USH1C

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0060122 inner ear receptor cell stereocilium organization	IBA GO_REF:0000033	ACCEPT	Summary: Harmonin is required for normal development and organization of hair-cell stereociliary bundles; harmonin-deficient mice have disorganized bundles and the protein is expressed specifically in inner ear sensory hair cells [PMID:10973247]. Reason: This is a core function of harmonin. The founding paper showed hair-cell-specific expression in the inner ear and identified USH1C mutations in deaf USH1C patients [PMID:10973247], and mouse models (deaf circler) show abnormal hair-bundle morphology when harmonin is lost (summarized in the deep research). The IBA is seeded from mouse Ush1c and PANTHER node PTN002750520 and is phylogenetically sound. Supporting Evidence: PMID:10973247 We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-deficient or isoform-disrupted mouse hair cells exhibit abnormal bundle morphology and altered MET currents/adaptation.
GO:0005929 cilium	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Harmonin's principal sites of action are actin-based protrusions (stereocilia, microvilli), which are not cilia; however, harmonin has been reported in the photoreceptor ciliary/periciliary region and harmonin-a1 can rescue a primary-cilium phenotype in USH1C patient fibroblasts. Reason: Stereocilia are actin-based and are not cilia in the GO sense, so this term does not capture harmonin's main sites of action. There is nonetheless genuine evidence connecting harmonin to ciliary biology in photoreceptors and patient fibroblasts (deep research: harmonin-a1 delivery reversed a primary-cilium phenotype in patient-derived fibroblasts), and the PAINT donors include mouse, rat and whirlin-family members with ciliary localization. Keep, but as a non-core, secondary localization rather than a core site of harmonin action. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md showed that harmonin-a1 delivery could reverse a primary-cilium phenotype in patient-derived fibroblasts.
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Harmonin is a cytoplasmic peripheral scaffold that acts immediately beneath the plasma membrane, anchoring the cytoplasmic tails of transmembrane cadherins (CDH23, CDHR2/CDHR5, USH2A, ADGRV1) to the actin cytoskeleton. Reason: Not wrong - harmonin genuinely works at the membrane-cytoskeleton interface, binding transmembrane protein tails - but 'plasma membrane' is very general for a submembranous scaffold, and its functional sites are much better captured by the specific terms already annotated (stereocilium tip, microvillus, brush border, stereocilia ankle link complex). Keep as a correct but non-core, coarse-grained localization. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-b is concentrated at the upper tip-link density of stereocilia, immediately below the plasma membrane where CDH23 enters the taller stereocilium.
GO:0001917 photoreceptor inner segment	IBA GO_REF:0000033	ACCEPT	Summary: Harmonin localizes to photoreceptor compartments including the inner segment; human retinal studies place harmonin in photoreceptors (inner/outer segments, synapses) and Mueller glia. Reason: The retinal localization of harmonin is well documented (rodent immunolocalization transferred by ISS from mouse Q9ES64, and human retina RNA-seq/immunolocalization summarized in the deep research). USH1C patients develop retinitis pigmentosa, consistent with a genuine retinal site of action. Phylogenetically reasonable IBA seeded by mouse and rat experimental data. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Protein was detected in rod outer segments, cone presynaptic pedicles, Müller-glial endfeet and apical microvilli, and Müller-glia–photoreceptor adhesive junctions at the outer limiting membrane
GO:0002142 stereocilia ankle link complex	IBA GO_REF:0000033	ACCEPT	Summary: During hair-bundle development harmonin associates with the transient ankle-link (USH2) complex at the stereocilium base, binding the cytoplasmic tails of usherin (USH2A) and ADGRV1 and bridging the USH1 and USH2 protein networks. Reason: Harmonin is unusual in belonging to both hair-cell scaffolding complexes: the upper tip-link density of mature stereocilia and the transient ankle-link/USH2 complex of developing bundles (with USH2A, ADGRV1, whirlin, PDZD7). Its PDZ1 binds the C-terminal PDZ-binding motifs of USH2A and ADGRV1 (Reiners 2005), and UniProt records the USH2A interaction. The IBA is seeded from mouse experimental annotations and is phylogenetically sound. Accepted as a bona fide, developmentally transient complex membership. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin PDZ1 recognizes C-terminal motifs in usherin/USH2A and ADGRV1, providing a physical bridge between USH1 and USH2 networks.
GO:0032426 stereocilium tip	IBA GO_REF:0000033	ACCEPT	Summary: Harmonin-b concentrates at the upper tip-link density, immediately below the point where the CDH23 tip link inserts near the tip of the taller stereocilium, anchoring the tip-link apparatus to the actin core. Reason: Core localization for the hearing function: the UTLD sits at/near the stereocilium tip of the taller row, and harmonin-b is one of its defining components together with MYO7A and SANS. IBA propagated from mouse and rat experimental data; consistent with UniProt ('Detected at the tip of cochlear hair cell stereocilia'). Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-b is concentrated at the upper tip-link density of stereocilia, immediately below the plasma membrane where CDH23 enters the taller stereocilium. There it forms part of a CDH23–harmonin–SANS–MYO7A assembly that anchors mechanically loaded tip links to the actin core.
GO:0007605 sensory perception of sound	IBA GO_REF:0000033	ACCEPT	Summary: USH1C mutations cause congenital profound sensorineural deafness (Usher syndrome type 1C and DFNB18), and harmonin is an essential scaffold of the hair-cell mechanotransduction apparatus. Reason: Core process. Human genetics (USH1C patients are congenitally profoundly deaf [PMID:10973247]) and mouse models both support an essential role in hearing. The IBA correctly includes the human gene's own experimental annotation among its sources, marking direct experimental grounding on the target. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: A soluble cytosolic pool of harmonin exists (UniProt SubCell mapping, ultimately from PMID:20142502), but harmonin functions when docked at actin-rich apical structures, not free in the cytosol. Reason: The annotation is mechanically mapped from the UniProt subcellular location 'Cytoplasm, cytosol'. It is not incorrect - unassembled harmonin is cytosolic - but the functionally relevant locations are the stereocilium, microvillus and brush border. Keep as a real but non-core location.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: Harmonin associates with the actin cytoskeleton; long harmonin-b isoforms bind F-actin directly and the protein couples cadherin complexes to actin filaments in stereocilia and microvilli. Reason: Correct though general; IEA terms may legitimately be broader than the literature-supported specific locations. The actin-cytoskeleton association is central to harmonin function (UniProt: 'Interacts with F-actin'; colocalizes with F-actin), so this broad location is acceptable. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Actin-cytoskeleton coupling: recruitment of MYO7A/MYO7B and direct actin association by long harmonin-b isoforms.
GO:0005902 microvillus	IEA GO_REF:0000120	ACCEPT	Summary: Harmonin is enriched at the distal tips of enterocyte brush border microvilli as a core component of the intermicrovillar adhesion complex (IMAC). Reason: Core location, independently established by direct experiments in this GOA set (IDA from PMID:24725409 and PMID:32209652). The ARBA electronic inference agrees with the experimental data. Supporting Evidence: PMID:32209652 Confocal imaging of rat BBs stained for USH1C revealed marked enrichment of this scaffold at the distal tips of microvilli, the normal site of IMAC function
GO:0005903 brush border	IEA GO_REF:0000117	ACCEPT	Summary: Harmonin is a resident of the enterocyte brush border, where it scaffolds the intermicrovillar adhesion complex at microvillar tips. Reason: Core location, corroborated by IDA annotations from proteomic and imaging studies of the enterocyte brush border (PMID:21330445, PMID:24725409). The electronic inference is consistent with experiment. Supporting Evidence: PMID:21330445 All three probes produced striking punctate staining at the apical surface, representative of microvillar labeling
GO:0007605 sensory perception of sound	IEA GO_REF:0000117	ACCEPT	Summary: Electronic (ARBA) annotation duplicating the well-supported role of harmonin in hearing; USH1C loss causes congenital profound deafness. Reason: Core process, supported independently by human genetics (IMP) and phylogenetic inference (IBA) in this annotation set. Duplication across evidence codes is acceptable. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:0050885 neuromuscular process controlling balance	IEA GO_REF:0000117	MODIFY	Summary: USH1C patients have vestibular dysfunction/areflexia because harmonin is required for vestibular hair-cell mechanotransduction; the balance defect is sensory (vestibular), not neuromuscular. Reason: The underlying biology is real - loss of harmonin abolishes vestibular function - but 'neuromuscular process controlling balance' mischaracterizes the mechanism: the defect is in vestibular hair-cell sensory transduction, not in a neuromuscular process. GO:0050957 'equilibrioception' (already annotated by IMP from PMID:10973247) is the accurate term. Recommend the ARBA mapping be replaced by equilibrioception. Proposed replacements: equilibrioception Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:1904106 protein localization to microvillus	IEA GO_REF:0000117	ACCEPT	Summary: Harmonin recruits its IMAC partners (CDHR2, CDHR5, MYO7B, ANKS4B) to microvillar tips; in its absence microvillar protocadherins are mislocalized. Reason: Core process for the intestinal role, directly demonstrated by IMP annotations from PMID:24725409 and PMID:26812018 in this set. The electronic inference agrees with experiment. Supporting Evidence: PMID:24725409 The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips.
GO:1904970 brush border assembly	IEA GO_REF:0000117	ACCEPT	Summary: Harmonin is essential for protocadherin-based intermicrovillar adhesion that drives assembly of the enterocyte brush border; harmonin-deficient mice show severe brush border defects. Reason: Core process, directly demonstrated (IMP, PMID:24725409; IDA, PMID:32209652) in this annotation set; the electronic inference is consistent. Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:0005515 protein binding	IPI PMID:20142502 The structure of the harmonin/sans complex reveals an unexpe...	MODIFY	Summary: Crystallographic/biophysical study showing that the harmonin N-domain-PDZ1 supramodule binds the SANS (USH1G) SAM domain and PDZ-binding motif, locking the two Usher scaffolds into a highly stable complex. Reason: The interaction is real, specific and mechanistically characterized, but bare 'protein binding' is uninformative. The paper demonstrates harmonin acting as a scaffold that stably tethers SANS within the USH1 protein network - this is better captured by GO:0030674 protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:20142502 We further show that the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ binding-motif interactions, between harmonin and Sans, lock the two scaffold proteins into a highly stable complex.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: High-throughput yeast two-hybrid human interactome map (HuRI pipeline) reporting USH1C interactions with RAC1, MIPOL1 and CTNNAL1. Reason: Proteome-scale Y2H screening evidence; the partners reported here (RAC1, MIPOL1, CTNNAL1) are unvalidated in a physiological context and 'protein binding' conveys no functional information. Not wrong as a binary interaction record, but an over-annotation as a molecular function of harmonin; harmonin's informative binding activities are captured elsewhere (adaptor activity toward USH1G/ANKS4B/MYO7B, spectrin binding).
GO:0005515 protein binding	IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam...	MARK AS OVER ANNOTATED	Summary: High-throughput variant-interaction pipeline confirming the USH1C-USH1G (SANS) interaction. Reason: The USH1G interaction itself is genuine and central to harmonin biology, but it is far better represented by the structurally characterized adaptor relationship (PMID:20142502) than by bare 'protein binding' from a massively-parallel cloning/interaction pipeline. Uninformative MF term; keep the interaction record but do not treat this as a core annotation.
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	MARK AS OVER ANNOTATED	Summary: High-throughput organelle-scale interaction landscape study reporting the USH1C-USH1G interaction. Reason: High-throughput interaction evidence for a partner (USH1G) already established by focused structural work; bare 'protein binding' is uninformative as a molecular function. Not a core annotation.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput human interactome (BioPlex-style community mapping) reporting the USH1C-USH1G interaction. Reason: High-throughput interaction evidence duplicating the well-established USH1G partnership; bare 'protein binding' is uninformative as a molecular function. Not a core annotation.
GO:0005515 protein binding	IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec...	MARK AS OVER ANNOTATED	Summary: LuTHy two-hybrid methods paper using the harmonin-SANS (USH1C-USH1G) pair as a benchmark interaction. Reason: Methods-development study quantitatively re-measuring an already established interaction (USH1G); bare 'protein binding' adds no functional information beyond the adaptor-activity characterization from PMID:20142502. Not a core annotation.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Population-variant interaction-disruption screen reporting the USH1C-USH1G interaction. Reason: High-throughput interaction evidence duplicating the established USH1G partnership; bare 'protein binding' is uninformative as a molecular function. Not a core annotation.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Neurodegenerative-disease interactome mapping study reporting the USH1C-USH1G interaction. Reason: High-throughput interactome evidence duplicating the established USH1G partnership; bare 'protein binding' is uninformative as a molecular function. Not a core annotation. (Cached record is abstract-only, but the annotation is an IntAct binary-interaction import, not a functional claim.)
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Dual proteome-scale interactome study (OpenCell/dual-network style) reporting the USH1C-USH1G interaction. Reason: High-throughput interaction evidence duplicating the established USH1G partnership; bare 'protein binding' is uninformative as a molecular function. Not a core annotation.
GO:0005515 protein binding	IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac...	MARK AS OVER ANNOTATED	Summary: Quantitative fragmentomics (holdup assay) affinity-mapping of PDZ-domain interactomes; harmonin's PDZ domains were profiled against large motif libraries, yielding dozens of binary partners (including viral E6 oncoproteins, channels, and junctional PDZ proteins). Reason: This in vitro affinity mapping usefully defines the binding specificity of harmonin's PDZ domains, but the ~50 resulting 'protein binding' GOA lines are in vitro motif-affinity measurements, most without in vivo validation, and the term conveys no functional information. Mark as over-annotation; harmonin's physiologically informative binding activities are captured by the adaptor activity, spectrin binding, and complex-assembly annotations.
GO:0005829 cytosol	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Human Protein Atlas immunofluorescence in cultured cell lines detects a cytosolic pool of harmonin. Reason: HPA immunofluorescence in generic cell lines reports where the unassembled protein sits, and a cytosolic pool is expected for a peripheral scaffold; but harmonin's functional locations are apical actin-based specializations (stereocilia, microvilli). Keep as a real but non-core location.
GO:0005902 microvillus	IDA PMID:32209652 The small EF-hand protein CALML4 functions as a critical myo...	ACCEPT	Summary: Direct immunolocalization of USH1C at the distal tips of brush border microvilli in native intestinal tissue and polarized CACO-2 BBE cells, as part of the intermicrovillar adhesion complex. Reason: Core location, directly demonstrated by confocal imaging of isolated brush borders in this paper and consistent with PMID:24725409. Supporting Evidence: PMID:32209652 Confocal imaging of rat BBs stained for USH1C revealed marked enrichment of this scaffold at the distal tips of microvilli, the normal site of IMAC function
GO:1904970 brush border assembly	IDA PMID:32209652 The small EF-hand protein CALML4 functions as a critical myo...	ACCEPT	Summary: The CALML4 study confirms USH1C as a core IMAC scaffold whose apical targeting is required for organized brush border assembly; USH1C is shared between the IMAC and the Usher complex. Reason: Core process. The paper directly assays IMAC integrity and shows USH1C at the distal tips of microvilli where the complex drives microvillar packing; complements the loss-of-function evidence in PMID:24725409. Supporting Evidence: PMID:32209652 Importantly, the USH1C scaffold is shared genetically between the IMAC and Usher complex, although different splice isoforms are utilized between these two complexes
GO:0001750 photoreceptor outer segment	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse harmonin (Q9ES64); human retinal studies subsequently detected harmonin protein in rod outer segments. Reason: The ISS transfer is corroborated by direct human-retina work (Nagel-Wolfrum et al. 2023, summarized in the deep research) placing harmonin in rod outer segments with an experimentally supported rhodopsin interaction. Genuine retinal localization relevant to the retinitis pigmentosa phenotype. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Protein was detected in rod outer segments, cone presynaptic pedicles, Müller-glial endfeet and apical microvilli, and Müller-glia–photoreceptor adhesive junctions at the outer limiting membrane
GO:0001917 photoreceptor inner segment	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse harmonin; harmonin is present in photoreceptor inner segments, consistent with rodent immunolocalization and human retina studies. Reason: Consistent with the IBA annotation and with human retinal expression/localization data summarized in the deep research; part of harmonin's genuine retinal distribution. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Protein was detected in rod outer segments, cone presynaptic pedicles, Müller-glial endfeet and apical microvilli, and Müller-glia–photoreceptor adhesive junctions at the outer limiting membrane
GO:0005886 plasma membrane	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse; harmonin is a peripheral, submembranous scaffold anchoring transmembrane cadherin tails to actin, not an integral membrane protein. Reason: As for the IBA plasma membrane annotation: correct at a coarse grain (harmonin works at membrane-cytoskeleton interfaces) but the specific apical-protrusion terms describe its sites of action far better. Keep as non-core.
GO:0030046 parallel actin filament bundle assembly	ISS GO_REF:0000024	ACCEPT	Summary: Long harmonin-b isoforms bind F-actin directly and bundle actin filaments (shown for mouse harmonin b, Boeda et al. 2002); stereocilia and microvilli cores are parallel actin bundles. Reason: Core activity of the b isoform class: direct actin binding/bundling is what lets harmonin-b anchor membrane complexes into the parallel actin core of the stereocilium. Transfer from mouse Q9ES64 is appropriate; the actin association is also recorded by UniProt and the deep research. Supporting Evidence: PMID:12485990 we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments file:human/USH1C/USH1C-deep-research-falcon.md Actin-cytoskeleton coupling: recruitment of MYO7A/MYO7B and direct actin association by long harmonin-b isoforms.
GO:0032420 stereocilium	ISS GO_REF:0000024	ACCEPT	Summary: Harmonin localizes to hair-cell stereocilia (mouse immunolocalization, transferred to human), concentrating at the upper tip-link density of the mature bundle. Reason: Core location for the auditory/vestibular function; abundantly supported by mouse localization data and by the disease genetics. Consistent with the TAS stereocilium annotation and the IBA stereocilium tip annotation. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-b is concentrated at the upper tip-link density of stereocilia, immediately below the plasma membrane where CDH23 enters the taller stereocilium.
GO:0042472 inner ear morphogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Harmonin loss disrupts hair-bundle development; at the organ scale this manifests as abnormal inner ear sensory epithelium morphology in mouse models. Reason: The morphogenesis phenotype is real but is a downstream, organ-level consequence of harmonin's specific role in stereocilium organization (GO:0060122), which is the more precise core annotation. Keep as non-core developmental context.
GO:0042491 inner ear auditory receptor cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Harmonin contributes to hair-cell differentiation insofar as bundle maturation is part of the differentiation program; the specific defect in mutants is stereociliary bundle disorganization. Reason: Broad developmental term; the precise, mechanistically supported process is stereocilium organization. Keep as non-core - harmonin is not a differentiation factor but a structural scaffold whose loss perturbs the final steps of receptor-cell differentiation.
GO:0045202 synapse	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Harmonin has been detected at hair-cell ribbon synapses and photoreceptor synapses (cone pedicles), with proposed modulation of presynaptic CaV1.3 channels. Reason: Genuine but secondary localization: synaptic harmonin is documented in rodent and human retina studies, and effects on CaV1.3 have been proposed, but the scaffold's primary, best-established sites are the stereociliary UTLD and microvillar tips. Keep as non-core. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin has also been detected at inner-hair-cell ribbon synapses, and studies have proposed effects on presynaptic CaV1.3-channel behavior and exocytosis.
GO:0051017 actin filament bundle assembly	ISS GO_REF:0000024	ACCEPT	Summary: Harmonin-b binds and bundles F-actin; this activity underlies the coupling of membrane adhesion complexes to the actin cores of stereocilia and microvilli. Reason: Core activity of the long b isoforms, transferred from mouse where direct bundling was demonstrated. Slightly more general parent of GO:0030046, which is also annotated; both are acceptable. Supporting Evidence: PMID:12485990 we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments file:human/USH1C/USH1C-deep-research-falcon.md Actin-cytoskeleton coupling: recruitment of MYO7A/MYO7B and direct actin association by long harmonin-b isoforms.
GO:0060122 inner ear receptor cell stereocilium organization	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse harmonin, whose loss (deaf circler) produces disorganized stereociliary bundles; duplicate of the IBA annotation. Reason: Core process; the mouse loss-of-function evidence is strong and transfer to human is warranted by the identical patient phenotype. Duplication with the IBA is fine. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-deficient or isoform-disrupted mouse hair cells exhibit abnormal bundle morphology and altered MET currents/adaptation.
GO:1904106 protein localization to microvillus	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse; harmonin recruits IMAC components (CDHR2, CDHR5, MYO7B) to microvillar tips. Reason: Core process for the intestinal role, directly demonstrated in human cell models (IMP annotations from PMID:24725409 and PMID:26812018 in this set); the mouse transfer is consistent. Supporting Evidence: PMID:24725409 The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips.
GO:1904970 brush border assembly	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse harmonin; Ush1c-mutant mice have severe brush border morphology defects. Reason: Core process, demonstrated by mouse knockout and human cell-culture experiments (PMID:24725409). Duplication across ISS/IMP/IDA/IEA is acceptable. Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:0005515 protein binding	IPI PMID:26812018 ANKS4B Is Essential for Intermicrovillar Adhesion Complex Fo...	MODIFY	Summary: Focused biochemical study mapping direct interactions of USH1C with ANKS4B and MYO7B; USH1C binding activates both partners, and only then does the tripartite IMAC cytoplasmic module assemble. Reason: The interactions are direct, specific and hierarchical, with USH1C acting as the activating hub that nucleates the ANKS4B-USH1C-MYO7B module linking protocadherins to actin. This adaptor/scaffold role is far more informative than bare 'protein binding'; propose GO:0030674 protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:26812018 ANKS4B interacts with USH1C and MYO7B, which link protocadherins to the actin cytoskeleton. PMID:26812018 However, a tripartite complex only forms if ANKS4B and MYO7B are first activated by USH1C.
GO:0065003 protein-containing complex assembly	IDA PMID:26812018 ANKS4B Is Essential for Intermicrovillar Adhesion Complex Fo...	ACCEPT	Summary: USH1C sits at the top of the assembly hierarchy of the intermicrovillar adhesion complex: ANKS4B and MYO7B must first be activated by USH1C before the tripartite cytoplasmic module can form. Reason: Directly demonstrated in vitro and in CACO-2 cells; harmonin's regulatory, nucleating role in IMAC assembly is a core function. The term is generic but there is no more specific GO term for IMAC assembly; the specific outcome (brush border assembly) is separately annotated. Supporting Evidence: PMID:26812018 However, a tripartite complex only forms if ANKS4B and MYO7B are first activated by USH1C.
GO:0005515 protein binding	IPI PMID:24725409 Intestinal brush border assembly driven by protocadherin-bas...	MODIFY	Summary: Focused study showing harmonin binds the cytoplasmic domains of the microvillar protocadherins CDHR2/CDHR5 and, with myosin-7b, promotes their localization to microvillar tips. Reason: Harmonin's demonstrated role here is that of an adaptor linking protocadherin tails to the myosin/actin machinery at microvillar tips - much more informative than bare 'protein binding'. Propose GO:0030674 protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:24725409 The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips.
GO:0032532 regulation of microvillus length	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse; as an IMAC scaffold harmonin controls microvillar organization and length during brush border differentiation (UniProt FUNCTION summary). Reason: Consistent with the demonstrated IMAC role: loss of harmonin or its partners produces disorganized microvilli of abnormal length in mouse intestine and CACO-2 models. Part of the core intestinal function. Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:1904106 protein localization to microvillus	IMP PMID:26812018 ANKS4B Is Essential for Intermicrovillar Adhesion Complex Fo...	ACCEPT	Summary: Knockdown experiments show USH1C is required for proper localization of IMAC components to microvillar tips; USH1C activates ANKS4B and MYO7B for complex formation. Reason: Direct loss-of-function evidence in CACO-2 BBE cells from a rigorous focused study; core process for the intestinal role. Supporting Evidence: PMID:26812018 However, a tripartite complex only forms if ANKS4B and MYO7B are first activated by USH1C.
GO:1904970 brush border assembly	IMP PMID:24725409 Intestinal brush border assembly driven by protocadherin-bas...	ACCEPT	Summary: Harmonin-deficient mice (Usher model) show mislocalized microvillar protocadherins and severe brush border morphology defects, demonstrating a requirement for harmonin in brush border assembly. Reason: Direct mutant-phenotype evidence; core process. This paper established the adhesion-based mechanism of brush border assembly and harmonin's essential scaffolding role within it. Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:0005902 microvillus	IDA PMID:24725409 Intestinal brush border assembly driven by protocadherin-bas...	ACCEPT	Summary: Direct localization of harmonin to brush border microvilli (microvillar tips) in intestinal epithelial models. Reason: Core location, directly imaged in this study and corroborated by PMID:32209652 and PMID:21330445. Supporting Evidence: PMID:24725409 The cytoplasmic domains of microvillar protocadherins interact with the scaffolding protein, harmonin, and myosin-7b, which promote localization to microvillar tips.
GO:0005903 brush border	IDA PMID:24725409 Intestinal brush border assembly driven by protocadherin-bas...	ACCEPT	Summary: Direct localization of harmonin to the enterocyte brush border, where it functions in the intermicrovillar adhesion complex. Reason: Core location, directly demonstrated; consistent with brush border proteomics (PMID:21330445) and IMAC studies (PMID:32209652). Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:1904106 protein localization to microvillus	IMP PMID:24725409 Intestinal brush border assembly driven by protocadherin-bas...	ACCEPT	Summary: Loss of harmonin causes mislocalization of the microvillar protocadherins CDHR2/CDHR5, showing harmonin is required for protein targeting to microvilli. Reason: Direct mutant evidence (harmonin-deficient mouse and knockdown models); core process for the intestinal role. Supporting Evidence: PMID:24725409 Finally, a mouse model of Usher syndrome lacking harmonin exhibits microvillar protocadherin mislocalization and severe defects in brush border morphology.
GO:0005903 brush border	IDA PMID:21330445 Proteomic analysis of the enterocyte brush border.	ACCEPT	Summary: Shotgun proteomics of isolated enterocyte brush borders identified harmonin among actin-membrane linking proteins, and immunofluorescence in CACO-2 BBE cells validated apical microvillar staining. Reason: Direct proteomic identification plus antibody validation in a human intestinal epithelial model; core location that presaged the later mechanistic IMAC work. Supporting Evidence: PMID:21330445 All three probes produced striking punctate staining at the apical surface, representative of microvillar labeling
GO:0030507 spectrin binding	IDA PMID:23704327 The giant spectrin βV couples the molecular motors to photot...	KEEP AS NON CORE	Summary: Harmonin was shown to associate with the giant spectrin betaV, which couples USH1 proteins and opsin to molecular motors along the photoreceptor trafficking route. Reason: The interaction is directly reported (abstract states spectrin betaV associates with harmonin), and it is an informative MF term, but it pertains to a secondary role (cargo coupling during photoreceptor protein trafficking) rather than harmonin's core scaffolding functions at stereocilia and microvilli. Cached record is abstract-only; deferring to the curator on assay details. Supporting Evidence: PMID:23704327 We showed that spectrin βV also associates with two USH1 proteins, sans (USH1G) and harmonin (USH1C).
GO:0045494 photoreceptor cell maintenance	IMP PMID:11398101 Mutations of the protocadherin gene PCDH15 cause Usher syndr...	ACCEPT	Summary: USH1C patients develop progressive retinitis pigmentosa, indicating harmonin is required for long-term photoreceptor survival/maintenance. The cited paper, however, reports PCDH15 mutations in USH1F families and mentions USH1C only as background. Reason: The biology is correct and core to the retinal side of USH1C disease: loss of harmonin causes progressive photoreceptor degeneration in patients, and human retina studies localize harmonin to photoreceptors. The specific reference appears misassigned (PMID:11398101 concerns PCDH15/USH1F; USH1C appears only in its introduction), so the annotation is accepted on the strength of the USH1C patient phenotype established in PMID:10973247 and later work; flagged in the reference review rather than removed, since the term itself is clearly correct for this gene. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:0000086 G2/M transition of mitotic cell cycle	IMP PMID:15219944 Expression of AIE-75 PDZ-domain protein induces G2/M cell cy...	MARK AS OVER ANNOTATED	Summary: Ectopic overexpression of AIE-75/harmonin in SW480 colorectal cancer cells (which do not express it) suppressed growth via G2/M arrest with mitotic slippage; PP2A catalytic subunits bound its PDZ domains in yeast two-hybrid. Reason: The assay is forced overexpression in a heterologous cancer cell line that normally lacks the protein; an arrest phenotype under overexpression does not establish that wild-type harmonin functions in the G2/M transition in any physiological context. The annotation also inverts the observation (expression induced arrest, i.e. blocked transition, rather than harmonin being a participant in the transition). No corroborating cell-cycle role for harmonin exists in two decades of subsequent literature, which uniformly characterizes it as an adhesion/cytoskeleton scaffold. The cached record for PMID:15219944 is abstract-only (full text not available), so per curation policy the experimental IMP is not removed outright; it is marked as an over-annotation arising from a non-physiological overexpression experiment. Supporting Evidence: PMID:15219944 Expression of AIE-75 suppressed growth of SW480 cells in vitro in correlation with the expression levels. It was due mainly to G2/M phase cell cycle arrest associated with mitotic slippage, resulting in emergence of hyperploid giant-nucleated or multi-nucleated cells.
GO:0005515 protein binding	IPI PMID:11311560 Interaction of MCC2, a novel homologue of MCC tumor suppress...	MARK AS OVER ANNOTATED	Summary: Yeast two-hybrid identification of MCC2 (USHBP1-related annotation target) as a binder of the first PDZ domain of AIE-75/harmonin via its C-terminal -DTFL motif. Reason: A mapped, direct PDZ1-ligand interaction, but of unknown physiological significance (proposed tumor-suppressor context never developed further), and bare 'protein binding' conveys no function. Keep the interaction record but do not treat as a core functional annotation. Supporting Evidence: PMID:11311560 MCC2 protein binds the first PDZ domain of AIE-75 with its C-terminal amino acids -DTFL.
GO:0005515 protein binding	IPI PMID:16464467 An isoform of GTPase regulator DOCK4 localizes to the stereo...	MARK AS OVER ANNOTATED	Summary: Yeast two-hybrid and biochemical study identifying a DOCK4 isoform (DOCK4-Ex49), a Rac GEF localized along stereocilia, as a harmonin-interacting protein, suggesting a Rac-DOCK4-harmonin pathway in stereociliary actin regulation. Reason: Direct interaction evidence with an interesting but never-confirmed downstream hypothesis; the bare 'protein binding' term is uninformative. Abstract-only cache; deferring to the curator on assay detail, but this binary interaction is not among harmonin's core, well-corroborated functional relationships. Supporting Evidence: PMID:16464467 we have used the yeast two-hybrid assay to isolate molecular partners of harmonin and identified DOCK4, an unconventional guanine exchange factor for the Rho family of guanosine triphosphatases (Rho GEF GTPases), as a protein interacting with harmonin
GO:0005737 cytoplasm	IDA PMID:10209257 Isoforms of the human PDZ-73 protein exhibit differential ti...	KEEP AS NON CORE	Summary: Immunohistochemistry with anti-PDZ-73 (harmonin) monoclonal antibodies showed strong cytoplasmic reactivity in epithelial cells of small intestine, colon and kidney tubules. Reason: Correct direct observation but a very general term; the same staining showed the functionally informative apical enrichment (annotated separately). Keep as a broad, non-core location. Supporting Evidence: PMID:10209257 Immunohistochemical staining with anti-PDZ 73 monoclonal antibodies showed strong cytoplasmic reactivity in epithelial cells of the small intestine, colon and kidney tubules, with a prominent apical staining pattern in cells of the small intestine.
GO:0032420 stereocilium	TAS PMID:16464467 An isoform of GTPase regulator DOCK4 localizes to the stereo...	ACCEPT	Summary: Harmonin's stereociliary localization is stated (traceable to prior mouse work) in the DOCK4 study; this is one of the best-established localizations of the protein. Reason: Core location. Although this particular line is TAS from a paper whose direct imaging concerned DOCK4-Ex49 in stereocilia, harmonin's stereociliary localization is beyond doubt from mouse immunolocalization and the ISS/IBA annotations in this set. Supporting Evidence: PMID:16464467 Mutations in the actin bundling and PDZ domain-containing protein harmonin are the causes of Usher syndrome type 1C (USH1C), a syndrome of congenital deafness and progressive blindness, as well as certain forms of non-syndromic deafness. file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-b is concentrated at the upper tip-link density of stereocilia, immediately below the plasma membrane where CDH23 enters the taller stereocilium.
GO:0045177 apical part of cell	IDA PMID:10209257 Isoforms of the human PDZ-73 protein exhibit differential ti...	ACCEPT	Summary: Immunohistochemistry showed a prominent apical staining pattern for PDZ-73/harmonin in small intestinal epithelial cells, presaging the brush border/microvillar tip localization later defined at higher resolution. Reason: Direct, correct observation of harmonin's apical enrichment in enterocytes - the location where all of its intestinal functions occur. Fully consistent with later brush border and microvillus annotations. Supporting Evidence: PMID:10209257 Immunohistochemical staining with anti-PDZ 73 monoclonal antibodies showed strong cytoplasmic reactivity in epithelial cells of the small intestine, colon and kidney tubules, with a prominent apical staining pattern in cells of the small intestine.
GO:0050957 equilibrioception	IMP PMID:10973247 A defect in harmonin, a PDZ domain-containing protein expres...	ACCEPT	Summary: USH1C patients have congenital vestibular dysfunction/areflexia; harmonin is expressed in vestibular as well as cochlear hair cells and is required for their mechanosensory function. Reason: Core process. Human IMP from the gene-discovery study: patients with USH1C mutations show vestibular dysfunction as a defining feature of USH1. Vestibular hair-cell mechanotransduction uses the same harmonin-scaffolded tip-link machinery as cochlear hair cells. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:0007605 sensory perception of sound	IMP PMID:11398101 Mutations of the protocadherin gene PCDH15 cause Usher syndr...	ACCEPT	Summary: USH1C patients are congenitally profoundly deaf, demonstrating harmonin's requirement for hearing. The cited paper, however, reports PCDH15 mutations in USH1F families; USH1C appears only in its background discussion. Reason: The function is unambiguously correct and core for USH1C - congenital profound deafness is the defining phenotype of USH1C patients (PMID:10973247), and the same term is independently annotated by IBA and IEA. The specific reference appears misassigned (the paper concerns PCDH15/USH1F), which is flagged in the reference review; the annotation itself is retained on the strength of the direct human genetics. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:0050953 sensory perception of light stimulus	IMP PMID:11398101 Mutations of the protocadherin gene PCDH15 cause Usher syndr...	ACCEPT	Summary: USH1C patients develop progressive retinitis pigmentosa and visual loss, demonstrating harmonin's requirement for sustained visual perception. The cited paper is about PCDH15/USH1F; support for USH1C comes from the USH1C gene-discovery literature. Reason: Correct for the gene: blindness due to progressive retinitis pigmentosa is part of the USH1C phenotype (PMID:10973247), and harmonin localizes to human photoreceptors. As with the other two annotations citing PMID:11398101, the reference appears misassigned (flagged in the reference review) but the biological claim stands on the direct USH1C patient genetics. Supporting Evidence: PMID:10973247 Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)
GO:1990435 upper tip-link density	ISS file:human/USH1C/USH1C-deep-research-falcon.md	NEW	Summary: Proposed new annotation refining the existing stereocilium tip (GO:0032426) localization: harmonin-b is a defining component of the upper tip-link density, the electron-dense plaque at the upper insertion point of the CDH23 tip link, where it acts with MYO7A and SANS to anchor the tip link to the actin core. Reason: GO has a precise term for harmonin's principal site of action in mature stereocilia (GO:1990435, a cellular anatomical entity), and mouse immunolocalization consistently places harmonin-b at the UTLD; the existing GOA set stops at the more general stereocilium tip. Transfer to human is warranted on the same basis as the accepted ISS/IBA stereocilium annotations. Supporting Evidence: file:human/USH1C/USH1C-deep-research-falcon.md Harmonin-b is concentrated at the upper tip-link density of stereocilia, immediately below the plasma membrane where CDH23 enters the taller stereocilium. There it forms part of a CDH23–harmonin–SANS–MYO7A assembly that anchors mechanically loaded tip links to the actin core.
GO:0051015 actin filament binding	ISS PMID:12485990 Myosin VIIa, harmonin and cadherin 23, three Usher I gene pr...	NEW	Summary: Proposed new annotation supplying the missing molecular-function companion to the accepted actin-bundle-assembly BP terms: long harmonin-b isoforms bind F-actin directly via their PST region, shown for mouse harmonin-b (Boeda et al. 2002) and recorded by UniProt ('Interacts with F-actin'). Reason: GOA carries the ISS BP annotations GO:0051017 and GO:0030046 (transferred from mouse, where direct binding/bundling was demonstrated) but no corresponding MF term; actin filament binding is the activity that underlies those processes and merits an explicit annotation on the same ISS basis. Supporting Evidence: PMID:12485990 we demonstrate that harmonin b is an F-actin-bundling protein, which is thus likely to anchor cadherin 23 to the stereocilia microfilaments file:human/USH1C/USH1C-deep-research-falcon.md Actin-cytoskeleton coupling: recruitment of MYO7A/MYO7B and direct actin association by long harmonin-b isoforms.

Gene Description

Existing Annotations Review

Core Functions

Adaptor within the transient ankle-link (USH2) complex of developing hair bundles: harmonin PDZ1 binds the C-terminal PDZ-binding motifs of the cytoplasmic tails of usherin (USH2A) and ADGRV1, physically bridging the USH1 and USH2 protein networks during stereociliary bundle development.

Actin filament binding and bundling by the long harmonin-b isoforms, which crosslink filaments of the parallel actin core of stereocilia and thereby couple the membrane-anchored tip-link machinery directly to the actin cytoskeleton during hair-bundle organization.

Scaffolding activity in retinal photoreceptors (principally isoform a1), localizing to inner and outer segments and synaptic regions and required for long-term photoreceptor maintenance; loss of harmonin causes progressive retinitis pigmentosa.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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