USH2A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005576 extracellular region	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Extracellular localization derived from the UniProt "Secreted" subcellular location of the short isoform 2 (isoform A), which lacks the transmembrane segment and associates with basement membranes. Reason: Correct but isoform-restricted. The short usherin isoform A is secreted and found in basement membranes of many tissues (PMID:12433396), consistent with this SL-0243 mapping. The functionally central long isoform b is a single-pass transmembrane protein acting at stereocilia ankle links and the photoreceptor periciliary membrane, so a bare extracellular-region location is not the core picture of the gene product; the basement-membrane pool is kept as a secondary, non-core localization. Supporting Evidence: PMID:12433396 Usherin is a basement membrane protein encoded by the USH2A gene.
GO:0045494 photoreceptor cell maintenance	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation of the retinal core function; USH2A loss causes retinitis pigmentosa, i.e. progressive failure of photoreceptor survival, in humans and in mouse models. Reason: This matches the human IMP annotation from USH2A patients (PMID:10090909) and the well-established requirement of the USH2 complex at the photoreceptor periciliary membrane for long-term photoreceptor survival (UniProt FUNCTION, by similarity to mouse Q2QI47). Retinal degeneration in USH2A patients documents progressive photoreceptor loss (PMID:15671307). Core retinal function. 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:0060113 inner ear receptor cell differentiation	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation of the cochlear core function; usherin is a component of the transient ankle links required for stereocilia bundle development in differentiating hair cells. Reason: Concordant with the IDA annotation from PMID:36964137 and with mouse Ush2a knockout phenotypes (disorganized stereocilia, congenital hearing loss). The ankle-link complex containing usherin acts specifically during hair-cell differentiation, when ankle links are present. Core inner-ear function. Supporting Evidence: PMID:36964137 Ankle links, a mesh of thin fibers connecting stereocilia at their basal regions, are indispensable for coordinating stereociliary development and thus are essential for hearing
GO:0060171 stereocilium membrane	IEA GO_REF:0000120	ACCEPT	Summary: Electronic transfer (from mouse Q2QI47/Ensembl and UniProt subcellular location) of the well-established localization of transmembrane usherin to the stereocilium membrane at the base of developing stereocilia. Reason: UniProt lists "Cell projection, stereocilium membrane; single-pass type I membrane protein" and mouse immunolocalization consistently places usherin in the stereociliary membrane at the ankle-link region during hair-bundle development. Core localization for the long isoform. Supporting Evidence: PMID:36964137 both USH2A and ADGRV1 are transmembrane adhesion proteins that form extracellular linkages
GO:0005515 protein binding	IPI PMID:20440071 PDZD7 is a modifier of retinal disease and a contributor to ...	MODIFY	Summary: IPI with PDZD7 (Q9H5P4). The paper shows by co-immunoprecipitation that PDZD7 PDZ1/PDZ2 domains bind USH2A, dependent on the USH2A C-terminal PDZ-binding motif. Reason: The underlying evidence is sound and functionally important (assembly of the USH2/ankle-link complex), but bare "protein binding" is uninformative. The interaction is explicitly mapped to PDZ domains of PDZD7 recognizing the usherin PDZ-binding motif, so GO:0030165 "PDZ domain binding" captures the actual molecular capability of the usherin cytoplasmic tail. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:20440071 the first and second PDZ domains of PDZD7 interact with USH2A by coimmunoprecipitation studies PMID:20440071 A truncated version of USH2A without the C-terminal PDZ-binding motif showed reduced interaction.
GO:0001917 photoreceptor inner segment	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse Ush2a of localization to the photoreceptor inner segment; usherin concentrates at the apical inner segment membrane (periciliary membrane compartment) around the connecting cilium. Reason: Consistent with mouse experimental localization (basis of the UniProt note that usherin "localizes at a plasma membrane microdomain in the apical inner segment that surrounds the connecting cilia") and with human ISS colocalization annotations. The periciliary membrane compartment is part of the apical inner segment, so this located_in is correct; the more precise compartment (GO:1990075) is separately annotated. Core retinal localization.
GO:0002141 stereocilia ankle link	IEA GO_REF:0000120	ACCEPT	Summary: Electronic transfer (ARBA plus mouse Q2QI47/Ensembl) of usherin localization to the stereocilia ankle links of developing hair bundles. Reason: One of the two defining localizations of usherin, established by mouse immunolocalization and knockout studies and by the phase-separation work on the ankle-link complex (PMID:36964137). The ankle link is a transient structure of developing bundles, which is faithfully reflected by the term. Core localization. Supporting Evidence: PMID:36964137 WHRN, PDZD7, ADGRV1 and USH2A have been identified to form the so-called ankle link complex (ALC) file:human/USH2A/USH2A-deep-research-falcon.md During early postnatal development, usherin localizes at the base of inner- and outer-hair-cell stereocilia, coincident with transient ankle links.
GO:0002142 stereocilia ankle link complex	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse of usherin membership in the ankle-link complex (USH2 complex) with ADGRV1, WHRN and PDZD7. Reason: Usherin is a defining component of the ankle-link complex; the four USH2 proteins form this complex at the stereociliary base and its assembly requires the usherin cytoplasmic tail (PMID:36964137, PMID:25406310). Core complex membership. Supporting Evidence: PMID:36964137 WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS)
GO:0005518 collagen binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation mirroring the direct IDA demonstration that the usherin laminin EGF-like (LE) domain binds the 7S domain of collagen IV. Reason: The collagen IV interaction is experimentally solid (PMID:14676276) but pertains to the basement-membrane pool of usherin (most relevant to the secreted isoform A and Bruch's membrane), not to the ankle-link/periciliary functions that account for the sensory phenotypes. Retained as a genuine but non-core molecular capability. Supporting Evidence: PMID:14676276 We demonstrate binding occurs between the LE domain of usherin and the 7S domain of type IV collagen.
GO:0005604 basement membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation of the basement-membrane localization originally shown by immunohistochemistry in many human and mouse tissues. Reason: Well documented experimentally (PMID:12433396) and consistent with the matrisome HDA annotation, but this reflects the secreted/short-isoform pool in epithelial basement membranes and Bruch's membrane rather than the core sensory-cell function of the transmembrane isoform. Kept as non-core. Supporting Evidence: PMID:12433396 Expression of usherin has been localized in the basement membrane of several tissues, however it is not ubiquitous.
GO:0016324 apical plasma membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation placing usherin in the apical plasma membrane; both of its functional sites (stereociliary base membrane of hair cells, periciliary membrane of the photoreceptor apical inner segment) are apical membrane subdomains. Reason: True but general. The informative localizations are the specific apical subdomains already annotated (GO:0060171 stereocilium membrane, GO:0002141 ankle link, GO:1990075 periciliary membrane compartment). Kept as a correct, non-core generalization.
GO:0017022 myosin binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic transfer (ARBA/mouse) of the interaction between the usherin cytoplasmic region and MYO7A-family myosins via their MyTH4-FERM domains. Reason: UniProt SUBUNIT records that usherin "Interacts (via the cytoplasmic region) with VEZT and MYO7A (via MyTH4-FERM domains)" (by similarity to mouse Q2QI47), and myosin VIIa is required for normal assembly/localization of the USH2 complex in cochlear hair cells. Myosin binding is an informative molecular-function term describing how usherin is coupled to the transport and anchoring machinery that delivers the complex to the stereociliary base.
GO:0032391 photoreceptor connecting cilium	IEA GO_REF:0000107	MODIFY	Summary: Ensembl transfer from mouse of localization at the photoreceptor connecting cilium region. Reason: Usherin is not a component of the connecting cilium proper; mouse experimental work localizes it to the periciliary membrane of the apical inner segment that surrounds the connecting cilium (UniProt subcellular location note; GO:1990075 annotations in this record). A located_in assertion on the ciliary structure itself over-states the localization, whereas the companion ISS annotation appropriately uses colocalizes_with. Recommend the periciliary membrane compartment term instead. Proposed replacements: periciliary membrane compartment
GO:0032421 stereocilium bundle	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse of localization within the stereocilium bundle (at the basal/ankle region of the stereocilia). Reason: Correct; usherin resides at the base of stereocilia within developing hair bundles, as part of the ankle-link complex. The finer-grained terms (ankle link, stereocilium membrane) are also annotated; this parent-level location is still accurate. Core localization.
GO:0035315 hair cell differentiation	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse of involvement in hair cell differentiation, reflecting the ankle-link complex requirement for stereocilia bundle development. Reason: Mouse Ush2a mutants show disorganized stereocilia bundles and hearing loss arising during hair-bundle development, and the ankle-link condensate work ties usherin directly to stereociliary development (PMID:36964137). Consistent with the more specific inner ear receptor cell differentiation annotations. Core process. Supporting Evidence: PMID:36964137 Ankle links, a mesh of thin fibers connecting stereocilia at their basal regions, are indispensable for coordinating stereociliary development and thus are essential for hearing
GO:0036064 ciliary basal body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ensembl transfer from mouse of localization at the ciliary basal body region of photoreceptors. Reason: USH2 proteins have been reported near the basal body/periciliary region of photoreceptors in rodent studies, and this transfer is plausible for the periciliary pool, but the basal body itself is not the defining compartment of usherin function; the periciliary membrane compartment and ankle-link terms carry the core localization signal. Kept as non-core.
GO:0042802 identical protein binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl transfer from mouse of a self-association (homomeric interaction) claim for usherin. Reason: Like bare protein binding, "identical protein binding" conveys essentially no functional information, and no human experiment establishes a functionally meaningful usherin homomer; the annotation is an electronic transfer of an interaction-detection result. Not wrong enough to remove, but an over-annotation relative to what is known about usherin's molecular function.
GO:1990075 periciliary membrane compartment	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse of localization in the periciliary membrane compartment (PMC) of the photoreceptor apical inner segment. Reason: This is the defining retinal localization of long-isoform usherin, established by mouse immunolocalization (basis of the UniProt note that in photoreceptors usherin "localizes at a plasma membrane microdomain in the apical inner segment that surrounds the connecting cilia called periciliary membrane complex"). Core localization. Supporting Evidence: file:human/USH2A/USH2A-deep-research-falcon.md Transmembrane usherin is concentrated around the connecting cilium/periciliary membrane region, at the boundary between the metabolically active inner segment and the photosensitive outer segment.
GO:1990696 USH2 complex	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl transfer from mouse of membership in the USH2 complex (ADGRV1-PDZD7-USH2A-WHRN). Reason: Usherin is a founding member of the USH2 quaternary complex; direct biochemical reconstruction shows WHRN and PDZD7 assemble USH2A and GPR98/ADGRV1 into one complex (PMID:25406310). Core complex membership. Supporting Evidence: PMID:25406310 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:0140144 non-collagenous component of basement membrane	HDA PMID:22159717 The matrisome: in silico definition and in vivo characteriza...	KEEP AS NON CORE	Summary: High-throughput matrisome proteomics/in-silico classification listing usherin among non-collagenous ECM glycoproteins of basement membranes. Reason: Consistent with the targeted experimental evidence for usherin as a basement-membrane glycoprotein (PMID:12433396, PMID:14676276). USH2A appears in the matrisome supplementary lists rather than the cached article body, so no verbatim quote is attached. As with the other basement-membrane annotations, this reflects the secreted/short-isoform pool and is kept as non-core relative to the sensory-cell membrane functions.
GO:0002141 stereocilia ankle link	IDA PMID:31644917 Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condens...	ACCEPT	Summary: BHF-UCL IDA placing usherin activity at the stereocilia ankle link, citing the Cell Reports study of Usher-protein condensates formed by liquid-liquid phase separation. Reason: The cached record for PMID:31644917 is abstract-only and the abstract describes the MYO7A/MYO7B-USH1C-ANKS4B/USH1G tip-link density complexes without naming USH2A, so the specific experiment behind this annotation cannot be verified from the cache; the curator read the full text and is not overruled on that basis. The asserted location is independently and firmly established for usherin by the companion IDA from PMID:36964137 and extensive mouse work placing usherin at the ankle links of developing stereocilia. Core localization. Supporting Evidence: PMID:36964137 WHRN, PDZD7, ADGRV1 and USH2A have been identified to form the so-called ankle link complex (ALC)
GO:0002141 stereocilia ankle link	IDA PMID:36964137 Temporal and spatial assembly of inner ear hair cell ankle l...	ACCEPT	Summary: IDA from the Nature Communications study showing that WHRN and PDZD7 orchestrate ADGRV1 and USH2A into the ankle-link complex through liquid-liquid phase separation, with in vivo mouse validation. Reason: Direct, modern evidence for usherin as an ankle-link component; the study maps the multivalent PDZ/PBM interactions of the USH2A cytoplasmic tail that drive ankle-link condensate assembly and shows deafness mutations weaken them. Core localization; note the ankle link is a transient structure of developing hair bundles (present ~P2-P12 in mouse). Supporting Evidence: PMID:36964137 WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS) PMID:36964137 Temporally, they only exist during the P2 to P12 stages during stereociliary development
GO:0016324 apical plasma membrane	TAS PMID:31644917 Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condens...	KEEP AS NON CORE	Summary: TAS statement that usherin resides in the apical plasma membrane, from the same BHF-UCL curation of the phase-separation literature. Reason: Correct but general; stereocilia and their ankle-link membrane domain are elaborations of the hair-cell apical membrane. The informative localizations are the specific subdomains (GO:0060171, GO:0002141, GO:1990075) already annotated. Kept as a correct, non-core generalization; the cached abstract-only record precludes quoting the supporting statement.
GO:0017022 myosin binding	IPI PMID:31644917 Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condens...	ACCEPT	Summary: BHF-UCL IPI with MYO7B (Q6PIF6) from the liquid-liquid phase separation study of Usher-protein assemblies. Reason: The cached record is abstract-only and does not name USH2A, so the specific binding experiment cannot be verified from the cache; the curator read the full text and is not overruled on that basis. The activity class is well supported for usherin - UniProt SUBUNIT records interaction of the usherin cytoplasmic region with MYO7A via its MyTH4-FERM domains (by similarity to mouse), and MYO7A-family myosins are required for USH2 complex localization in hair cells - so myosin binding is an appropriate, informative molecular function for the cytoplasmic tail.
GO:0060113 inner ear receptor cell differentiation	IDA PMID:36964137 Temporal and spatial assembly of inner ear hair cell ankle l...	ACCEPT	Summary: IDA from the ankle-link condensate study, which combined biochemical reconstitution with an in vivo mouse model showing that disrupting USH2 complex multivalency abolishes WHRN distribution at the stereociliary base during bundle development. Reason: The paper directly ties usherin-containing ankle-link condensates to stereociliary development in differentiating inner-ear hair cells, and shows deafness mutations in ALC genes impair the complex. Core inner-ear process for usherin. Supporting Evidence: PMID:36964137 Ankle links, a mesh of thin fibers connecting stereocilia at their basal regions, are indispensable for coordinating stereociliary development and thus are essential for hearing PMID:36964137 utilizing the in vivo mouse model, we show that disruption of the USH2 multivalency for LLPS abolishes the native distribution of the long WHRN at the basal region of stereocilia
GO:0060113 inner ear receptor cell differentiation	NAS PMID:25406310 Whirlin and PDZ domain-containing 7 (PDZD7) proteins are bot...	ACCEPT	Summary: ComplexPortal NAS annotation attributing inner-ear receptor cell differentiation to the USH2 quaternary complex characterized in this paper. Reason: The complex-level attribution is sound; the paper establishes the USH2 quaternary complex biochemically and frames its in vivo role in hair cells and photoreceptors, and the process itself is directly demonstrated for the ankle-link complex elsewhere (PMID:36964137, mouse knockouts). Core process, duplicate of stronger evidence lines. Supporting Evidence: PMID:25406310 WHRN and PDZD7 heterodimerization and their interactions with USH2A and GPR98 are required for USH2 complex formation.
GO:0002141 stereocilia ankle link	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse Ush2a (Q2QI47) of ankle-link localization. Reason: The mouse experimental localization of usherin to ankle links is the primary evidence base for this compartment and transfers soundly to human, where USH2A mutations produce the corresponding hearing phenotype. Core localization. (Note the part_of qualifier on a fiber-like structure; the is_active_in IDA lines cover the same biology.)
GO:0045184 establishment of protein localization	ISS GO_REF:0000024	MODIFY	Summary: ISS transfer from mouse of usherin's requirement for the normal localization of its USH2 complex partners (ADGRV1, WHRN) at the stereociliary base and photoreceptor periciliary membrane. Reason: The underlying mouse genetics is solid - loss of Ush2a mislocalizes the other ankle-link complex proteins - but "establishment of protein localization" is far too general to be informative. The partners are plasma-membrane proteins localized to specific membrane subdomains, so protein localization to plasma membrane (GO:0072659) captures the biology at a useful level; in the retina the still more specific GO:1903621 (protein localization to photoreceptor connecting cilium region) applies to the complex. Proposed replacements: protein localization to plasma membrane
GO:1990075 periciliary membrane compartment	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse Ush2a of periciliary membrane compartment localization in photoreceptors. Reason: Defining retinal localization of long-isoform usherin, from mouse immunolocalization and knockout studies underlying the UniProt subcellular location note. Core localization.
GO:0001917 photoreceptor inner segment	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer of colocalization with the photoreceptor inner segment, consistent with the periciliary membrane pool at the apical inner segment. Reason: Matches the mouse/rat immunolocalization of usherin at the apical inner segment periciliary region and the human whirlin-usherin colocalization data (PMID:16434480). Core retinal localization at parent level.
GO:0002142 stereocilia ankle link complex	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse of membership in the ankle-link complex. Reason: Core complex membership, grounded in mouse localization/knockout work and confirmed biochemically for the human proteins (PMID:25406310, PMID:36964137). Supporting Evidence: PMID:36964137 All four USH2-associated proteins localize at the basal region of hair cell stereocilia to form the ankle link complex (also known as the USH2 protein complex)
GO:0005515 protein binding	IPI PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei...	MODIFY	Summary: IPI with whirlin (WHRN, Q9P202); the paper demonstrates direct association of whirlin with USH2A isoform b in the cochlea and retina. Reason: Sound and central evidence (the whirlin-usherin interaction anchors the USH2 complex), but bare "protein binding" is uninformative. Whirlin is a PDZ scaffold and the usherin cytoplasmic tail binds its PDZ domains via the C-terminal PDZ-binding motif (UniProt DOMAIN note; PMID:25406310 maps USH2A binding to WHRN PDZ1/PDZ2). GO:0030165 "PDZ domain binding" is the informative replacement. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:16434480 we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b
GO:0032391 photoreceptor connecting cilium	ISS GO_REF:0000024	MODIFY	Summary: Curator ISS transfer of colocalization with the photoreceptor connecting cilium, matching direct colocalization data for whirlin, USH2A and Vlgr1b at the connecting cilium. Reason: The colocalizes_with qualifier makes this defensible - usherin sits in the periciliary membrane immediately surrounding the connecting cilium and colocalizes with it at light-microscopy resolution (PMID:16434480) - but as for the IEA located_in row, the compartment that actually contains usherin is the periciliary membrane compartment (GO:1990075), which is the preferred term for this localization signal. Proposed replacements: periciliary membrane compartment Supporting Evidence: PMID:16434480 whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear
GO:0043025 neuronal cell body	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator ISS transfer of colocalization with neuronal cell bodies (spiral ganglion neurons), from the whirlin-interactome localization studies. Reason: The source-era data reported usherin/whirlin colocalization in spiral ganglion neurons (PMID:16434480), but later knockout-validated localization studies of the USH2 complex concentrate on hair-cell ankle links and the photoreceptor periciliary membrane, and a neuronal cell-body pool has no established function. Kept, with the appropriately cautious colocalizes_with qualifier, as non-core. Supporting Evidence: PMID:16434480 whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear
GO:0043195 terminal bouton	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator ISS transfer of colocalization with synaptic terminals, from reports of USH2A/whirlin colocalization at photoreceptor and hair-cell synaptic regions. Reason: Based on the whirlin-interactome era synaptic localization (PMID:16434480). The synaptic pool of USH2 proteins was not confirmed as a major site in subsequent knockout-controlled mouse studies, and no synaptic function of usherin is established; kept as a hedged (colocalizes_with) non-core localization. Supporting Evidence: PMID:16434480 These proteins co-localize with whirlin at the synaptic regions of both photoreceptor cells and outer hair cells in the cochlea.
GO:1990696 USH2 complex	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse of USH2 complex membership. Reason: Core complex membership; the quaternary ADGRV1-PDZD7-USH2A-WHRN complex has been reconstructed biochemically (PMID:25406310) and its assembly characterized by phase separation (PMID:36964137). Supporting Evidence: PMID:25406310 both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98.
GO:0032421 stereocilium bundle	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse of localization within the stereocilium bundle. Reason: Correct parent-level localization; usherin resides at the basal region of stereocilia within developing hair bundles. Core localization.
GO:0035315 hair cell differentiation	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse of involvement in hair cell differentiation. Reason: Mouse Ush2a loss disrupts stereocilia bundle development and causes hearing loss; the transfer to human is validated by the congenital hearing impairment of USH2A patients. Core process, consistent with the more specific GO:0060113 annotations.
GO:0060171 stereocilium membrane	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS transfer from mouse of stereocilium membrane localization. Reason: Core localization of the transmembrane isoform at the stereociliary base (ankle-link region), matching the UniProt subcellular location.
GO:0045494 photoreceptor cell maintenance	IMP PMID:10090909 A mutation (2314delG) in the Usher syndrome type IIA gene: h...	ACCEPT	Summary: Human IMP from USH2A patients carrying the common 2314delG mutation, who develop retinitis pigmentosa, i.e. progressive photoreceptor degeneration. Reason: Patient loss-of-function phenotypes are acceptable IMP evidence, and retinitis pigmentosa in biallelic USH2A patients directly demonstrates that the gene is required for long-term photoreceptor survival. The cached record for this 1999 AJHG letter is title-only, so no verbatim quote can be attached, but the title and the extensive downstream literature (RP39; photoreceptor disease with outer-nuclear-layer thinning, PMID:15671307) support the annotation. Core retinal function. 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:0048496 maintenance of animal organ identity	IMP PMID:15671307 Disease expression in Usher syndrome caused by VLGR1 gene mu...	MODIFY	Summary: Human IMP from a clinical study of retinal disease expression in USH2A patients (compared with USH2C), documenting progressive photoreceptor dysfunction and outer nuclear layer thinning. Reason: The evidence is sound human patient data, but the term is a poor fit - "maintenance of animal organ identity" denotes preserving an organ's developmental identity, whereas the paper documents degenerative loss of photoreceptor structure and function in a formed retina. The biology the curator captured is photoreceptor cell maintenance (GO:0045494), which is already annotated from PMID:10090909 and is the appropriate replacement. Legacy term-choice issue, not an evidence problem. 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:0005518 collagen binding	IDA PMID:14676276 A domain-specific usherin/collagen IV interaction may be req...	KEEP AS NON CORE	Summary: Direct IDA showing 1:1 binding between the usherin LE (laminin EGF-like) domain and the 7S domain of collagen IV, abolished by USH2A disease missense mutations in LE loop b. Reason: High-quality direct biochemistry with disease-variant validation; the interaction stabilizes usherin in basement membranes (70% collagen IV reduction in Alport mice is accompanied by a similar usherin reduction). However, this concerns the basement-membrane pool of usherin (secreted isoform A / Bruch's membrane) rather than the ankle-link and periciliary membrane functions that define the sensory phenotype, so it is retained as a genuine but non-core molecular function. Supporting Evidence: PMID:14676276 This report demonstrates a specific interaction between type IV collagen and usherin in the basement membrane, with a 1:1 stoichiometry for binding. PMID:14676276 We demonstrate binding occurs between the LE domain of usherin and the 7S domain of type IV collagen.
GO:0005604 basement membrane	IDA PMID:12433396 Usherin expression is highly conserved in mouse and human ti...	KEEP AS NON CORE	Summary: IDA immunohistochemistry localizing usherin to basement membranes of many (but not all) human and mouse tissues, including retina and cochlea. Reason: Directly demonstrated and reproducible localization, but attributable chiefly to the secreted/short-isoform pool of usherin in epithelial basement membranes and Bruch's membrane; the phenotype-relevant core localizations of the transmembrane isoform are the stereociliary ankle-link region and the photoreceptor periciliary membrane. Kept as non-core. Supporting Evidence: PMID:12433396 Usherin is a basement membrane protein encoded by the USH2A gene. PMID:12433396 Immunohistochemistry detected usherin in the following human tissues: retina, cochlea, small and large intestine, pancreas, bladder, prostate, esophagus, trachea, thymus, salivary glands, placenta, ovary, fallopian tube, uterus, and testis.
GO:0005737 cytoplasm	IDA PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei...	MARK AS OVER ANNOTATED	Summary: IDA cytoplasm annotation from the whirlin-interactome paper; the cached abstract reports membrane-domain and synaptic-region colocalization and does not describe a functional cytoplasmic pool. Reason: Usherin is a secreted or single-pass type I membrane protein; any cytoplasmic immunostaining most plausibly reflects biosynthetic/vesicular intermediates or heterologously expressed fragments used in the interaction assays. The annotation is not demonstrably false (full text not in cache, so the curator's basis cannot be inspected), but "cytoplasm" carries no functional information for this protein and misrepresents its topology as a steady-state location. Treated as an over-annotation rather than removed.
GO:0007605 sensory perception of sound	IMP PMID:10090909 A mutation (2314delG) in the Usher syndrome type IIA gene: h...	ACCEPT	Summary: Human IMP from USH2A patients with the 2314delG mutation, who have congenital sensorineural hearing impairment. Reason: Usher syndrome type 2A includes congenital moderate-to-severe hearing loss, directly implicating USH2A in hearing; this is mechanistically explained by the ankle-link requirement for stereocilia bundle development. The cached record for this letter is title-only so no quote can be attached, but the phenotype is textbook USH2A (the UniProt disease note describes USH2 as characterized by congenital hearing impairment). Core process.
GO:0050953 sensory perception of light stimulus	IMP PMID:10090909 A mutation (2314delG) in the Usher syndrome type IIA gene: h...	ACCEPT	Summary: Human IMP from USH2A patients, whose retinitis pigmentosa causes progressive loss of vision. Reason: The retinal component of Usher syndrome type 2A (and nonsyndromic RP39) demonstrates that USH2A function is required for sustained visual perception, via maintenance of photoreceptors at the periciliary membrane. Cached record is title-only (letter), so no verbatim quote; supported by the companion clinical literature (PMID:15671307). Core process. 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:0005198 structural molecule activity	TAS PMID:36964137 Temporal and spatial assembly of inner ear hair cell ankle l...	NEW	Summary: Proposed NEW annotation. No GOA line captures the primary molecular activity of the usherin ectodomain, which is structural rather than catalytic - it is one of the fibrous components of the ankle links that physically interconnect stereocilia at their bases in developing hair bundles, and it contributes to the architecture of the photoreceptor periciliary membrane as part of the USH2 complex. Reason: The existing MF annotations (PDZ domain binding, myosin binding, collagen binding) describe how usherin is anchored and trafficked, but not what it does - the phenotype-defining activity is formation of extracellular structural links. The ankle-link literature explicitly describes USH2A and ADGRV1 as the transmembrane adhesion proteins whose ectodomains form the extracellular linkages of the ankle-link mesh, a structural contribution to the ankle link and USH2 complex that GO:0005198 captures without asserting an unassayed adhesion-receptor activity. Supporting Evidence: PMID:36964137 both USH2A and ADGRV1 are transmembrane adhesion proteins that form extracellular linkages PMID:36964137 Ankle links, a mesh of thin fibers connecting stereocilia at their basal regions, are indispensable for coordinating stereociliary development and thus are essential for hearing

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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