MYO7A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Family-level phylogenetic assertion that myosins act in the cytoplasm. True for MYO7A, but far less informative than the sites where it actually works, namely stereocilia and the upper tip-link density, the RPE apical cortex, and melanosome and lysosome surfaces. Reason: The IBD node placement is uncontroversial, since every characterised myosin is a cytoplasmic actin-based motor, so there is no reason to challenge it. It is retained as a correct but generic location that does not capture the core biology; the specific compartments (GO:0032420 stereocilium, GO:0042470 melanosome, GO:0005765 lysosomal membrane, GO:0032391 photoreceptor connecting cilium) are annotated separately.
GO:0006897 endocytosis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic transfer of an endocytosis role from a node containing myosins with documented endocytic-trafficking functions. MYO7A does participate in membrane traffic, including phagosome handling in RPE and hair-cell vesicle trafficking of aminoglycosides, but endocytosis proper is not its defining activity. Reason: There is no target-specific evidence of loss or divergence that would justify arguing with the node placement, and the general membrane-trafficking role is consistent with the RPE phagosome and lysosome literature. It is nonetheless peripheral relative to the motor and tension-bearing functions in stereocilia and the RPE actin cortex, so it is kept as non-core.
GO:0007015 actin filament organization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Family-level assertion that these myosins act on the organisation of actin filaments. For MYO7A the corresponding phenotype is progressive disorganisation of the actin-filled stereocilia bundle when the motor is lost. Reason: Plausible at the node and consistent with hair-bundle phenotypes, but MYO7A is not an actin nucleator, bundler or severing factor; its effect on bundle architecture is an indirect consequence of tension-bearing and adhesion-link anchoring. Retained as a correct but non-core generalisation; the specific process in human tissue is stereocilium organisation.
GO:0007423 sensory organ development	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic transfer from a node seeded by Drosophila crinkled and mouse Myo7a, both of which have sensory-organ phenotypes affecting bristles and hair cells respectively. Reason: The node placement is sound, since the sensory-organ requirement for class VII myosins is conserved from fly bristles to vertebrate hair cells, but this is a broad developmental umbrella term. The mechanistically informative annotations for the human gene are the sensory-perception and stereocilium terms; this one is retained as non-core pleiotropic and developmental context.
GO:0015629 actin cytoskeleton	IBA GO_REF:0000033	ACCEPT	Summary: MYO7A is an actin-based motor that works while bound to F-actin; the human protein binds F-actin with high affinity even in the presence of ATP. Reason: This is the correct site of action for the motor and is directly supported by human biochemistry as well as by the phylogenetic assertion. Accepted as a core location. Supporting Evidence: PMID:21687988 Our results show that human myosin-7a is a slow motor with a rate-limiting ADP release step from actomyosin and a high affinity for F-actin, even in the presence of ATP.
GO:0016020 membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Generic membrane association, reflecting the fact that unconventional myosin tails bind membranous cargo. For MYO7A the relevant memberships are the melanosome, lysosome and apical plasma membranes. Reason: Correct but uninformative at this level. The specific membranes MYO7A engages are separately annotated (GO:0005765 lysosomal membrane, GO:0042470 melanosome, GO:0016324 apical plasma membrane), so this root-level term is retained only as non-core context.
GO:0000146 microfilament motor activity	IBA GO_REF:0000033	ACCEPT	Summary: Actin-based (microfilament) motor activity, the defining molecular function of MYO7A, asserted phylogenetically and directly measured for the human motor domain. Reason: This is the core molecular function. Note that MYO7A itself appears in the WITH/FROM list, which is expected, because its own experimental annotation (PMID:21687988) is one of the descendant evidences the PAINT curator used to place the IBD, and the IBA additionally asserts that the activity is inherited rather than lineage-specific. Supporting Evidence: PMID:21687988 A rate-limiting, slow ADP release step causes long lifetimes of strong actin-binding intermediates and results in a high duty ratio.
GO:0030048 actin filament-based movement	IBA GO_REF:0000033	ACCEPT	Summary: Actin-based movement is the process counterpart of the motor activity; for MYO7A this covers cargo movement along cortical actin (melanosomes, phagosomes, lysosomes) and tension-bearing at actin-anchored adhesion links. Reason: Directly supported by in vitro motility measurements with the human motor domain and by cellular melanosome and phagosome phenotypes. MYO7A appearing in its own WITH/FROM reflects experimental grounding on the target itself, not circularity. Supporting Evidence: PMID:21687988 These specific kinetic adaptations indicate that human myosin-7a is a slow molecular motor with a high duty ratio, suitable for moving cargoes and mediating tension in the cytoskeleton.
GO:0007605 sensory perception of sound	IBA GO_REF:0000033	ACCEPT	Summary: Hearing requires myosin-VIIa; the node is seeded by Drosophila crinkled, mouse Myo7a (shaker-1) and human MYO7A itself, whose loss causes congenital profound deafness in Usher syndrome type 1B. Reason: Core biological process, independently supported by human loss-of-function genetics. The IBD placement is well supported by conserved auditory and mechanosensory requirements across the clade. Supporting Evidence: PMID:7870171 Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B.
GO:0000146 microfilament motor activity	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assertion of actin-based motor activity, duplicating the IBA and the human IDA for the same term. Reason: Correct core molecular function; duplication across evidence codes is expected and unproblematic. Supporting Evidence: PMID:21687988 Our results show that human myosin-7a is a slow motor with a rate-limiting ADP release step from actomyosin and a high affinity for F-actin, even in the presence of ATP.
GO:0003774 cytoskeletal motor activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro myosin-head signature (IPR001609) mapped to the parent motor-activity term. Reason: The domain-to-term mapping is correct; the term is simply the parent of the more specific GO:0000146 microfilament motor activity that is also annotated. A broader IEA sitting above a well-supported specific term is acceptable and needs no change.
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP binding by the myosin motor domain, inferred from the InterPro myosin head signature and directly demonstrated by nucleotide-binding kinetics on the human motor domain. Reason: Correct and mechanistically central, since ATP binding and the rate-limiting ADP release step define the duty ratio that makes MYO7A a tension-bearing motor. Supporting Evidence: PMID:21687988 A defining feature of the myosin-7a actin-activated ATPase cycle is the rate-limiting ADP release step.
GO:0005737 cytoplasm	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic cytoplasm assignment combining UniProt subcellular location and mouse orthology. Reason: Correct but generic; retained as non-core for the same reasons as the IBA cytoplasm annotation.
GO:0005829 cytosol	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine-learning assignment of a cytosolic location. Reason: MYO7A carries out its functions bound to F-actin and to organelle and plasma membranes, not free in the cytosol. A soluble, autoinhibited monomeric pool undoubtedly exists, and an IDA for cytosol is also present, so the assignment is not wrong; but cytosol here is the default localisation an unsupervised rule gives a protein with no transmembrane or signal features and it does not describe a functional site. Retained as non-core.
GO:0005856 cytoskeleton	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Generic cytoskeleton location from combined automatic methods. Reason: True but subsumed by the more informative GO:0015629 actin cytoskeleton annotation; kept as non-core.
GO:0005938 cell cortex	IEA GO_REF:0000044	ACCEPT	Summary: UniProt subcellular-location mapping to the cell cortex, matching the cortical actin sites where myosin-VIIa works, namely the apical actin-rich microvilli of the RPE and the actin core of stereocilia. Reason: This is a genuinely informative and correct location for a motor whose documented jobs, melanosome capture on apical cortical actin and tension at the stereocilia tip-link insertion, are both cortical. Supporting Evidence: PMID:11964381 In the pigment epithelium cells, MyRIP and Rab27A were observed in the microvilli that surround the tips of the photoreceptor outer segments
GO:0007040 lysosome organization	IEA GO_REF:0000117	MODIFY	Summary: ARBA rule mirroring the experimental finding that a population of myosin-VIIa is tightly bound to the lysosome surface and is proposed to act as a lysosome motor. Reason: The underlying biology, RPE phagosome and lysosome positioning and digestion, is real, but the process MYO7A performs is positioning and transport of the organelle rather than lysosome biogenesis or the arrangement of its constituent parts. GO:0032418 lysosome localization is the accurate term, as proposed for the corresponding IDA. Proposed replacements: lysosome localization Supporting Evidence: PMID:16001398 These studies suggest that myosin-VIIa is a lysosome motor.
GO:0007601 visual perception	IEA GO_REF:0000117	ACCEPT	Summary: Electronic assertion of a role in vision, duplicating the human IMP annotation based on the retinitis pigmentosa of Usher syndrome type 1B. Reason: Correct; MYO7A is expressed in human photoreceptors and RPE and its loss causes progressive retinal degeneration. Supporting Evidence: PMID:8842737 In the adult human retina, myosin VIIA was present in both cell types.
GO:0007605 sensory perception of sound	IEA GO_REF:0000117	ACCEPT	Summary: Electronic duplicate of the well-supported hearing annotation. Reason: Core process, supported experimentally in human by loss-of-function genetics.
GO:0008092 cytoskeletal protein binding	IEA GO_REF:0000117	ACCEPT	Summary: Broad binding term covering the experimentally demonstrated actin-filament binding and spectrin binding of myosin-VIIa. Reason: This is a parent of two annotations already supported by direct experiment (GO:0051015 actin filament binding, IDA; GO:0030507 spectrin binding, IDA), so the electronic assertion is correct if unspecific. Broader IEAs above well-supported children are acceptable and do not need modification.
GO:0016020 membrane	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Root-level membrane association from an ARBA rule. Reason: Correct in that the MyTH4-FERM tail engages membrane cargo, but uninformative; the specific membranes are annotated elsewhere.
GO:0016459 myosin complex	IEA GO_REF:0000002	ACCEPT	Summary: InterPro myosin-head mapping placing the heavy chain in a myosin complex. Myosin-VIIa functions as a heavy chain carrying calmodulin and CALML4 light chains on its five IQ motifs. Reason: Appropriate, since the functional unit is the heavy chain plus its IQ-bound light chains, and calmodulin binding is independently annotated for this gene.
GO:0030048 actin filament-based movement	IEA GO_REF:0000117	ACCEPT	Summary: Electronic duplicate of the IBA and IDA actin-filament-based movement annotations. Reason: Correct core process; duplication across evidence codes is expected.
GO:0045202 synapse	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Automatic assignment of a synaptic location, matching the immunolocalisation of myosin-VIIa to the synaptic ending region of human photoreceptor cells. Reason: The localisation is real, but no function has been demonstrated for myosin-VIIa at the photoreceptor or hair-cell synapse; the proposed role in ribbon-synaptic vesicle trafficking remains a hypothesis. Retained as a non-core location. Supporting Evidence: PMID:8842737 in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles
GO:0048666 neuron development	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA machine-learning generalisation of the sensory-cell phenotypes of MYO7A into a broad neuronal developmental term. Reason: The two cell types where MYO7A function is established are cochlear and vestibular hair cells, which are mechanosensory epithelial cells and not neurons, and photoreceptors, where the motor acts in transport and maintenance of an already differentiated cell rather than in its development. The term is not strictly false, since photoreceptors are neurons, but it generalises well beyond what the evidence shows, so it is flagged as an over-annotation rather than kept as a substantive process.
GO:0090596 sensory organ morphogenesis	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Broad morphogenesis term reflecting the hair-bundle shaping defects seen when myosin-VIIa is lost. Reason: Consistent with the documented role in hair bundle differentiation, morphogenesis and organisation, but developmental and non-specific. Retained as non-core context alongside the mechanistically informative stereocilium and sound-perception annotations.
GO:0097733 photoreceptor cell cilium	IEA GO_REF:0000117	ACCEPT	Summary: Ciliary localisation in photoreceptors, the parent of the connecting-cilium term also annotated for this gene. Reason: Consistent with detection of myosin-VIIa in the connecting-cilium region of photoreceptors and with the opsin-transport delay seen when the motor is absent. Accepted as a correct, if broad, location. Supporting Evidence: PMID:23704327 A delay of opsin trafficking has been observed in the retinal photoreceptor cells of myosin VIIa-deficient mice.
GO:0008104 intracellular protein localization	IEA GO_REF:0000107	MODIFY	Summary: Ensembl Compara transfer from mouse Myo7a of a very general protein-localisation term. The underlying mouse evidence concerns delayed opsin transport through the photoreceptor connecting cilium in Myo7a-null animals. Reason: The essence is right but the term is far too general, since almost any trafficking protein qualifies. The specific process supported by the source evidence, and by the identification of spectrin betaV as a scaffold coupling myosin VIIa to rhodopsin, is opsin transport (GO:0036372). Proposed replacements: opsin transport Supporting Evidence: PMID:23704327 A failure of the spectrin βV-mediated coupling between myosin VIIa and opsin molecules thus probably accounts for the opsin transport delay in myosin VIIa-deficient mice.
GO:0016324 apical plasma membrane	IEA GO_REF:0000107	ACCEPT	Summary: Orthology transfer from mouse of apical membrane localisation, consistent with myosin-VIIa acting in the apical actin-rich microvillar domain of the RPE and at the apical surface of hair cells. Reason: Correct and functionally meaningful, because the apical cortical domain is where the melanosome-capture and phagosome-handling activities take place.
GO:0019904 protein domain specific binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Uninformative binding term transferred from mouse. Reason: Like bare protein binding, this term conveys no functional information. The biologically meaningful interactions of MYO7A, with harmonin/USH1C and sans/USH1G at the upper tip-link density, with MYRIP on melanosomes, with CIB2 and with spectrin betaV, are better captured by the specific binding and localisation annotations. Flagged as an uninformative over-annotation rather than removed, since the underlying interactions are real.
GO:0032391 photoreceptor connecting cilium	IEA GO_REF:0000107	ACCEPT	Summary: Connecting-cilium localisation transferred from mouse Myo7a, the compartment through which opsin passes en route to the outer segment and where opsin accumulates when the motor is absent. Reason: Supported by the mouse experimental source and coherent with the opsin-transport phenotype. Myosin-VIIa is present at lower levels here than in the RPE, but the localisation is reproducible. Supporting Evidence: PMID:23704327 A delay of opsin trafficking has been observed in the retinal photoreceptor cells of myosin VIIa-deficient mice.
GO:0032420 stereocilium	IEA GO_REF:0000107	ACCEPT	Summary: Stereocilium localisation transferred from mouse. Myosin-VIIa is concentrated in hair-cell stereocilia, in particular clustered at the upper tip-link density together with sans and harmonin-b. Reason: A core location and the site of the best-characterised function of MYO7A, maintaining resting tension on the tip link. The sub-compartment GO:1990435 upper tip-link density is proposed as a more precise addition rather than a replacement. Supporting Evidence: PMID:21709241 we now show that MYO7A and sans, a MYO7A-interacting protein, cluster at the UTLD file:human/MYO7A/MYO7A-deep-research-falcon.md MYO7A is enriched in the actin-rich stereocilia of cochlear and vestibular hair cells
GO:0042470 melanosome	IEA GO_REF:0000107	ACCEPT	Summary: Melanosome localisation in the retinal pigment epithelium, where myosin-VIIa is recruited via the RAB27A effector MYRIP. Reason: Core location for the RPE arm of MYO7A function. Immunoelectron microscopy places myosin-VIIa, MYRIP and RAB27A together on retinal melanosomes, and knockdown in human RPE cells alters melanosome motility. Supporting Evidence: PMID:11964381 In the retinal pigment epithelium cells, MyRIP, myosin VIIa and Rab27A are associated with melanosomes. file:human/MYO7A/MYO7A-deep-research-falcon.md Correct apical melanosome positioning contributes to light absorption and retinal protection.
GO:0120044 stereocilium base	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Localisation to the tapered basal region of the stereocilium, transferred from mouse experimental data. Reason: Myosin-VIIa is distributed along stereocilia, including the basal and ankle-link region of developing bundles, so the annotation is defensible and the mouse curator's evidence is not something to overturn from here. It is kept as non-core because the functionally decisive site in the mature bundle is the upper tip-link density near the tip-link insertion on the taller stereocilium, not the base.
GO:0005737 cytoplasm	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator sequence-similarity transfer of cytoplasmic localisation from mouse Myo7a. Reason: Correct but generic; see the IBA and IEA cytoplasm entries.
GO:0008104 intracellular protein localization	ISS GO_REF:0000024	MODIFY	Summary: Curator ISS transfer from mouse Myo7a of a very general protein-localisation term, ultimately resting on the delayed opsin transport of Myo7a-null photoreceptors. Reason: Same reasoning as for the Ensembl IEA of this term. The substance is right but the term is too general to be useful, and GO:0036372 opsin transport names the actual process supported by the source evidence. Proposed replacements: opsin transport Supporting Evidence: PMID:23704327 A failure of the spectrin βV-mediated coupling between myosin VIIa and opsin molecules thus probably accounts for the opsin transport delay in myosin VIIa-deficient mice.
GO:0032420 stereocilium	ISS GO_REF:0000024	ACCEPT	Summary: Curator ISS duplicate of the stereocilium localisation. Reason: Core location; see the corresponding IEA entry.
GO:0042490 mechanoreceptor differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transfer from mouse of a role upstream of or within hair-cell differentiation, reflecting the progressive disorganisation of stereocilia bundles in Myo7a mutants. Reason: Supported by the mouse phenotype and by the UniProt summary of a role in differentiation, morphogenesis and organisation of cochlear hair cell bundles. It is nevertheless a developmental consequence of the mechanical role of the motor rather than a distinct core function, and conditional postnatal deletion shows the requirement persists in mature bundles. Kept as non-core.
GO:0120044 stereocilium base	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Curator ISS duplicate of the stereocilium-base localisation. Reason: Same assessment as the Ensembl-transferred annotation for this term.
GO:0005737 cytoplasm	IDA PMID:23704327 The giant spectrin βV couples the molecular motors to photot...	KEEP AS NON CORE	Summary: Direct observation of myosin-VIIa in the cytoplasm of photoreceptor cells in the spectrin betaV study. Reason: The observation is sound but the term is generic. The informative content of this paper for MYO7A is the spectrin betaV interaction and the coupling of the motor to opsin along its trafficking route.
GO:0030507 spectrin binding	IDA PMID:23704327 The giant spectrin βV couples the molecular motors to photot...	ACCEPT	Summary: Myosin-VIIa binds the giant beta-heavy spectrin, spectrin betaV, which is distributed from the Golgi to the base of the photoreceptor outer segment and also binds rhodopsin, sans (USH1G) and harmonin (USH1C). Reason: An informative molecular function term backed by direct binding experiments, and it explains mechanistically how the actin motor is coupled to opsin cargo along the photoreceptor trafficking route. Retained as a core molecular interaction. Supporting Evidence: PMID:23704327 We identified spectrin βV, the mammalian β-heavy spectrin, as a myosin VIIa- and rhodopsin-interacting partner in photoreceptor cells.
GO:0005515 protein binding	IPI PMID:23023331 Alterations of the CIB2 calcium- and integrin-binding protei...	MARK AS OVER ANNOTATED	Summary: Interaction with CIB2 (UniProtKB:O75838), a calcium- and integrin-binding protein of hair-cell stereocilia mutated in USH1J and DFNB48, captured only as bare protein binding. Reason: The interaction itself is real and curator-verified, but GO:0005515 conveys no functional information and should not be treated as an informative molecular function. The biologically meaningful content, that MYO7A is a hub of the stereocilia USH interactome, is better represented by the stereocilium and upper tip-link density localisations and by the specific binding terms for spectrin, calmodulin and actin filaments. Note also that CIB2 localisation to stereocilia tips is unchanged in Myo7a mutant mice, so this is not a recruitment relationship. Supporting Evidence: PMID:23023331 Since CIB2 is concentrated in stereocilia and interacts with myosin VIIa and whirlin
GO:0000146 microfilament motor activity	IDA PMID:21687988 Functional characterization of the human myosin-7a motor dom...	ACCEPT	Summary: Direct kinetic and in vitro motility characterisation of the human myosin-7a motor domain, a slow high-duty-ratio actin-based motor with rate-limiting ADP release, high F-actin affinity and Mg2+-sensitive regulation. Reason: The strongest available human evidence for the core molecular function. Accepted as core. Supporting Evidence: PMID:21687988 A rate-limiting, slow ADP release step causes long lifetimes of strong actin-binding intermediates and results in a high duty ratio.
GO:0030048 actin filament-based movement	IDA PMID:21687988 Functional characterization of the human myosin-7a motor dom...	ACCEPT	Summary: The human myosin-7a motor domain drives actin filament sliding in an in vitro motility assay, with velocity modulated by free Mg2+. Reason: Direct demonstration that the human protein produces actin-based movement. The same kinetics indicate it can switch between cargo-moving and tension-bearing modes, which is the behaviour required at the tip-link insertion and on RPE cortical actin. Supporting Evidence: PMID:21687988 These specific kinetic adaptations indicate that human myosin-7a is a slow molecular motor with a high duty ratio, suitable for moving cargoes and mediating tension in the cytoskeleton.
GO:0051015 actin filament binding	IDA PMID:21687988 Functional characterization of the human myosin-7a motor dom...	ACCEPT	Summary: The human motor domain binds F-actin with high affinity, including in the presence of nucleotide, consistent with long-lived strong-binding states. Reason: Core molecular function, directly measured for the human protein. It complements the motor-activity annotation by specifying the track that is bound. Supporting Evidence: PMID:21687988 Our results show that human myosin-7a is a slow motor with a rate-limiting ADP release step from actomyosin and a high affinity for F-actin, even in the presence of ATP.
GO:0042462 eye photoreceptor cell development	IC PMID:8842737 Human Usher 1B/mouse shaker-1: the retinal phenotype discrep...	MODIFY	Summary: Curator inference, made from GO:0001917 photoreceptor inner segment, that the presence of myosin-VIIA in developing and adult human photoreceptors implies a role in photoreceptor development. Reason: The localisation data are solid, but presence in a cell during development does not establish a developmental function, and the interpretation offered by the paper itself concerns disk renewal and synaptic-vesicle trafficking, that is, maintenance of an already differentiated cell. The human disease is a progressive, post-developmental retinal degeneration. GO:0045494 photoreceptor cell maintenance captures the inference the data actually support. Proposed replacements: photoreceptor cell maintenance Supporting Evidence: PMID:8842737 we suggest that myosin VIIA might play a role in the trafficking of ribbon-synaptic vesicle complexes and the renewal processes of the outer photoreceptor disks
GO:0050957 equilibrioception	IMP PMID:7870171 Defective myosin VIIA gene responsible for Usher syndrome ty...	ACCEPT	Summary: Human loss-of-function evidence. MYO7A mutations cause Usher syndrome type 1B, which includes constant vestibular dysfunction alongside congenital deafness. Reason: Vestibular hair cells use the same myosin-VIIa-dependent stereociliary mechanotransduction machinery as cochlear hair cells, so balance perception is a genuine core process for this gene, established by human genetics. Supporting Evidence: PMID:7870171 Usher syndrome type 1 (USH1) is characterized by a profound congenital sensorineural hearing loss, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa.
GO:0007605 sensory perception of sound	IMP PMID:11398101 Mutations of the protocadherin gene PCDH15 cause Usher syndr...	ACCEPT	Summary: Hearing role of MYO7A, annotated against a paper whose primary subject is PCDH15 and Usher syndrome type 1F. Reason: The claim itself is beyond doubt, since MYO7A mutations cause USH1B, DFNB2 and DFNA11 deafness, and the cited paper does state this, so the annotation is accepted rather than removed. The citation is nonetheless a poor choice, because the experimental work in PMID:11398101 concerns PCDH15 mutations in USH1F families and MYO7A appears only as background. PMID:7870171, also annotated, is the appropriate primary support, and the reference is flagged in the references section. Supporting Evidence: PMID:11398101 Mutations in MYO7A / Myo7a are found in patients with DFNB2 , USH1B , DFNA11 , and in shaker-1 ( sh1 ) mice
GO:0050953 sensory perception of light stimulus	IMP PMID:11398101 Mutations of the protocadherin gene PCDH15 cause Usher syndr...	ACCEPT	Summary: Broad light-perception term for MYO7A, annotated against the same PCDH15 paper. Reason: This is the parent of GO:0007601 visual perception, which is separately annotated with human IMP evidence from PMID:7870171, and the substance, retinitis pigmentosa in USH1B, is correct. Retained, with the same caveat that the citation is a PCDH15 paper mentioning MYO7A only as background. Supporting Evidence: PMID:11398101 Mutations in MYO7A / Myo7a are found in patients with DFNB2 , USH1B , DFNA11 , and in shaker-1 ( sh1 ) mice
GO:0001750 photoreceptor outer segment	IDA PMID:8842737 Human Usher 1B/mouse shaker-1: the retinal phenotype discrep...	ACCEPT	Summary: Immunolocalisation of myosin-VIIA in human photoreceptors places the protein at the base of the outer segment, as well as in the inner segment and synaptic region. Reason: Direct observation in human retina. The signal is concentrated at the base of the outer segment, the region adjacent to the connecting cilium through which opsin is delivered, which fits the opsin-transport role. Accepted, noting that the protein is not distributed throughout the outer segment. Supporting Evidence: PMID:8842737 in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles
GO:0001917 photoreceptor inner segment	IDA PMID:8842737 Human Usher 1B/mouse shaker-1: the retinal phenotype discrep...	ACCEPT	Summary: Myosin-VIIA is mainly localised in the inner segment of human photoreceptor cells. Reason: Direct human immunolocalisation. The inner segment is where newly synthesised opsin is trafficked and where it accumulates when the motor is missing, making this a core photoreceptor location. Supporting Evidence: PMID:8842737 in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles
GO:0005515 protein binding	IPI PMID:11964381 MyRIP, a novel Rab effector, enables myosin VIIa recruitment...	MARK AS OVER ANNOTATED	Summary: Direct interaction between the myosin-VIIa MyTH4-FERM tail and MYRIP (UniProtKB:Q8NFW9), the RAB27A effector that links the motor to retinal melanosomes, recorded only as bare protein binding. Reason: The interaction is well demonstrated by yeast two-hybrid, co-immunoprecipitation, GST pull-down and direct in vitro binding, and is mechanistically important, but GO:0005515 is uninformative. The functional content is better captured by the melanosome localisation and by a melanosome-localisation process annotation. MYRIP is moreover not a passive hook, since it converts the monomeric motor into a processive one. Flagged as uninformative rather than removed. Supporting Evidence: PMID:11964381 Taken together, these results demonstrate that MyRIP specifically binds to myosin VIIa.
GO:0005516 calmodulin binding	IMP PMID:15300860 Impaired calmodulin binding of myosin-7A causes autosomal do...	ACCEPT	Summary: The fifth IQ motif of MYO7A binds calmodulin, and the DFNA11 mutation p.R853C at an invariant IQ5 residue abolishes constitutive calmodulin binding, causing dominant progressive hearing loss. Reason: Calmodulin light chains on the five IQ motifs constitute the lever arm that converts motor-domain conformational changes into force, and Ca2+-dependent calmodulin release is how the motor is switched off. This is a core molecular function, supported by a human mutation with a measured effect on calmodulin binding. The IMP evidence code is unusual for a binding term but the experiment does test the interaction directly in cells. Supporting Evidence: PMID:15300860 analysis of calmodulin-dependent vasoconstriction suggests constitutive binding of CaM to the wildtype, but not the p.R853C-mutated IQ5 motif at all physiologically relevant Ca2+ concentrations
GO:0005765 lysosomal membrane	IDA PMID:16001398 The unconventional myosin-VIIa associates with lysosomes.	ACCEPT	Summary: In differentiated human ARPE-19 retinal pigment epithelial cells a population of myosin-VIIa is tightly associated with the surface of cathepsin D- and RAB7-positive lysosomes, shown by immunofluorescence, density-gradient co-purification and extraction experiments. Reason: Strong direct evidence in a human RPE cell model, and mechanistically coherent with the delayed phagosome-to-lysosome trafficking and digestion seen in myosin-VIIa-deficient RPE. Accepted as a core location for the RPE arm of MYO7A function. Supporting Evidence: PMID:16001398 Myosin-VIIa copurified with lysosomes on density gradients, and fractionation and extraction experiments suggested that it was tightly associated with the lysosome surface.
GO:0005829 cytosol	IDA PMID:15300860 Impaired calmodulin binding of myosin-7A causes autosomal do...	KEEP AS NON CORE	Summary: Cytosolic localisation recorded from the DFNA11 study, which expressed MYO7A IQ5-containing peptides in smooth muscle cells of microarteries. Reason: Full text is not in the local cache, so the basis for the curator's call cannot be re-read and the observation is not challenged. As a functional statement, however, cytosol is not where myosin-VIIa acts, since it works bound to F-actin and to organelle and plasma membranes, and the experiments in this paper used isolated IQ-motif peptides in a heterologous smooth-muscle system. Retained as non-core.
GO:0007040 lysosome organization	IDA PMID:16001398 The unconventional myosin-VIIa associates with lysosomes.	MODIFY	Summary: Association of myosin-VIIa with lysosomes in human RPE cells led the authors to propose that it is a lysosome motor, positioning lysosomes and phagosomes for fusion and digestion. Reason: The evidence supports transport and positioning of lysosomes rather than their biogenesis or the arrangement of their constituent parts, which is what GO:0007040 denotes. GO:0032418 lysosome localization is the accurate term for a motor that moves and retains the organelle. The association is independent of RAB7 status and of an intact actin and microtubule cytoskeleton, arguing for a direct motor-cargo relationship rather than a role in lysosome assembly. Proposed replacements: lysosome localization Supporting Evidence: PMID:16001398 These studies suggest that myosin-VIIa is a lysosome motor.
GO:0007601 visual perception	IMP PMID:7870171 Defective myosin VIIA gene responsible for Usher syndrome ty...	ACCEPT	Summary: Human loss-of-function evidence. Biallelic MYO7A mutations cause the progressive retinitis pigmentosa of Usher syndrome type 1B. Reason: Core process supported by human genetics, and mechanistically underpinned by the melanosome, phagosome and lysosome, and opsin-transport roles of the motor in RPE and photoreceptors. Notably, human but not rodent photoreceptors express myosin-VIIA, which is why shaker-1 mice lack the retinal phenotype. Supporting Evidence: PMID:7870171 Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B.
GO:0007605 sensory perception of sound	IMP PMID:7870171 Defective myosin VIIA gene responsible for Usher syndrome ty...	ACCEPT	Summary: MYO7A mutations, comprising two premature stop codons, a six-base-pair deletion and two missense changes clustered in the motor domain, segregate with USH1B, which features profound congenital sensorineural hearing loss. Reason: Definitive human loss-of-function evidence for the core auditory function of this gene. The mutations map to the amino-terminal motor domain and are expected to abolish functional protein. Supporting Evidence: PMID:7870171 These mutations, which are located at the amino-terminal end of the motor domain of the protein, are likely to result in the absence of a functional protein.
GO:0045202 synapse	IDA PMID:8842737 Human Usher 1B/mouse shaker-1: the retinal phenotype discrep...	KEEP AS NON CORE	Summary: Myosin-VIIA is detected in the synaptic ending region of human photoreceptor cells, co-localised with synaptic vesicles. Reason: A genuine direct human observation, but the proposed function there, trafficking of ribbon-synaptic vesicle complexes, remains a suggestion, and no synaptic phenotype has been established for MYO7A. Kept as a non-core location. Supporting Evidence: PMID:8842737 in the photoreceptor cells, myosin VIIA is mainly localized in the inner and base of outer segments as well as in the synaptic ending region where it is co-localized with the synaptic vesicles
GO:0007605 sensory perception of sound	IMP PMID:7870171 Defective myosin VIIA gene responsible for Usher syndrome ty...	ACCEPT	Summary: Duplicate of the sound-perception IMP with the acts_upstream_of_or_within qualifier, contributed by MGI. Reason: Same well-established human genetic evidence. The weaker qualifier is appropriate for an annotation derived from an organism-level phenotype, and duplication with different qualifiers is not a problem. Supporting Evidence: PMID:7870171 Here we present evidence that a gene encoding myosin VIIA is responsible for USH1B.
GO:1990435 upper tip-link density	ISS PMID:21709241 Myosin VIIa and sans localization at stereocilia upper tip-l...	NEW	Summary: In mature cochlear and vestibular hair bundles, MYO7A clusters with sans (USH1G) and harmonin-b (USH1C) at the upper tip-link density, the plaque at the upper insertion of the CDH23-PCDH15 tip link, with eight or more MYO7A molecules estimated per density. Reason: This is the sub-stereociliary compartment in which the best-defined mechanical function of MYO7A occurs, pulling on CDH23 to maintain resting tip-link tension and thereby set the operating point of the mechanotransduction channels, and it is missing from the current annotation set, which stops at GO:0032420 stereocilium and GO:0120044 stereocilium base. The cited immunolocalisation and heterologous co-transfection work used rodent hair cells and tagged constructs, so ISS is the appropriate evidence code for the human protein; the human orthologue is 96 to 97 percent identical over the motor domain and its partners USH1C and USH1G are the same USH1 proteins. This is a tension-bearing complex of the mature bundle, distinct from the transient ankle-link complex of developing bundles. Supporting Evidence: PMID:21709241 Analysis of the immunofluorescence intensity indicates that eight or more MYO7A molecules are present at each UTLD, consistent with a direct role for MYO7A in maintaining tip-link tension. PMID:21709241 In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link.
GO:0032400 melanosome localization	IMP PMID:19643958 Function of MYO7A in the human RPE and the validity of shake...	NEW	Summary: RNAi knockdown of MYO7A in primary human retinal pigment epithelial cells changes melanosome motility, converting normal short-range movement into the longer-range fast movements characteristic of myosin-VIIa-null RPE, indicating that the motor normally captures and retains melanosomes on apical cortical actin after microtubule-based delivery. Reason: Melanosome positioning in the RPE is one of the two best-established cellular functions of MYO7A, is mechanistically explained by the RAB27A-MYRIP-MYO7A module already annotated at the level of localisation and interaction, and yet no process term for it exists in the current set, which offers only the generic GO:0030048 actin filament-based movement. The evidence is a loss-of-function experiment in human cells, so IMP is appropriate. GO:0032400 melanosome localization is preferred over GO:0032402 melanosome transport because the demonstrated effect is constraint and retention rather than net directed transport. Supporting Evidence: PMID:19643958 RNAi knockdown studies showed that MYO7A functions to constrain rapid, long-range movements of melanosomes. PMID:19643958 Melanosome motility was also comparable, and, after RNAi knockdown, consisted of longer-range fast movements characteristic of melanosomes in shaker1 RPE.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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