with construct-dependent coupling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000832 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. InterPro:IPR026919 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ADGRV1 has documented intracellular membrane-associated pools within the cytoplasm. Reason: GO:0005737 includes subcellular structures outside the nucleus and plasma membrane; it does not mean soluble cytosol. PMID:36139365 localizes human VLGR1 C-terminal constructs to ER/MAM-enriched fractions in HEK293T cells and ER-associated regions in HeLa cells, with endogenous photoreceptor immunoelectron microscopy in pig and zebrafish. PMID:35630584 also reports perinuclear cytoplasmic staining in mouse astrocytes. Retain this broader contextual localization as non-core; the best-established sensory structural functions occur at specialized cell-surface membranes. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00026971 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The cytoplasm judgment rests on the separately cited primary evidence, not an invented rule explanation. Supporting Evidence: PMID:36139365 VLGR1_CTF was detected together with the MAM core proteins S1R and ACSL4 in crude mitochondria fraction, the ER and more importantly also in the fraction enriched for MAMs. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping; ADGRV1 is an integral plasma-membrane receptor demonstrated at the cell surface of transfected cells and at specialized plasma-membrane domains in sensory cells. Reason: Directly supported by surface biotinylation of recombinant VLGR1 [PMID:10976914] and by localization to stereociliary/periciliary membrane domains in vivo. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Seeded UniProt subcellular-location mapping assessed against the relevant primary localization evidence and intact membrane architecture. Supporting Evidence: PMID:10976914 As demonstrated by cell surface labeling with a biotin derivative, the recombinant protein is expressed on the surface of transfected mammalian cells. |
| GO:0007154 cell communication | IEA GO_REF:0000002 | MODIFY | Summary: Extremely general InterPro mapping. Not wrong, but adds no information beyond the more specific GPCR signaling pathway annotations already present. Reason: GO:0007154 is close to the root and uninformative for a receptor with well-supported specific pathway annotations. The specific descendant GO:0007186 (already annotated by IEA/ISS/TAS) captures the intended biology. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR003644 UNRESOLVED The Calx-beta domain mapping is broad. Independent receptor signaling supports the more informative pathway replacement, without treating this repeat as sufficient evidence of a specific communication mechanism. Proposed replacements: G protein-coupled receptor signaling pathway |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-derived pathway annotation; correct at a general level for a cell-surface adhesion GPCR. Reason: True and compatible with the more specific GPCR signaling pathway annotations; acceptable breadth for an IEA. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR017981 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: ADGRV1 participates in G protein-coupled receptor signaling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000832 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0007605 sensory perception of sound | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction concordant with the human IMP and IBA annotations; ADGRV1 loss causes congenital hearing loss (USH2C). Reason: Core function; see review of the IMP annotation from PMID:14740321. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00033578 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The sensory perception of sound judgment rests on the separately cited primary evidence, not an invented rule explanation. |
| GO:0016020 membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Broad but correct membrane localization for a multi-pass transmembrane receptor. Reason: True; broader than the plasma membrane/stereocilium membrane annotations but acceptable for an automated method. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028763 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The membrane judgment rests on the separately cited primary evidence, not an invented rule explanation. InterPro:IPR000832 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. InterPro:IPR003644 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. InterPro:IPR017981 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. InterPro:IPR026919 SUPPORTS TRANSFER Seeded InterPro mapping retained and assessed against receptor architecture and primary signaling evidence. Domain classification supports the family-level assertion; it does not establish a native-cell G protein or ligand. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | MODIFY | Summary: Root-level complex term from ARBA. ADGRV1 is indeed part of well-defined complexes; the specific terms (USH2 complex, stereocilia ankle link complex) are far more informative and already annotated. Reason: GO:0032991 is the root of the complex branch and conveys no specific information. The USH2 quaternary complex (ADGRV1-USH2A-WHRN-PDZD7) is experimentally established [PMID:25406310]; replace with the specific term. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00028902 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The protein-containing complex judgment rests on the separately cited primary evidence, not an invented rule explanation. Proposed replacements: USH2 complex Supporting Evidence: PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. In this USH2 quaternary complex, WHRN prefers to bind to USH2A, whereas PDZD7 prefers to bind to GPR98. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MODIFY | Summary: The developmental contribution of ADGRV1 is resolved to the organization of sensory hair-cell stereocilia. Reason: ADGRV1 supplies the ankle-link structure in developing cochlear hair bundles. Full PMID:17567809 localizes the receptor to these links and documents disorganized bundles after its loss. GO:0060122 inner ear receptor cell stereocilium organization captures this specific structural contribution more precisely than animal organ development. The broader inner ear development assertion is independently retained as non-core context; the ARBA rule internals remain unresolved. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00029247 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The animal organ development judgment rests on the separately cited primary evidence, not an invented rule explanation. Proposed replacements: inner ear receptor cell stereocilium organization Supporting Evidence: PMID:17567809 Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. |
| GO:0050793 regulation of developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ADGRV1 contributes to regulation of developing hair-bundle morphology. Reason: In the full mouse study PMID:17567809, peripheral microvilli normally regress but persist and acquire stereocilia-like features in Vlgr1 mutants; the authors infer that Vlgr1 restrains their differentiation. This provides a concrete regulatory developmental context in addition to the receptor's structural ankle-link role. Retain the broad process as non-core. The ARBA rule conditions themselves were not recovered, so the annotation judgment rests on independent primary biology rather than an assumed rule mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00028689 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The regulation of developmental process judgment rests on the separately cited primary evidence, not an invented rule explanation. Supporting Evidence: PMID:17567809 This indicates that Vlgr1, which is present in these peripheral microvilli, prevents their differentiation and is required for their regression. |
| GO:0050953 sensory perception of light stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction concordant with human IMP annotations; ADGRV1 mutations cause retinitis pigmentosa in USH2C. Reason: The human USH2C genetic study (PMID:14740321) and clinical rod/cone-function measurements (PMID:15671307) support the broad light-perception association. Retain this as non-core physiological involvement, with the periciliary maintenance mechanism represented by GO:0045494. The ARBA condition set remains unrecovered; independent human evidence supports the target judgment without validating the internal rule or assigning a directly measured light-evoked signaling step to ADGRV1. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00091469 UNRESOLVED The seeded ARBA identifier is preserved, but its condition set was not independently recovered. The sensory perception of light stimulus judgment rests on the separately cited primary evidence, not an invented rule explanation. |
| GO:0060171 stereocilium membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping; ADGRV1 is an integral membrane protein of the stereociliary base (ankle-link region) in developing hair bundles. Reason: Well supported by the ankle-link literature [PMID:25406310] and UniProt localization (stereocilium membrane; localizes at the ankle region of the stereocilia). Most precise CC for the hair-cell pool of ADGRV1. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0303 SUPPORTS TRANSFER Seeded UniProt subcellular-location mapping assessed against the relevant primary localization evidence and intact membrane architecture. Supporting Evidence: PMID:25406310 In hair cells, proteins encoded by the four genes are colocalized at the ankle link region of the mechanosensitive structure, the hair bundle, during development |
| GO:0005515 protein binding | IPI PMID:20440071 PDZD7 is a modifier of retinal disease and a contributor to ... | MODIFY | Summary: IPI for the direct interaction of the ADGRV1/GPR98 cytoplasmic PDZ-binding motif with the PDZ2 domain of PDZD7 (Y2H and co-IP). The interaction is real and important, but bare protein binding is uninformative; the ADGRV1-side molecular function is PDZ domain binding. Reason: The paper demonstrates by yeast two-hybrid and coimmunoprecipitation that the GPR98 C-terminal PDZ-binding motif binds the PDZD7 PDZ2 domain. GO:0030165 PDZ domain binding captures this specifically; generic GO:0005515 should be avoided per curation best practice. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:20440071 We confirmed this interaction by coimmunoprecipitation studies and showed that it is mediated by the PDZ2 domain of PDZD7 and the PDZ-binding motif of GPR98. |
| GO:0032420 stereocilium | IEA GO_REF:0000107 | ACCEPT | Summary: Rat-to-human Ensembl Compara transfer of stereocilium localization is consistent with conserved sensory-cell organization. Reason: The seeded donor pair is UniProtKB:A0A096MK89 and Ensembl:ENSRNOP00000068422. The exact rat donor experiment was not recovered. Independent mouse Vlgr1 immunolocalization and ankle-link experiments in PMID:17567809, together with human Usher syndrome genetics, support conservation of this specialized receptor location. Retain the annotation without presenting the unexamined rat evidence as a newly verified assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:A0A096MK89 UNRESOLVED Seeded rat Compara donor identifier retained; its exact experimental source was not recovered. Independent mouse sensory localization supports the human annotation. ensembl:ENSRNOP00000068422 UNRESOLVED Seeded rat Compara donor identifier retained; its exact experimental source was not recovered. Independent mouse sensory localization supports the human annotation. Supporting Evidence: PMID:17567809 Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. |
| GO:0060113 inner ear receptor cell differentiation | NAS PMID:25406310 Whirlin and PDZ domain-containing 7 (PDZD7) proteins are bot... | KEEP AS NON CORE | Summary: Author-statement annotation reflecting the accepted view that the USH2 ankle-link complex genes are required for hair cell development. The role is real but developmental and is more precisely captured by the stereocilium organization annotation. Reason: The cited paper states the four USH2 genes are important for hair cell development (based on mouse knockout hair-bundle phenotypes). ADGRV1's contribution is to hair-bundle (stereocilium) organization during a transient developmental window; keep as a non-core developmental process annotation alongside the more specific GO:0060122 ISS annotation. Supporting Evidence: PMID:25406310 Consequently, the four USH genes, USH2A , GPR98 , WHRN , and PDZD7 , are believed to be important for hair cell development and photoreceptor survival, although each may have relatively different roles in these cellular processes. |
| GO:0007186 G protein-coupled receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 participates in G protein-coupled receptor signaling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Receptor-fragment coupling in PMID:24962568 is independently complemented by human constructs in PMID:35630584. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0001917 photoreceptor inner segment | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-based transfer of the periciliary/apical inner segment localization of ADGRV1 in photoreceptors. Reason: Core cellular component; concordant with the IEA annotation and the periciliary membrane complex literature [PMID:20440071]. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Conserved sensory-cell membrane architecture and the primary periciliary localization evidence support this transfer. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-based transfer of the plasma-membrane localization. Reason: Core cellular component; supported experimentally by cell-surface biotinylation [PMID:10976914] and in vivo membrane localization at stereocilia and the periciliary region. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Cell-surface receptor localization is independently demonstrated for human VLGR1a. |
| GO:0002141 stereocilia ankle link | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse Adgrv1 ortholog is an extracellular structural constituent of stereocilia ankle links. Reason: PMID:17567809 shows matching spatiotemporal localization of the Vlgr1 ectodomain and ankle links, their joint loss after BAPTA or subtilisin treatment, and missing links in Vlgr1 mutants. These localization and biochemical-disruption observations support the structural assignment beyond a general necessity phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The full mouse ankle-link study directly supports the donor structure and conserved sensory role. Supporting Evidence: PMID:17567809 Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. |
| GO:0045184 establishment of protein localization | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 helps establish the position of ankle-link complex partners in developing hair bundles. Reason: The full mouse study PMID:17567809 shows loss of usherin, whirlin and vezatin from the stereocilia base in Vlgr1 mutants. Receptor cytoplasmic interactions and its extracellular link-forming role provide a physical basis for retaining this localization process as part of the core sensory-complex architecture. This does not assign ADGRV1 the myosin VIIa motor activity or demonstrate direct recognition of vesicle cargo. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse partner mislocalization is paired with physical tail interactions and receptor structural anchoring; no transport-motor activity is transferred. Supporting Evidence: PMID:17567809 We conclude that Vlgr1 is required to maintain usherin at the stereocilia base |
| GO:1990075 periciliary membrane compartment | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-based transfer: ADGRV1, usherin and whirlin form the periciliary membrane complex, a plasma-membrane microdomain of the photoreceptor apical inner segment surrounding the connecting cilium. Reason: Core cellular component for the photoreceptor pool of ADGRV1; supported by localization of GPR98 at the connecting cilium region and its dependence on PDZD7 [PMID:20440071] and by the mouse periciliary membrane complex literature. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Periciliary sensory-complex localization is conserved and consistent with human retinal disease. Supporting Evidence: PMID:20440071 reduced Gpr98 localization in the region of the photoreceptor connecting cilium |
| GO:0002142 stereocilia ankle link complex | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-based transfer: ADGRV1 is the transmembrane core of the ankle-link complex (ADGRV1, USH2A, WHRN, PDZD7) at the base of developing stereocilia. Reason: Core cellular component; the quaternary USH2/ankle-link complex and ADGRV1's membership are experimentally established [PMID:25406310]. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse ankle-link membership is supported by localization and biochemical interaction studies. Supporting Evidence: PMID:25406310 In hair cells, proteins encoded by the four genes are colocalized at the ankle link region of the mechanosensitive structure, the hair bundle, during development |
| GO:0005515 protein binding | IPI PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei... | MODIFY | Summary: Whirlin binding can be represented as PDZ domain binding by the ADGRV1 cytoplasmic tail. Reason: The full original PMID:16434480 tests human VLGR1b cytoplasmic-tail fragments. Its Figure 4 combines GST pull-down, yeast two-hybrid domain mapping and co-immunoprecipitation; WHRN PDZ1 binds the tail and deleting its terminal PDZ-binding motif disrupts the interaction. Independent mouse-fragment experiments in PMID:25406310 corroborate the domain specificity. Replace generic protein binding with GO:0030165, without describing the fragment studies as assays of intact human VLGR1b. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:16434480 we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b, two proteins that we previously reported to be part of the Usher protein interactome PMID:25406310 the GPR98 cytoplasmic fragment interacts only with WHRN PDZ1 domain. |
| GO:0060122 inner ear receptor cell stereocilium organization | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse Adgrv1 ortholog organizes developing inner-ear stereocilia through ankle-link architecture. Reason: PMID:17567809 documents progressive hair-bundle disorganization, abnormal bundle polarity and persistent peripheral microvilli in Vlgr1 mutants, together with structural localization of the receptor ectodomain at ankle links. This is a conserved core organizing contribution, not an assignment of channel pore activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse structural and developmental hair-bundle evidence supports conserved participation. Supporting Evidence: PMID:17567809 Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. PMID:17567809 This indicates that Vlgr1, which is present in these peripheral microvilli, prevents their differentiation and is required for their regression. |
| GO:1990696 USH2 complex | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 belongs to the USH2 receptor-scaffold complex. Reason: The mouse-derived constructs in PMID:25406310 establish a quaternary complex containing GPR98 and USH2A cytoplasmic regions bridged by WHRN and PDZD7. Human interaction and disease evidence is concordant. The biochemical reconstruction uses fragments and supports complex membership and PDZ docking; it is not a stoichiometric measurement of intact endogenous human receptors. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse-fragment reconstruction supports USH2 membership, without extrapolating intact-human stoichiometry. Supporting Evidence: PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. |
| GO:0001965 G-protein alpha-subunit binding | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 associates with G-alpha subunits and supports G protein signaling. Reason: Mouse intracellular-domain pull-downs in PMID:24191038 identify Gs/Gq association, while human VLGR1a/CTF affinity proteomics and signaling assays in PMID:35630584 identify context-dependent G-alpha interactions. Mouse beta-subunit Gi signaling in PMID:24962568 provides complementary functional evidence. These data support the specific binding function without implying that Gs or Gq inhibits adenylate cyclase. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse intracellular-domain Gs/Gq association and beta-subunit Gi signaling support specific G-alpha coupling; human constructs provide complementary evidence. Supporting Evidence: PMID:24191038 MASS1 interacts with GΞ±s/GΞ±q and activates PKA and PKC in response to extracellular calcium. PMID:35630584 we found the association of a full-length VLGR1a with GΞ±i and GΞ±s |
| GO:0004930 G protein-coupled receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 has experimentally supported G protein-coupled receptor activity, with construct-dependent coupling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse signaling and independent human VLGR1a/CTF assays support receptor function. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Ortholog-based transfer of plasma-membrane localization. Reason: Correct localization for this multi-pass receptor; duplicates of the same GO id with different evidence are acceptable. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The transferred cell-surface compartment agrees with human recombinant surface labeling. |
| GO:0007601 visual perception | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-based transfer consistent with the human USH2C retinitis pigmentosa phenotype and the periciliary role of ADGRV1 in photoreceptors. Reason: Mouse Adgrv1 is the curated ortholog donor, and independent human USH2C genetics and retinal-function measurements support involvement in visual physiology (PMID:14740321; PMID:15671307). The conserved sensory-complex architecture and PDZ interactions support maintenance of photoreceptor integrity. Retain the original acts_upstream_of_or_within assertion as non-core; GO:0045494 represents the mechanistic maintenance role. This does not claim a lineage-specific loss or infer a direct phototransduction reaction from degeneration. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Mouse sensory architecture is concordant with directly observed human USH2C retinal disease. |
| GO:0010855 adenylate cyclase inhibitor activity | ISS GO_REF:0000024 | MODIFY | Summary: Gi-coupled ADGRV1 signaling suppresses cAMP in cell assays; a pathway term captures the demonstrated mechanism. Reason: The live GO:0010855 definition requires binding to and decreasing the activity of adenylate cyclase. PMID:24962568 establishes Gi-dependent signaling using mouse Vgain and beta-subunit constructs, PTX sensitivity and G protein chimeras, rather than a direct receptor-cyclase inhibitory interaction. Replace with GO:0007193 while retaining the separate GPCR molecular-function annotations. This is a mechanistic scope correction, not a claim that every possible physical contact with cyclase has been excluded. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q8VHN7 UNRESOLVED Mouse Adgrv1 is the curated donor. The source demonstrates Gi-dependent pathway inhibition, not direct adenylate cyclase inhibitor binding. Proposed replacements: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway Supporting Evidence: PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0048839 inner ear development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-based transfer: Adgrv1 mouse mutants show defective hair-bundle development. Real developmental role, but the gene's core contribution is the specific ankle-link/stereocilium organization function. Reason: Correct but broad developmental process annotation; kept as non-core in favor of the more precise GO:0060122 inner ear receptor cell stereocilium organization. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The donor has abnormal developing hair bundles; the broad developmental context is retained as non-core. |
| GO:0050910 detection of mechanical stimulus involved in sensory perception of sound | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 ankle links contribute to normal hair-bundle mechanical responsiveness. Reason: The full mouse study PMID:17567809 reports reduced excitatory transduction currents in outer, but not inner, hair cells at postnatal day 7; both types show abnormal responses to reverse deflection. The receptor contributes the cohesive bundle architecture on which directional mechanotransduction depends. This supports participation without assigning ADGRV1 the ion-conducting pore. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The full mouse study distinguishes outer and inner hair-cell current phenotypes; conserved structural support is transferred without channel-pore activity. Supporting Evidence: PMID:17567809 the MET currents elicited by mechanical stimulations of the hair bundle in the stimulatory direction were impaired in P7 Vlgr1 β/β OHCs compared with wild-type, whereas these currents were not affected in Vlgr1 β/β IHCs at the same stage. |
| GO:0097264 self proteolysis | ISS GO_REF:0000024 | ACCEPT | Summary: ADGRV1 undergoes GPS-site self-cleavage, supported directly by mouse receptor constructs. Reason: PMID:24962568 tests cleavage of a mouse Vgain construct containing the GAIN domain and seven-transmembrane region, cleavage-site mutants and hydroxylamine-assisted processing; retinal transfection and endogenous cochlear fragment detection provide further context. This supports transfer of self-proteolysis to the conserved human receptor. It does not establish protease activity toward unrelated substrates or mean that all signaling experiments used intact VLGR1b. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. Direct mouse GAIN/GPS cleavage experiments support the self-processing function; receptor-fragment scope is explicit. Supporting Evidence: PMID:24962568 VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. |
| GO:0030501 positive regulation of bone mineralization | ISS GO_REF:0000024 | UNDECIDED | Summary: The mouse donor supports a role in bone metabolism, but the specific positive-mineralization process remains unresolved. Reason: PMID:22419726 links human variants with bone mineral density and reports lower density and greater fragility in Gpr98-deficient mice. Its accessible primary abstract also describes increased osteoblast Rankl and osteoclastogenic activity. Net bone density reflects formation and resorption; those observations alone do not establish positive regulation of mineral deposition. The full experimental paper was not recovered, so retain UNDECIDED for this specific ISS term without rejecting the donor's broader bone biology. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q8VHN7 UNRESOLVED Mouse Adgrv1 is the curated donor. The donor bone-density and osteoclastogenesis abstract is recovered, but full mineral-deposition evidence is inaccessible. Supporting Evidence: |
| GO:0031647 regulation of protein stability | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Adgrv1 signaling promotes MAG stability in a calcium-dependent cellular context. Reason: The full primary study PMID:24191038 measures slower MAG degradation during cycloheximide chase with mini-MASS1, reduced MAG ubiquitylation, effects of Calx-beta deletion, and reduced MAG in Frings oligodendrocytes. This supports regulation of protein stability, transferred from mouse as a non-core function. ADGRV1 is the upstream receptor, not the ubiquitin-conjugating or deubiquitylating enzyme. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The full mouse/mini-MASS1 study tests MAG turnover and ubiquitylation; no target-specific loss is evident, but the human physiological setting remains contextual. Supporting Evidence: PMID:24191038 MASS1 inhibits the ubiquitylation of MAG, thus enhancing the stability of this protein |
| GO:0071277 cellular response to calcium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Extracellular calcium-dependent ADGRV1 signaling regulates MAG abundance in the studied myelin-forming-cell context. Reason: PMID:24191038 combines Frings mouse oligodendrocyte findings with mini-MASS1 constructs, calcium manipulation and signaling perturbations. The shortened construct requires its Calx-beta domains to enhance MAG abundance through Gs/Gq-associated PKA/PKC signaling. This supports the mouse-derived calcium-response annotation as a context-specific role. The separate ER-to-mitochondria calcium-homeostasis experiments do not substitute for this extracellular-calcium response. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8VHN7 SUPPORTS TRANSFER Mouse Adgrv1 is the curated donor. The source directly perturbs extracellular calcium and Calx-beta domains; human transfer is plausible for the conserved receptor with contextual physiological limits. Supporting Evidence: PMID:24191038 MASS1 interacts with GΞ±s/GΞ±q and activates PKA and PKC in response to extracellular calcium. |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | UNDECIDED | Summary: The ADGRV1-specific signaling-receptor-complex evidence from the sorting-neixin screen remains unverified. Reason: PMID:23382219 studies PX-FERM cargo recognition by SNX17, SNX27 and SNX31. The cached extraction includes abstract, discussion and a methods pointer but not the target-specific screen/results or supporting data. Full-text/SI retrieval did not recover the ADGRV1 observation. Known USH2 membership does not by itself establish the specific signaling-complex claim made by this source. Preserve the IDA assertion and use UNDECIDED without alleging an erroneous curator assignment. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | UNDECIDED | Summary: The urinary-exosome proteomic study is relevant, but the ADGRV1 identification cannot be individually assessed. Reason: The cached PMID:19056867 abstract describes the human urinary-exosome LC-MS/MS survey; it does not list the ADGRV1 accession or peptides. The target-specific supplementary identification was not recovered. Keep UNDECIDED pending that evidence, with no inference of contamination, shedding or absence from vesicles. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0045494 photoreceptor cell maintenance | IMP PMID:14740321 Mutations in the VLGR1 gene implicate G-protein signaling in... | ACCEPT | Summary: Human IMP: biallelic VLGR1/ADGRV1 truncating mutations cause USH2C with progressive retinitis pigmentosa, i.e. failure of long-term photoreceptor survival/maintenance. Reason: Core function. The progressive (rather than congenital) nature of the retinal degeneration in USH2C indicates a maintenance role for the periciliary USH2 complex; human patient genetics is acceptable IMP evidence. Supporting Evidence: PMID:14740321 These results establish VLGR1 as the USH2C gene and implicate the protein, which is the largest cell surface receptor known (McMillan et al. 2002 ), in the pathogenesis of USH2. |
| GO:0048496 maintenance of animal organ identity | IMP PMID:15671307 Disease expression in Usher syndrome caused by VLGR1 gene mu... | MODIFY | Summary: Photoreceptor cell maintenance is the specific process supported by the clinical phenotype. Reason: The live GO:0048496 definition concerns preservation of organ identity and is_a negative regulation of cell differentiation. PMID:15671307 reports rod/cone dysfunction and outer nuclear layer thinning in USH2C, directly supporting degeneration of photoreceptors. GO:0045494 captures that maintenance phenotype more precisely, without asserting a cell-fate mechanism from the clinical observations. Proposed replacements: photoreceptor cell maintenance Supporting Evidence: PMID:15671307 USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. |
| GO:0005509 calcium ion binding | IDA PMID:10976914 Sequence similarities between a novel putative G protein-cou... | ACCEPT | Summary: Isolated human VLGR1 Calx-beta repeat fragments bind calcium in vitro. Reason: PMID:10976914 tests bacterial fusion proteins containing two or four repeats by calcium overlay and competition. This directly supports calcium binding. It does not measure every one of the 35 repeats in VLGR1b or establish that calcium occupancy itself supplies the structural ankle-link function. Supporting Evidence: PMID:10976914 Bacterial fusion proteins containing two or four repeats specifically bind 45Ca in overlay experiments; binding is competed poorly by Mg2+ but competed well by neomycin, Al3+, and Gd3+. |
| GO:0007605 sensory perception of sound | IMP PMID:14740321 Mutations in the VLGR1 gene implicate G-protein signaling in... | ACCEPT | Summary: Human IMP: VLGR1/ADGRV1 mutations cause the congenital hearing loss of Usher syndrome type 2C. Reason: Core function, established by human genetics (four isoform-specific truncating mutations segregating with USH2C) and mechanistically explained by the ankle-link role in cochlear hair bundles. Supporting Evidence: PMID:14740321 These results establish VLGR1 as the USH2C gene and implicate the protein, which is the largest cell surface receptor known (McMillan et al. 2002 ), in the pathogenesis of USH2. |
| GO:0009986 cell surface | IDA PMID:10976914 Sequence similarities between a novel putative G protein-cou... | ACCEPT | Summary: Recombinant human VLGR1 reaches the cell surface. Reason: PMID:10976914 directly demonstrates surface biotinylation of the then-characterized 1,967-residue receptor, subsequently named VLGR1a. Retain cell-surface localization, while distinguishing that tested isoform from the much longer VLGR1b and retaining the source isoform metadata exactly as seeded. Supporting Evidence: PMID:10976914 As demonstrated by cell surface labeling with a biotin derivative, the recombinant protein is expressed on the surface of transfected mammalian cells. |
| GO:0050877 nervous system process | IMP PMID:12402266 A nonsense mutation of the MASS1 gene in a family with febri... | KEEP AS NON CORE | Summary: A human MASS1 variant reported in a seizure family provides non-core nervous-system phenotype evidence. Reason: The accessible PMID:12402266 abstract reports S2652X in one family with febrile and afebrile seizures after screening 48 families. The authors do not consider MASS1 a major explanation for their cohort. Retain the broad curated IMP as non-core, with no assertion of a quantified penetrance or a proven human neuronal signaling mechanism. Supporting Evidence: PMID:12402266 a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures |
| GO:0050953 sensory perception of light stimulus | IMP PMID:14740321 Mutations in the VLGR1 gene implicate G-protein signaling in... | KEEP AS NON CORE | Summary: Human IMP: USH2C patients with ADGRV1 mutations develop progressive retinitis pigmentosa. Reason: The full human genetic study establishes VLGR1/ADGRV1 mutations as a cause of USH2C, with progressive retinal degeneration and impaired vision. Retain the clinical IMP at that physiological scope as non-core. The periciliary complex provides a mechanistic basis for photoreceptor maintenance, GO:0045494, but this source does not resolve a separate receptor-dependent step in light-stimulus reception or signal conversion. No claim that such a signaling role is impossible is made. Supporting Evidence: PMID:14740321 is classified phenotypically as congenital hearing loss and progressive retinitis pigmentosa |
| GO:0050953 sensory perception of light stimulus | IMP PMID:15671307 Disease expression in Usher syndrome caused by VLGR1 gene mu... | KEEP AS NON CORE | Summary: Human IMP: detailed psychophysical and imaging phenotyping of USH2C siblings shows abnormal photoreceptor-mediated function in all retinal regions with greater rod than cone dysfunction. Reason: The cached clinical abstract reports perimetry, electroretinography and OCT in three USH2C siblings, with rod/cone dysfunction and reduced outer nuclear layer thickness. These are positive measurements of impaired visual function, so the IMP is retained as non-core physiological involvement. The same structural degeneration supports photoreceptor maintenance, GO:0045494, as the core interpretation. The abstract does not distinguish a primary ADGRV1 light-signaling defect from loss of photoreceptor integrity; it is not treated as a molecular phototransduction assay. Supporting Evidence: PMID:15671307 The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. |
| GO:0005737 cytoplasm | IDA PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei... | KEEP AS NON CORE | Summary: Human VLGR1b cytoplasmic-tail fragments localize to the cytoplasm of transfected COS-1 cells, with whirlin-dependent retention. Reason: The externally recovered full PMID:16434480 Figure 5 shows a 150-residue human VLGR1b tail in both nucleus and cytoplasm when expressed alone, and confined to cytoplasm when co-expressed with whirlin; removing the PDZ-binding motif prevents that retention. Retain this IDA as non-core with its fragment/overexpression scope. The Figure 5 caption states: "Whirlin co-localized with the cytoplasmic tails of USH2A and VLGR1b" (original author PDF, p. 757, https://www.ag-wolfrum.bio.uni-mainz.de/files/2019/01/VanWijk_et_al_2006_Whirlin_Usher_Network_HumMolGen.pdf). This directly supports the source-specific localization; it does not mean intact ADGRV1 is a soluble cytosolic receptor. The primary PDF was read externally, while the immutable local cache remains abstract-only. Supporting Evidence: |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:15203201 The human and mouse repertoire of the adhesion family of G-p... | ACCEPT | Summary: TAS from the survey defining the human/mouse adhesion GPCR family repertoire, which includes VLGR1/GPR98. Family-level statement consistent with later direct evidence of G-protein coupling. Reason: Appropriate family-level pathway annotation, concordant with the IEA/ISS annotations of the same term. Supporting Evidence: PMID:15203201 The adhesion G-protein-coupled receptors (GPCRs) (also termed LN-7TM or EGF-7TM receptors) are membrane-bound proteins with long N-termini containing multiple domains. |
| GO:0016020 membrane | TAS PMID:15203201 The human and mouse repertoire of the adhesion family of G-p... | ACCEPT | Summary: TAS from the adhesion-GPCR repertoire survey; broad but correct for a membrane-bound receptor family member. Reason: Correct, if general; more specific membrane locations are annotated elsewhere. Supporting Evidence: PMID:15203201 The adhesion G-protein-coupled receptors (GPCRs) (also termed LN-7TM or EGF-7TM receptors) are membrane-bound proteins with long N-termini containing multiple domains. |
| GO:0004930 G protein-coupled receptor activity | NAS PMID:11606593 Very large G protein-coupled receptor-1, the largest known c... | ACCEPT | Summary: ADGRV1 has experimentally supported G protein-coupled receptor activity, with construct-dependent coupling. Reason: The mouse donor is the Adgrv1 ortholog, and independent human VLGR1a/CTF experiments in PMID:35630584 support receptor-mediated second-messenger signaling. Those experiments use the shorter VLGR1a isoform and engineered C-terminal constructs; they do not measure coupling of intact VLGR1b in native human hair cells or photoreceptors. GPCR activity is supported without assigning one physiological G protein to every receptor pool. Supporting Evidence: PMID:35630584 Overexpressing VLGR1a revealed a dose-dependent increase of cAMP PMID:24962568 The cleaved VLGR1 Ξ²-subunit constitutively inhibited adenylate cyclase (AC) activity through GΞ±i coupling. |
| GO:0007399 nervous system development | NAS PMID:11606593 Very large G protein-coupled receptor-1, the largest known c... | KEEP AS NON CORE | Summary: Developmental neural expression underlies the original nervous-system-development author statement. Reason: The full original PMID:11606593 was read externally: mouse embryo in situ hybridization identifies ventricular-zone and eye expression, and the discussion explicitly frames a developmental role as an inference. Retain the broad NAS as non-core in that limited sense. Neither those expression data nor a seizure phenotype establishes a particular developmental cell-fate or signaling mechanism. Supporting Evidence: PMID:11606593 Strong expression in the ventricular zone, home of neural progenitor cells during embryonal neurogenesis, suggests a fundamental role for VLGR1 in the development of the central nervous system. |
| GO:0016020 membrane | NAS PMID:11606593 Very large G protein-coupled receptor-1, the largest known c... | ACCEPT | Summary: Author statement; VLGR1 is described as the largest known cell surface protein with a 7TM domain. Reason: Correct, if general; consistent with all other localization evidence. Supporting Evidence: PMID:11606593 VLGR1b is apparently the largest known cell surface protein. |
| GO:0098609 cell-cell adhesion | NAS PMID:11606593 Very large G protein-coupled receptor-1, the largest known c... | MARK AS OVER ANNOTATED | Summary: The original cell-cell-adhesion statement is based on domain analogy rather than an ADGRV1 cell-cell adhesion assay. Reason: The full PMID:11606593 introduction and discussion use sponge aggregation-factor Calx-beta repeats as an analogy and explicitly speculate about possible VLGR1 homotypic interactions. The demonstrated ankle links connect projections of a single hair cell and do not establish adhesion between different cells. Mark this particular NAS mapping as over-annotated, without claiming that ADGRV1 can never participate in intercellular adhesion in another context. Supporting Evidence: PMID:11606593 Similar repeats are found in the extracellular aggregation factor of marine sponges, which mediates species-specific cell aggregation. |
| GO:0005198 structural molecule activity | ISS PMID:17567809 Molecular characterization of the ankle-link complex in coch... | NEW | Summary: Proposed structural molecule activity for the receptor ectodomain in ankle links. Reason: The primary mouse study PMID:17567809 combines ectodomain localization with the temporal presence of ankle links, their joint disruption by BAPTA/subtilisin, and their absence in mutants. The receptor is a physical link constituent contributing cohesive bundle architecture. These data support a structural molecular function beyond necessity alone. Retain the pre-existing NEW proposal with mouse-to-human transfer; another gene review's proposed annotation is not evidence for it. Supporting Evidence: PMID:17567809 Several lines of evidence indicate that very large G-protein-coupled receptor 1 (Vlgr1) makes up the ankle links that connect the stereocilia of hair cells at their base. |
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Q: Which ADGRV1-specific peptides or interaction measurements support the urinary-exosome and PX-FERM screen annotations whose supplementary evidence remains inaccessible?
Q: Does the mouse bone-density phenotype reflect altered mineral deposition, altered resorption, or both?
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