WHRN encodes whirlin, a multivalent PDZ-domain scaffold protein (two harmonin-N-like/harmonin-homology domains, three PDZ domains, a proline-rich region and a C-terminal PDZ-binding motif) that organizes macromolecular complexes in the sensory cells of the inner ear and retina. Distinct isoforms produced from alternative promoters carry out two spatially and temporally separable roles in cochlear hair cells. The long (full-length) isoform is a component of the transient ankle-link/USH2 complex at the base of developing stereocilia, where its N-terminal PDZ domains bind the cytoplasmic PDZ-binding motifs of the large transmembrane proteins usherin (USH2A) and ADGRV1 (VLGR1/GPR98) and heterodimerize with the paralogous scaffold PDZD7; multivalent interactions among these four proteins drive condensate-like assembly of the ankle-link complex, which maintains hair-bundle cohesion during morphogenesis. The short (C-terminal) isoform localizes to stereocilia tips, where together with the motor MYO15A and the actin regulator EPS8 it forms the tip complex that controls stereocilia elongation and staircase architecture. In retinal photoreceptors, whirlin scaffolds USH2A and ADGRV1 at the periciliary membrane complex adjacent to the connecting cilium, supporting periciliary organization and protein trafficking toward the outer segment, and it also interacts with MPP1/p55, CASK and CIB2. Whirlin self-associates, a property required for its phase-separation-mediated scaffolding. Biallelic loss of the long isoform causes Usher syndrome type 2D (deafness with retinitis pigmentosa), while variants disrupting the C-terminal region cause DFNB31 nonsyndromic sensorineural deafness. Whirlin has additionally been reported at hair-cell and photoreceptor synapses, in neuronal growth cones, and at axonal paranodes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred ciliary localization, consistent with whirlin's well-documented localization at the photoreceptor connecting cilium and periciliary region (a true microtubule-based cilium, distinct from the actin-based stereocilia). Reason: Whirlin, USH2A and VLGR1b co-localize at the connecting cilium of photoreceptors (PMID:16434480), and whirlin is also found at the ciliary axoneme with MPP1 (PMID:17584769). The IBA is seeded from mouse and rat experimental members of the family and the human protein clearly inherits this localization; the term is broad but correct. Supporting Evidence: PMID:16434480 we demonstrate that 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:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred plasma membrane localization. Whirlin is a peripheral (cytoplasmic) scaffold that acts at specialized plasma membrane domains - the ankle-link region at the stereocilia base and the photoreceptor periciliary membrane - by binding the cytoplasmic tails of the transmembrane proteins USH2A and ADGRV1. Reason: Broad but correct; whirlin's function is executed at membrane-apposed scaffolds (ankle-link complex, periciliary membrane complex), which are captured more precisely by other annotations in this set. The is_active_in qualifier is appropriate since whirlin acts at these membrane domains. Supporting Evidence: PMID:25406310 In photoreceptors, USH2A, GPR98, and WHRN proteins are colocalized at the periciliary membrane complex of the inner segment apex and immediately below the outer segment |
| GO:0002142 stereocilia ankle link complex | IBA GO_REF:0000033 | ACCEPT | Summary: Core complex membership. The long whirlin isoform is one of the four components (WHRN, PDZD7, USH2A, ADGRV1) of the transient ankle-link complex at the base of developing stereocilia, and together with PDZD7 it bridges USH2A and ADGRV1 into the quaternary USH2 complex. Reason: Direct biochemical and localization evidence supports this complex membership (PMID:25406310, PMID:16434480). This is one of the two core hair-cell roles of whirlin (long-isoform, developing bundles) and its disruption underlies USH2D. The IBA correctly places the function at the right level. 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 PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. |
| GO:0032426 stereocilium tip | IBA GO_REF:0000033 | ACCEPT | Summary: Core localization. The short (C-terminal) whirlin isoform localizes to stereocilia tips, where it forms the elongation-promoting tip complex with MYO15A and EPS8; MYO15A is required to deliver whirlin to the tips. Reason: Tip localization is one of the two core hair-cell roles of whirlin (short isoform, stereocilia elongation) and is well supported experimentally in mouse and corroborated by interaction of human WHRN with CIB2 at stereocilia tips (PMID:23023331). Loss of tip function causes DFNB31 nonsyndromic deafness. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia file:human/WHRN/WHRN-deep-research-falcon.md MYO15A acts as an actin-based motor that delivers or retains the complex at stereociliary tips, whereas EPS8 supplies actin-regulatory activity. |
| GO:0007605 sensory perception of sound | IBA GO_REF:0000033 | ACCEPT | Summary: Core process. Whirlin is required for hearing; human WHRN mutations cause DFNB31 nonsyndromic deafness and USH2D (deafness plus retinitis pigmentosa), and mouse whirler mutants are profoundly deaf with short stereocilia. Reason: Human genetic evidence (DFNB31, USH2D) and mouse models converge; the target's own experimental annotation (IMP from PMID:17171570) appears in the WITH/FROM, indicating experimental grounding on the target itself with the function inherited within the clade. Supporting Evidence: PMID:17171570 We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. |
| GO:0060088 auditory receptor cell stereocilium organization | IBA GO_REF:0000033 | ACCEPT | Summary: Core process. Whirlin is essential for elongation and organization of cochlear hair cell stereocilia, acting at the tip complex (with MYO15A/EPS8) and at the ankle-link complex during bundle development. Reason: This term precisely captures whirlin's core developmental function in auditory hair cells; whirler mice have abnormally short stereocilia and the elongation role is well established (PMID:16434480 abstract summarizes it as established knowledge). Supporting Evidence: PMID:16434480 Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear |
| GO:0001917 photoreceptor inner segment | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic transfer of whirlin localization to the photoreceptor inner segment; the periciliary membrane complex where whirlin scaffolds USH2A and ADGRV1 lies at the apex of the inner segment. Reason: Consistent with direct localization data in photoreceptors (mouse) and with the periciliary membrane compartment annotation; correct though less specific than GO:1990075, which is also present in this set. Supporting Evidence: PMID:25406310 In photoreceptors, USH2A, GPR98, and WHRN proteins are colocalized at the periciliary membrane complex of the inner segment apex and immediately below the outer segment |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Whirlin is a soluble cytoplasmic scaffold (no transmembrane segment or signal peptide); this general term is correct but uninformative relative to the specific subcellular structures where it acts. Reason: Correct but very general; whirlin's functionally relevant locations are the stereocilium tip, ankle-link region and periciliary membrane compartment, all annotated more specifically in this set. |
| GO:0030426 growth cone | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location transfer; whirlin has been reported in neuronal growth cones (via studies of mouse whirlin in neurons, e.g. with LRRC4C/NGL-1), reflecting broader neuronal expression beyond sensory cells. Reason: Plausible neuronal localization from the UniProt SubCell mapping, but peripheral to whirlin's core sensory hair-cell and photoreceptor scaffold functions; no human experimental support in the cached literature. |
| GO:0032420 stereocilium | IEA GO_REF:0000120 | ACCEPT | Summary: Whirlin localizes within stereocilia, both at tips (short isoform, with MYO15A/EPS8) and at the base/ankle region (long isoform, with USH2A/ADGRV1/PDZD7). Reason: Well supported by extensive experimental work in mouse hair cells and consistent with more specific tip and ankle-link annotations in this set. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Whirlin co-localizes with USH2A and VLGR1b at synaptic regions of photoreceptors and cochlear outer hair cells, suggesting a role in organizing the pre- and/or postsynaptic scaffold of sensory synapses. Reason: Experimentally grounded localization (PMID:16434480) but a secondary site relative to the stereociliary and periciliary scaffold roles; the functional significance of synaptic whirlin remains less well defined. 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:0005515 protein binding | IPI PMID:12421765 Protein-protein interactions between large proteins: two-hyb... | MARK AS OVER ANNOTATED | Summary: High-throughput yeast two-hybrid screen among large KIAA proteins (whirlin = KIAA1526) detecting binary interactions; supports that whirlin engages in protein-protein interactions but the term itself carries no functional information. Reason: The interaction evidence is from a large-scale Y2H screen and the term 'protein binding' is uninformative; whirlin's actual molecular function is scaffolding/adaptor activity, better captured by its complex and localization annotations. Not wrong, but adds no functional insight. Supporting Evidence: PMID:12421765 To comprehensively study protein-protein interactions between large KIAA proteins, we have constructed a library composed of 1087 KIAA cDNA clones |
| GO:0005515 protein binding | IPI PMID:22117215 Guanylate kinase domains of the MAGUK family scaffold protei... | MARK AS OVER ANNOTATED | Summary: This study showed that a phosphorylated whirlin peptide (pSer685) binds the CASK SH3-GK module, i.e. whirlin is a phospho-dependent ligand of the MAGUK scaffold CASK. Reason: The interaction is real and mechanistically interesting (phosphorylation-dependent CASK binding), but in this study whirlin is the target peptide of CASK's GK domain rather than exercising its own scaffold function, and the bare 'protein binding' term conveys no function. Not wrong, but uninformative. Supporting Evidence: PMID:22117215 we predicted a possible CASK SH3-GK-binding peptide sequence of whirlin, which is a reported binding target of CASK |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary interactions detected for WHRN in the systematic human reference interactome (HuRI) yeast two-hybrid map; high-throughput evidence without functional characterization. Reason: Proteome-scale Y2H interactions (11 GOA lines from this reference) are unvalidated individually and the term 'protein binding' is uninformative; whirlin's informative molecular function is as a PDZ scaffold/adaptor within the USH2 and tip complexes. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MARK AS OVER ANNOTATED | Summary: Quantitative fragmentomics/holdup affinity profiling of PDZ-domain-mediated interactions; hundreds of GOA lines (over 400 partner pairs) derive from this single high-throughput affinity-mapping study. Reason: In vitro affinity measurements between isolated PDZ domains and peptide motifs demonstrate binding capability, not physiological interaction; the sheer number of partners annotated from this one paper illustrates why bare 'protein binding' over-annotates. Whirlin's real function is selective scaffolding within specific sensory-cell complexes. |
| GO:0042802 identical protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | ACCEPT | Summary: Whirlin self-association. UniProt records that whirlin forms homooligomers, and self-association/multivalency of whirlin is mechanistically required for the phase-separation-mediated assembly of both the tip complex and the ankle-link condensate. Reason: Unlike generic protein binding, self-association is a specific, mechanistically important property of whirlin - deafness mutations (e.g. A64D, R223H) that impair whirlin self-association compromise condensate scaffold assembly (Wang et al. 2023, Nat Commun; see deep research). The IPI evidence from affinity mapping is consistent with this documented property. Supporting Evidence: file:human/WHRN/WHRN-deep-research-falcon.md WHRN A64D and R223H retained partner binding but impaired WHRN self-association and LLPS, showing that dimerization/oligomerization contributes independently to scaffold function. |
| GO:0001895 retina homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse of whirlin's requirement for photoreceptor maintenance; loss of long-isoform whirlin causes progressive retinal degeneration (retinitis pigmentosa in USH2D patients, slow retinal degeneration in Whrn mutant mice). Reason: Concordant with the human IMP annotation from USH2D patients (PMID:17171570) and mouse Whrn mutant retinal phenotypes; whirlin's periciliary scaffold role supports photoreceptor survival. Supporting Evidence: PMID:17171570 characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP) |
| GO:0002141 stereocilia ankle link | IEA GO_REF:0000107 | MODIFY | Summary: Electronic transfer placing whirlin at the stereocilia ankle link. The ankle link itself is the extracellular fibrous filament formed by the ectodomains of USH2A and ADGRV1; whirlin is the intracellular scaffold of the ankle-link complex that anchors these links at the stereocilia base. Reason: Whirlin is a cytoplasmic protein and is not a component of the extracellular link filament itself; its location/membership is more accurately described by GO:0002142 (stereocilia ankle link complex), which is already among its annotations. The biology (ankle-region localization) is sound; the term choice is imprecise. Proposed replacements: stereocilia ankle link complex 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:0002142 stereocilia ankle link complex | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of ankle-link complex membership from mouse; duplicates the IBA annotation and is well supported by direct biochemistry (WHRN-PDZD7-USH2A-ADGRV1 quaternary complex). Reason: Core complex membership of the long whirlin isoform, supported by PMID:25406310 and mouse localization studies. Supporting Evidence: PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. |
| GO:0005884 actin filament | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer placing whirlin on actin filaments. Whirlin acts within the actin-filled stereocilium and its tip complex promotes actin bundling via EPS8, but whirlin is not itself an actin-filament-bound structural component. Reason: Whirlin localizes to actin-rich stereocilia (tips and base) via MYO15A transport and membrane-protein anchoring, not by decorating actin filaments; the localization intent is better captured by the stereocilium, stereocilium tip and ankle-link complex terms already present. Likely an over-propagated Ensembl transfer. |
| GO:0005929 cilium | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of ciliary localization, matching the IBA annotation; reflects whirlin at the photoreceptor connecting cilium and ciliary axoneme. Reason: Consistent with co-localization of whirlin, USH2A and VLGR1b at the connecting cilium (PMID:16434480) and with MPP1-whirlin co-localization at basal bodies and ciliary axoneme (PMID:17584769). Supporting Evidence: PMID:17584769 MPP1 and whirlin colocalize in the retina at the OLM, at the outer synaptic layer and at the basal bodies and the ciliary axoneme. |
| GO:0021694 cerebellar Purkinje cell layer formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of a mouse phenotype-derived annotation; whirlin is expressed in the developing brain, but a cerebellar developmental role is peripheral to its established sensory functions and has no support in the cached human-relevant literature. Reason: Cannot be verified from cached publications, but embryonic brain expression of whirlin is documented (PMID:16434480) and the mouse-derived annotation plausibly reflects a minor neuronal role; clearly non-core relative to hair-cell and photoreceptor scaffolding. Supporting Evidence: PMID:16434480 in embryonic development, the gene is not only expressed in the inner ear, but also in the developing brain and the retina |
| GO:0032391 photoreceptor connecting cilium | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of whirlin localization at/adjacent to the photoreceptor connecting cilium, where it scaffolds the USH2 proteins of the periciliary membrane complex. Reason: Directly supported by co-localization of whirlin with USH2A and Vlgr1b at the connecting cilium (PMID:16434480); core to whirlin's retinal role. Supporting Evidence: PMID:16434480 we demonstrate that 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:0032421 stereocilium bundle | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of hair-bundle localization; whirlin acts at two sites within the stereocilium bundle (tips and ankle region) during bundle development and maintenance. Reason: Correct and consistent with the extensive mouse localization literature and with the more specific stereocilium tip/ankle-link annotations. 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:0032426 stereocilium tip | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of stereocilium tip localization, duplicating the IBA annotation; the short whirlin isoform forms the MYO15A-EPS8-whirlin elongation complex at stereocilia tips. Reason: Core localization for whirlin's stereocilia elongation function; well supported experimentally. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia |
| GO:0036064 ciliary basal body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer of basal body localization; MPP1 and whirlin co-localize at photoreceptor basal bodies and the ciliary axoneme. Reason: Experimentally grounded in retinal co-localization data (PMID:17584769), but a secondary site relative to whirlin's principal periciliary membrane and stereociliary scaffold locations. Supporting Evidence: PMID:17584769 MPP1 and whirlin colocalize in the retina at the OLM, at the outer synaptic layer and at the basal bodies and the ciliary axoneme. |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of whirlin self-association; whirlin forms homooligomers and self-association is required for its condensate-forming scaffold activity. Reason: Consistent with the IPI annotation and with UniProt (forms homooligomers); whirlin multivalent self-interaction underlies phase-separation-mediated assembly of the tip and ankle-link complexes. |
| GO:0050910 detection of mechanical stimulus involved in sensory perception of sound | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer implying a role in the mechanotransduction (detection) step itself. Whirlin builds and maintains the stereocilia architecture that makes mechanotransduction possible, but it is not an established component of the transduction apparatus. Reason: Whirlin acts upstream of stimulus detection, via stereocilium organization and elongation (GO:0060088/GO:0060122) - losing whirlin degrades hearing because bundles are malformed, not because a detection molecule is absent. 'Sensory perception of sound' plus the stereocilium organization terms capture the biology; the detection term likely over-interprets the mouse phenotype. |
| GO:0060122 inner ear receptor cell stereocilium organization | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of the core process annotation covering both cochlear and vestibular hair-cell stereocilium organization; whirlin is required for stereocilia elongation and bundle cohesion in both organs. Reason: Core function; whirler mice show stereocilia defects in cochlear and vestibular hair cells, and whirlin is essential for stereocilia elongation (PMID:16434480). Supporting Evidence: PMID:16434480 Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear |
| GO:1990075 periciliary membrane compartment | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of whirlin localization to the photoreceptor periciliary membrane complex, the specialized inner-segment membrane domain surrounding the connecting cilium where whirlin anchors USH2A and ADGRV1. Reason: Core retinal localization; whirlin recruits USH2A and GPR98/ADGRV1 to the periciliary membrane complex and its loss destabilizes them (PMID:25406310). Supporting Evidence: PMID:25406310 WHRN is able to recruit USH2A and GPR98 to the periciliary membrane complex |
| GO:1990227 paranodal junction maintenance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of a mouse finding that whirlin contributes to paranodal organization in myelinated axons (Whrn-deficient mice show paranodal decompaction and axonal swellings, with largely preserved nerve conduction). Reason: Reflects a documented but peripheral cytoskeletal-linker role in mouse myelinated neurons (see deep research citing James Green 2013 thesis work); no human phenotype is attributed to this function, and it is clearly non-core relative to the sensory roles. Supporting Evidence: file:human/WHRN/WHRN-deep-research-falcon.md Whrn-deficient mice exhibit paranodal decompaction, cytoskeletal disruption, and axonal swellings from two weeks to one year of age, suggesting a broader cytoskeletal-linker role. |
| GO:1990696 USH2 complex | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic transfer of USH2 complex membership; whirlin is one of the four components of the quaternary USH2 complex (USH2A, ADGRV1/GPR98, WHRN, PDZD7), in which WHRN preferentially binds USH2A and bridges to ADGRV1 via PDZD7. Reason: Core complex membership demonstrated by systematic interaction analysis (PMID:25406310) and underlying USH2D disease biology. Supporting Evidence: PMID:25406310 In this USH2 quaternary complex, WHRN prefers to bind to USH2A, whereas PDZD7 prefers to bind to GPR98. Interaction between WHRN and PDZD7 is the bridge between USH2A and GPR98. |
| GO:0001917 photoreceptor inner segment | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-judged sequence-similarity transfer (from mouse Whrn) of inner-segment localization; the periciliary membrane complex sits at the inner segment apex. Reason: Well supported by mouse photoreceptor localization data; concordant with the periciliary membrane compartment annotations. Supporting Evidence: PMID:25406310 In photoreceptors, USH2A, GPR98, and WHRN proteins are colocalized at the periciliary membrane complex of the inner segment apex and immediately below the outer segment |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of general cytoplasmic localization; correct for this soluble scaffold protein but uninformative. Reason: Correct but very general; the functionally relevant subcellular locations are annotated more specifically elsewhere in this set. |
| GO:0045202 synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of synaptic localization, grounded in co-localization of whirlin with USH2A/VLGR1b at photoreceptor and outer hair cell synapses. Reason: Experimentally grounded (PMID:16434480) but secondary to the stereociliary and periciliary scaffold roles; functional significance at the synapse remains unclear. 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:0060113 inner ear receptor cell differentiation | NAS PMID:25406310 Whirlin and PDZ domain-containing 7 (PDZD7) proteins are bot... | MODIFY | Summary: NAS annotation from the USH2 quaternary complex paper, which states (citing prior work) that the four USH2 genes are important for hair cell development. Whirlin's contribution to hair-cell development is specifically through stereocilium bundle morphogenesis rather than cell differentiation per se. Reason: The underlying biology is whirlin-dependent stereocilium organization/elongation during hair-bundle development; 'inner ear receptor cell differentiation' is broader than the evidence supports (whirler hair cells differentiate but form defective bundles). GO:0060122 (inner ear receptor cell stereocilium organization) captures the same developmental role more precisely and is already experimentally supported. Proposed replacements: inner ear receptor cell stereocilium organization Supporting Evidence: PMID:25406310 the four USH genes, USH2A , GPR98 , WHRN , and PDZD7 , are believed to be important for hair cell development and photoreceptor survival |
| GO:0002141 stereocilia ankle link | ISS GO_REF:0000024 | MODIFY | Summary: Sequence-similarity transfer asserting whirlin is part of the ankle link. The link filament itself is extracellular (USH2A/ADGRV1 ectodomains); whirlin is part of the intracellular ankle-link complex anchoring it. Reason: As for the IEA to the same term - whirlin belongs in GO:0002142 (stereocilia ankle link complex), not the extracellular link structure itself; part_of the link filament is anatomically imprecise for a cytoplasmic scaffold. Proposed replacements: stereocilia ankle link complex |
| GO:0032426 stereocilium tip | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of stereocilium tip localization from mouse, where whirlin forms the tip elongation complex with MYO15A and EPS8. Reason: Core localization for the stereocilia elongation function; extensively validated in mouse and consistent with human WHRN interactions (CIB2 at tips). Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia |
| GO:0045184 establishment of protein localization | ISS GO_REF:0000024 | MODIFY | Summary: Sequence-similarity transfer reflecting that whirlin is required to localize its USH2 partners - it recruits USH2A and ADGRV1/GPR98 to the periciliary membrane complex and is mutually required for ankle-link complex localization. Reason: The biology is sound but the term is extremely general. Whirlin's documented role is recruiting/retaining USH2A and ADGRV1 at specific plasma-membrane domains (periciliary membrane, ankle-link region); GO:0072659 (protein localization to plasma membrane) states this more informatively. Proposed replacements: protein localization to plasma membrane Supporting Evidence: PMID:25406310 WHRN is able to recruit USH2A and GPR98 to the periciliary membrane complex |
| GO:1990075 periciliary membrane compartment | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of periciliary membrane complex localization from mouse photoreceptor studies. Reason: Core retinal localization of full-length/long whirlin; well supported (PMID:25406310, PMID:16434480 connecting-cilium region co-localization). Supporting Evidence: PMID:25406310 In photoreceptors, USH2A, GPR98, and WHRN proteins are colocalized at the periciliary membrane complex of the inner segment apex and immediately below the outer segment |
| GO:0002141 stereocilia ankle link | ISS GO_REF:0000024 | MODIFY | Summary: Sequence-similarity transfer placing whirlin at the ankle link; as above, whirlin resides in the cytoplasmic ankle-link complex rather than the extracellular link fiber. Reason: Same rationale as the other GO:0002141 entries - the precise and already-annotated term for whirlin is GO:0002142 (stereocilia ankle link complex). Proposed replacements: stereocilia ankle link complex |
| GO:0032426 stereocilium tip | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of tip localization (duplicate of the part_of ISS and IBA/IEA entries). Reason: Core localization; well supported. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia |
| GO:0001917 photoreceptor inner segment | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (colocalizes_with qualifier) of inner-segment localization. Reason: Concordant with mouse localization of whirlin at the periciliary membrane complex at the inner segment apex. Supporting Evidence: PMID:25406310 In photoreceptors, USH2A, GPR98, and WHRN proteins are colocalized at the periciliary membrane complex of the inner segment apex and immediately below the outer segment |
| GO:0002142 stereocilia ankle link complex | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of ankle-link complex membership (duplicate of IBA and IEA entries); core long-isoform complex. Reason: Core complex membership supported by direct biochemistry and localization (PMID:25406310). Supporting Evidence: PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. |
| GO:0005515 protein binding | IPI PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei... | MODIFY | Summary: Direct association of whirlin with USH2A isoform b and VLGR1b (ADGRV1) via PDZ-domain interactions - the founding evidence that whirlin scaffolds the USH2 protein network in cochlea and retina. Reason: The interaction evidence is excellent and functionally central, but the bare 'protein binding' term is uninformative. Whirlin's molecular function here is that of a PDZ scaffold/adaptor tethering the transmembrane proteins USH2A and ADGRV1 into the USH2 complex; GO:0030674 (protein-macromolecule adaptor activity) expresses this. Proposed replacements: protein-macromolecule adaptor activity 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 |
| GO:0032391 photoreceptor connecting cilium | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer (colocalizes_with) of connecting-cilium localization, grounded in co-localization of whirlin with USH2A and Vlgr1b. Reason: Directly consistent with PMID:16434480 co-localization data; core to the retinal periciliary scaffold role. Supporting Evidence: PMID:16434480 we demonstrate that 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:0032420 stereocilium | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of stereocilium localization (both tip and ankle-region pools). Reason: Core localization; extensively supported in mouse hair cells and consistent with the more specific annotations in this set. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of localization in neuronal cell bodies, reflecting whirlin detection in spiral ganglion neurons of the inner ear. Reason: Grounded in the spiral ganglion neuron staining reported by PMID:16434480, but peripheral to the core stereociliary/periciliary scaffold functions. Supporting Evidence: PMID:16434480 we demonstrate that 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:0001895 retina homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the retinal maintenance role; whirlin loss (long isoform) causes progressive retinal degeneration in humans (USH2D) and mice. Reason: Concordant with human IMP evidence (PMID:17171570) and mouse Whrn mutant retinal phenotypes; whirlin's periciliary USH2 scaffold supports long-term photoreceptor health. Supporting Evidence: PMID:17171570 characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP) |
| GO:0050910 detection of mechanical stimulus involved in sensory perception of sound | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Sequence-similarity transfer implying participation in the auditory mechanotransduction step; whirlin's role is to build/maintain the stereocilia bundle upstream of transduction. Reason: Same rationale as the IEA to this term - whirlin enables hearing through stereocilium organization and elongation, and is not an established component of the mechanotransduction machinery itself; the sensory perception of sound and stereocilium organization annotations capture the biology. |
| GO:1990696 USH2 complex | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of USH2 complex membership (duplicate of the IEA); whirlin is an obligatory member of the quaternary USH2 complex. Reason: Core complex membership; both WHRN and PDZD7 are required for the quaternary complex with USH2A and GPR98/ADGRV1 (PMID:25406310). Supporting Evidence: PMID:25406310 Importantly, both WHRN and PDZD7 are required for the complex formation with USH2A and GPR98. |
| GO:0005515 protein binding | IPI PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei... | MARK AS OVER ANNOTATED | Summary: Targeted co-immunoprecipitation showing that CIB2 (mutated in USH1J/DFNB48) interacts with whirlin at stereocilia tips, placing whirlin in the wider Usher interactome; whirlin is not required for CIB2 tip localization in vivo. Reason: The interaction is real and links whirlin to Ca2+-regulatory machinery at stereocilia tips, but 'protein binding' itself is uninformative and the functional consequence of the whirlin-CIB2 interaction is not established (whirlin loss does not mislocalize CIB2). Retained as documented interaction evidence rather than a core molecular function. Supporting Evidence: PMID:23023331 We show that CIB2 can multimerize and interacts with whirlin, which is localized at the tips of stereocilia PMID:23023331 in vivo, myosin VIIa and whirlin are not required for localization of CIB2 in mouse inner ear hair cell stereocilia |
| GO:0005515 protein binding | IPI PMID:17584769 MPP1 links the Usher protein network and the Crumbs protein ... | MODIFY | Summary: Targeted study showing strong, direct interaction of whirlin with MPP1/p55 via both a PDZ-to-PBM mechanism and internal epitopes, linking the Usher protein network to the Crumbs polarity complex in the retina. Reason: Well-characterized direct interaction in which whirlin acts as the multi-PDZ scaffold connecting protein networks at the retinal outer limiting membrane; the bare 'protein binding' term undersells this. GO:0030674 (protein-macromolecule adaptor activity) better represents whirlin's molecular function in this interaction. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:17584769 We demonstrate that both proteins interact strongly by both a classical PDZ domain-to-PDZ binding motif (PBM) mechanism, and a mechanism involving internal epitopes. |
| GO:0060122 inner ear receptor cell stereocilium organization | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the core stereocilium organization role covering cochlear and vestibular hair cells (duplicate of the IEA entry). Reason: Core function; whirlin is essential for stereocilia elongation and bundle organization in inner ear hair cells. Supporting Evidence: PMID:16434480 Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear |
| GO:0001895 retina homeostasis | IMP PMID:17171570 A novel gene for Usher syndrome type 2: mutations in the lon... | ACCEPT | Summary: Human IMP from USH2D patients - compound heterozygous mutations affecting the long whirlin isoform cause progressive retinitis pigmentosa, demonstrating that long-isoform whirlin is required for retinal (photoreceptor) maintenance in humans. Reason: Direct human genetic evidence; the long isoform scaffolds the periciliary USH2 complex whose loss leads to progressive photoreceptor degeneration. Human patient-based IMP is appropriate evidence for this wild-type maintenance function. Supporting Evidence: PMID:17171570 While mutations in the C-terminal half of whirlin have previously been reported in non-syndromic deafness (DFNB31), both alterations identified in our USH2 family affect the long protein isoform. PMID:17171570 We propose that mutations causing Usher syndrome are probably restricted to exons 1-6 that are specific for the long isoform and probably crucial for retinal function. |
| GO:0005737 cytoplasm | IDA PMID:16434480 The DFNB31 gene product whirlin connects to the Usher protei... | KEEP AS NON CORE | Summary: Direct assay evidence of cytoplasmic localization from the whirlin/USH2A/VLGR1 study (cached record is abstract-only; the full text presumably shows cytoplasmic distribution in expression or tissue staining experiments). Reason: Whirlin is indeed a cytoplasmic protein and the curator read the full text; however the term is uninformative relative to whirlin's specific sites of action (stereocilium tip, ankle-link region, periciliary membrane), so it is kept as a non-core general localization. |
| GO:0007605 sensory perception of sound | IMP PMID:17171570 A novel gene for Usher syndrome type 2: mutations in the lon... | ACCEPT | Summary: Human IMP - WHRN mutations in a German USH2 family cause sensorineural hearing loss (with RP), directly demonstrating whirlin's requirement for human hearing. Reason: Core function established by human genetics (both DFNB31 nonsyndromic deafness and USH2D include sensorineural hearing loss); patient-based IMP is sound evidence for the wild-type role in audition. Supporting Evidence: PMID:17171570 We describe a novel genetic subtype for Usher syndrome, which we named USH2D and which is caused by mutations in whirlin. |
| GO:0050953 sensory perception of light stimulus | IMP PMID:17171570 A novel gene for Usher syndrome type 2: mutations in the lon... | ACCEPT | Summary: Human IMP - USH2D patients with long-isoform whirlin mutations develop retinitis pigmentosa with progressive visual impairment, demonstrating the requirement of (long-isoform) whirlin for vision. Reason: Direct human genetic evidence that whirlin is needed for visual function; mechanistically explained by its periciliary USH2 scaffold role in photoreceptors. Core for the long isoform. Supporting Evidence: PMID:17171570 characterized by sensorineural hearing loss, variable vestibular dysfunction, and visual impairment due to retinitis pigmentosa (RP) |
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