EYS is a multidomain protein containing EGF-like and laminin G domains that supports extracellular organization and photoreceptor maintenance. Its structural role helps preserve the architecture surrounding sensory cells, and loss of EYS disrupts cone ciliary-pocket integrity before progressive photoreceptor degeneration in zebrafish. In primate retina, EYS is associated with photoreceptor outer segments and the region near the connecting cilium; a human retinoblastoma cell line also contains ciliary and centrosomal pools. The precise topology of these pools and their relationship to extracellular structural support remain unresolved. Biallelic pathogenic EYS variants cause autosomal recessive retinitis pigmentosa. Human EYS has two long multidomain products and two much shorter products with different domain content; their individual functions, localization and processing are not established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001750 photoreceptor outer segment | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain the observed outer-segment pool as a contextual location. Reason: PMID:27737822 Figure 2 shows rhesus macaque outer-segment staining with antibody-blocking controls and human donor signal in the corresponding cone region; PMID:27846257 independently finds EYS along macaque rod and cone outer segments. These positive observations support outer-segment localization. Its relationship to the conserved extracellular structural activity remains unresolved, so retain this pool as non-core rather than assigning that activity to the entire outer segment or all four products. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0458 SUPPORTS TRANSFER The current controlled-vocabulary mapping and independent primate retinal evidence support this location. |
| GO:0005201 extracellular matrix structural constituent | IBA GO_REF:0000033 | ACCEPT | Summary: Retain inherited extracellular structural activity. Reason: The actual PAINT tree places human EYS PTN000621604 beneath IBD node PTN008602128; the target MSA equals the displayed 3165-residue sequence and there is no target-path NOT. The fly donor is correctly identified as eys/FBgn0031414. In PMID:18297055, secreted fly Spam coats intact Prominin-expressing Kc cells, protects their shape during osmotic or chemical challenge, and increases resistance to indentation after actin disruption. This is direct structural work, not only a loss phenotype. Zebrafish ciliary-pocket collapse preceding degeneration in PMID:27737822 supports conserved structural function. Retain the phylogenetic inference without claiming an isolated human mechanical assay, a proven human extracellular subcompartment, or equivalent activity of the short products. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008602128 SUPPORTS TRANSFER Valid target descent and exact target/donor MSAs; donor experiments establish extracellular structural support. Off-path NOTs include LAMC2 and do not apply to EYS. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Retain predicted calcium-binding EGF domains as a supporting molecular facet. Reason: Current InterPro IPR001881 and IPR018097 both map to calcium ion binding, and their actual EYS matches include 20 calcium-binding EGF-domain intervals and five conserved-site intervals. This is stronger than inference from a generic EGF label, but it remains domain-based prediction: the reviewed EYS originals do not quantify calcium binding or establish a separate calcium-dependent mechanism. Keep it as a non-core supporting property without transferring the complete long-protein domain architecture to the short products. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR001881 SUPPORTS TRANSFER The current domain and conserved-site mappings are exact; target experimental affinity and physiological contribution remain unmeasured in the reviewed sources. InterPro:IPR018097 SUPPORTS TRANSFER The current domain and conserved-site mappings are exact; target experimental affinity and physiological contribution remain unmeasured in the reviewed sources. Supporting Evidence: GO_REF:0000002 |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | MODIFY | Summary: Refine inherited extracellular localization to extracellular matrix. Reason: The extracellular IBD is on the verified EYS ancestral path and is experimentally grounded in fly eys. PMID:18297055 independently demonstrates secreted extracellular coating with a structural function. Conserved matrix-associated support is consistent with the zebrafish ciliary-pocket phenotype in PMID:27737822. Extracellular matrix is a supported descendant of extracellular region and describes this inherited pool more precisely. This refinement does not locate every human product outside cells or resolve interphotoreceptor-matrix versus intracellular ciliary signal; those questions remain separate. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN008602128 SUPPORTS TRANSFER The PAINT placement is valid; the proposed descendant identifies the structurally supported matrix pool, not universal secretion. Proposed replacements: extracellular matrix |
| GO:0005813 centrosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain centrosomal enrichment in the human-cell context. Reason: SL-0048 accurately maps the curated centrosome statement. PMID:27846257 Figure 3D and Results show endogenous EYS enrichment with CEP135 in human Y79 retinoblastoma cells. This supports the location without establishing a centrosome-assembly activity. The tested split 3144-residue protein fragments and the two short proteins did not reproduce this enrichment, so their cytoplasmic behavior must not be generalized to the endogenous centrosomal pool. Retain this contextual localization as non-core; the distinct sperm centriole experiment does not specify the Y79 subcompartment. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0048 SUPPORTS TRANSFER Actual Y79 endogenous protein imaging supports centrosomal enrichment; no core centrosome-organizing activity is claimed. Supporting Evidence: |
| GO:0005814 centriole | IDA GO_REF:0000052 | UNDECIDED | Summary: Leave the specific sperm centriole assignment unresolved. Reason: HPA027103 produces positive focal signal near the human sperm head–flagellum junction, consistent with the source flagellar-centriole annotation at optical resolution. However, HPA rates this assay uncertain, and the available evidence does not resolve whether that signal specifically identifies EYS at the centriole. Its antigen matches both long EYS products but neither short product; sequence matching does not establish antibody specificity. The independent Y79 centrosome observation is a different cell and compartment context. Retain the positive observation while leaving the specific assignment undecided, without treating the uncertain rating as evidence that localization is false. Supporting Evidence: GO_REF:0000052 |
| GO:0005856 cytoskeleton | IEA GO_REF:0000117 | MODIFY | Summary: Refine broad cytoskeleton to the supported axoneme association. Reason: The recovered ARBA rule matches an actual EYS FunFam feature, but cytoskeleton is unnecessarily broad. PMID:27846257 Figure 3E shows endogenous EYS with acetylated tubulin in a ciliated human Y79 cell, and Figure 8 shows partial overlap with acetylated tubulin and RP1 in macaque photoreceptors. Axoneme includes associated proteins and is a part of the cytoskeleton; this localization does not assert that EYS is a motor, a microtubule polymer, or that every retinal EYS pool is intracellular. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00029228 SUPPORTS TRANSFER Current ARBA condition matches; independently read imaging supports a more precise cytoskeletal compartment. Proposed replacements: axoneme Supporting Evidence: |
| GO:0005929 cilium | IEA GO_REF:0000044 | MODIFY | Summary: Replace broad cilium with the supported axoneme and outer-segment locations. Reason: The SL-0066 mapping is sound but broad. Independent human Y79 and macaque imaging in PMID:27846257 supports axoneme-associated EYS, while PMID:27737822 supports primate photoreceptor outer-segment localization. Both are descendants of cilium and neither is an ancestor of the other. These replacements preserve the distinct observed pools; signal near the connecting-cilium base alone is not being relabeled as a resolved ciliary-pocket lumen or assigned to all natural products. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB-SubCell:SL-0066 SUPPORTS TRANSFER The current mapping is valid; actual imaging allows two nonredundant, more precise ciliary locations. Proposed replacements: axoneme photoreceptor outer segment |
| GO:0005930 axoneme | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain axoneme-associated EYS as a contextual location. Reason: Native human Y79 staining with acetylated tubulin and partial overlap with acetylated tubulin and RP1 in macaque retina support axoneme association (PMID:27846257 Figures 3E and 8). The axoneme term includes associated proteins. This positive location is retained as non-core because the experiments do not establish that this pool performs the conserved extracellular structural work. No motor activity, complete molecular colocalization or equivalent localization of the short products is inferred. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0304 SUPPORTS TRANSFER Exact current mapping and independently inspected human-cell/primate-tissue source support axoneme association. Supporting Evidence: |
| GO:0031012 extracellular matrix | IEA GO_REF:0000117 | ACCEPT | Summary: Retain the conserved extracellular matrix pool with an explicit rule-version boundary. Reason: The current ARBA00027396 payload was recovered, but none of its condition sets matches the captured target InterPro, FunFam, PANTHER and taxonomic features. This limits reconstruction of the historical rule application; it is not evidence of biological absence. Independent valid PAINT ancestry and the actual fly extracellular-coating experiment in PMID:18297055 support matrix localization, with vertebrate structural corroboration from PMID:27737822. Retain the supported gene-level matrix pool without treating the current rule mismatch as resolved or inferring that every EYS product is secreted. Propagation Review Root cause: UNRESOLVED Sources checked: ARBA:ARBA00027396 UNRESOLVED The current rule is accessible but does not reproduce the target match from captured features. Independent phylogenetic and experimental evidence supports the biological location. |
| GO:0033165 interphotoreceptor matrix | IEA GO_REF:0000044 | UNDECIDED | Summary: Retain uncertainty about precise human interphotoreceptor-matrix placement. Reason: UniProt explicitly assigns secreted interphotoreceptor matrix with ECO:0000269 from PMID:27737822, in addition to its hedged secretion note. That curated experimental assertion is positive evidence. In the original, macaque signal is enclosed by the PNA-positive cone sheath and the less well-preserved human sample shows a similar regional signal; these observations do not distinguish the surrounding extracellular matrix from the enclosed outer segment. The ciliary-pocket lumen is a proposed model, and specific immuno-EM was unsuccessful. Independent Y79 and macaque axoneme-associated observations in PMID:27846257 leave topology unresolved. Broad conserved extracellular structural activity is supported by separate fly mechanics and vertebrate structural evidence; it does not settle this precise human compartment. Keep UNDECIDED without rejecting the curated assertion or making immuno-EM a universal localization requirement. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0146 UNRESOLVED The SL-0146 mapping and explicit curated ECO:0000269 assignment are verified. The original regional imaging supports association near photoreceptors but leaves the extracellular subcompartment unresolved. |
| GO:0043403 skeletal muscle tissue regeneration | IMP PMID:21826682 Association of common variants in the human eyes shut orthol... | MARK AS OVER ANNOTATED | Summary: The cited association study proposes regeneration as a hypothesis rather than testing it. Reason: PMID:21826682 reports a suggestive association with severe statin-induced myopathy in humans and EYS transcript characterization. Its skeletal-muscle regeneration interpretation is explicitly proposed from domain similarity and possible Notch/agrin-related mechanisms; no EYS perturbation, injured-fiber regrowth or regeneration assay is reported in the operative Methods and Results. GO:0043403 specifically describes postnatal regrowth of injured or damaged skeletal muscle. The genetic association and muscle transcript observations do not establish that process participation. Mark this specific functional interpretation as over-annotated without rejecting the reported association or asserting a contradicted muscle role. The historical 3196-residue retinal/spinal transcript and muscle 3-prime amplification are not equated with all four current UniProt products. Supporting Evidence: |
| GO:0048589 developmental growth | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Do not equate structural maintenance with developmental growth. Reason: The actual ARBA00044390 conditions match EYS FunFam/taxonomic features. Nevertheless, developmental growth specifically requires an increase in size or mass during development. The inspected vertebrate original PMID:27737822 shows ciliary pockets already present at 7 days, later pocket collapse and progressive photoreceptor loss, supporting maintenance rather than a demonstrated developmental size-increase role. Fly extracellular structural support does not by itself establish this specific growth process for human EYS. The broad rule prediction therefore overstates the evidenced process; this is not a claim that EYS lacks every developmental effect. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00044390 SUPPORTS TRANSFER Rule applicability is verified, but a conserved structural-maintenance phenotype does not establish the more specific developmental-growth endpoint. |
| GO:0050877 nervous system process | IEA GO_REF:0000117 | MODIFY | Summary: Replace the broad nervous-system assertion with photoreceptor cell maintenance. Reason: The current ARBA rule matches two EYS FunFam features in Metazoa, but its broad nervous-system term does not explain the supported role. PMID:27737822 shows progressive cone and later rod loss after disruption of ciliary-pocket architecture, while the conserved extracellular structural activity has independent experimental grounding in PMID:18297055. GO:0045494 describes prevention of photoreceptor degeneration and fits this maintenance role. This is an explicit lateral role correction, not an asserted descendant of nervous system process, and does not assign photon-to-molecular-signal conversion or an enzymatic trafficking activity to EYS. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00029146 SUPPORTS TRANSFER Actual rule feature match is retained; independently supported structural maintenance provides the more informative biological role. Proposed replacements: photoreceptor cell maintenance |
| GO:0050908 detection of light stimulus involved in visual perception | IMP PMID:18836446 EYS, encoding an ortholog of Drosophila spacemaker, is mutat... | MODIFY | Summary: Refine human retinal-disease evidence to photoreceptor maintenance. Reason: PMID:18836446 identifies recessive human retinal-dystrophy variants and retinal expression; its Figure 2B localization uses porcine retina. UniProt CC FUNCTION assigns maintenance of photoreceptor integrity from this paper. Human degeneration establishes a requirement, while independent zebrafish ciliary-pocket disruption before degeneration (PMID:27737822) and direct fly extracellular mechanical protection (PMID:18297055) support a conserved structural contribution to maintenance. Together they justify GO:0045494, not participation in the light-reception-to-signal-conversion series. This is a lateral role refinement; historical sequence lengths are not equated with all current products. Proposed replacements: photoreceptor cell maintenance |
| GO:0050908 detection of light stimulus involved in visual perception | IMP PMID:18976725 Identification of a 2 Mb human ortholog of Drosophila eyes s... | MODIFY | Summary: Refine EYS-associated photoreceptor degeneration to maintenance. Reason: PMID:18976725 links recessive human EYS variants to progressive rod/cone dystrophy and abnormal electroretinograms. Those findings do not locate EYS within the light-to-molecular-signal sequence. Together with independent evidence that Eys preserves vertebrate ciliary-pocket architecture before degeneration (PMID:27737822) and performs extracellular structural work in fly cells (PMID:18297055), they support photoreceptor cell maintenance. The refinement retains the human genetic evidence without representing this study as a direct human mechanics assay or verifying its proposed molecular partners. Proposed replacements: photoreceptor cell maintenance |
| GO:0050908 detection of light stimulus involved in visual perception | IMP PMID:20696082 Identification of a novel homozygous nonsense mutation in EY... | MODIFY | Summary: Refine the segregating retinal-degeneration phenotype to maintenance. Reason: PMID:20696082 reports three affected siblings homozygous for p.Glu1836Ter, progressive retinal degeneration and severely reduced electroretinographic responses. The predicted truncation was not an experimentally characterized protein. The clinical requirement is consistent with maintenance; the participation argument comes from the independently supported structural role, including ciliary-pocket collapse before degeneration in zebrafish (PMID:27737822) and fly mechanical protection (PMID:18297055). Refine to GO:0045494 without assigning EYS a demonstrated light-reception or signal-conversion step. Proposed replacements: photoreceptor cell maintenance |
| GO:0050908 detection of light stimulus involved in visual perception | IMP PMID:22363543 Two novel mutations in the EYS gene are possible major cause... | MODIFY | Summary: Refine the human retinal-dystrophy association to maintenance. Reason: PMID:22363543 reports EYS variants and rod/cone dysfunction in a Japanese retinitis-pigmentosa cohort: eighteen patients carried variants classified as very likely pathogenic, with two detected mutant alleles in nine. These clinical observations do not distinguish a phototransduction step from loss of healthy photoreceptors. Independent vertebrate architecture and fly structural experiments (PMID:27737822; PMID:18297055) support a maintenance contribution, making GO:0045494 the better role. This preserves the cohort limits and does not convert genetic necessity alone into a molecular mechanism. Proposed replacements: photoreceptor cell maintenance |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: A single-peptide urinary-fraction observation is retained as a limited localization context. Reason: The original PMID:19056867 profiles a low-density urinary membrane fraction enriched in exosomes from eight pooled healthy human donors. The authors' relocated NHLBI database explicitly lists EGFL11, NP_938024, one peptide, reference 2 (this paper). This verifies a target-specific observation beyond the abstract. The study used target-decoy and additional single-peptide inspection, but gene-level peptide uniqueness allowed splice-product sharing. Current NP_938024.1 is the 594-residue EYS product; the historical database hit and uninspected peptide spectrum do not identify which current product was present. Retain the imported HDA compartment as non-core, without treating fraction recovery as a universal secretion pathway, a purified-vesicle localization or a core renal function. Supporting Evidence: |
| GO:0140149 non-collagenous component of interstitial matrix | TAS PMID:36399478 MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge d... | UNDECIDED | Summary: The specific matrisome compartment remains unresolved across captured sources. Reason: The official human matrisome masterlist identifies EYS as a core-matrisome ECM glycoprotein, but that classification does not locate it in non-collagenous interstitial matrix. The captured GOA assertion is GO:0140149, whereas the captured UniProt GO cross-reference lists GO:0140144, non-collagenous component of basement membrane. These are distinct compartments, and the UniProt cross-reference alone does not identify which target dataset or annotation version accounts for the difference. The target-level MatrisomeDB tissue/peptide evidence was unavailable. Keep UNDECIDED: neither a generic ECM classification nor this version discrepancy establishes which precise location is correct. Supporting Evidence: |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | UNDECIDED | Summary: Leave the broad animal developmental-process transfer unresolved. Reason: The exact current ARBA00098139 resource returns HTTP 404, so its conditions and original target rationale cannot be inspected. The term denotes progression of an animal gross anatomical part during development. Available vertebrate experiments establish structural maintenance and degeneration, while fly eye morphogenesis is a distinct organismal context. Neither the inaccessible rule nor these different endpoints establish the intended human developmental assertion sufficiently. Preserve the source without treating its absence from the current rule service as biological loss. Propagation Review Root cause: UNRESOLVED Sources checked: ARBA:ARBA00098139 UNRESOLVED The exact rule is currently unavailable; no conditions, historical transfer path or biological loss are invented. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which native retinal EYS pools are extracellular, membrane-associated or intracellular, and where does structural support occur relative to the ciliary pocket and outer segment?
Q: Which of the four natural human EYS products are expressed in relevant cells, and how do their localization, processing and structural activity differ?
Q: Does human EYS directly change extracellular mechanical properties in a way that preserves photoreceptor architecture, and which molecular partners are required?
Experiment: Map endogenous EYS in human retinal tissue or appropriately matured retinal organoids using independently validated epitopes, extracellular accessibility and protease-protection assays, and immuno-electron microscopy with loss-of-EYS controls. Relate signal to the ciliary-pocket membrane, outer segment and PNA-positive sheath. Confirm that endogenous tagging preserves expression and architecture; do not infer topology from sheath enclosure or optical overlap alone.
Hypothesis: Distinct EYS pools may occupy different membrane topologies, so conventional colocalization need not identify the site of extracellular structural activity.
Type: Endogenous topology and ultrastructural localization
Experiment: Combine transcript-junction measurements and product-discriminating peptides with sequence-verified full-length product rescue at matched expression. Assess localization, N-terminal processing, extracellular recovery and retinal architecture separately for the four products, controlling for aggregation and tag effects. Distinguish the predicted signal sequence from directly measured cleavage and preserve literal accession-to-sequence correspondence rather than relying on historical isoform names.
Hypothesis: The long and short natural products may have different localization or activity, independently of the behavior of historical fragments and shared antibody epitopes.
Type: Product-resolved expression, processing and functional rescue
Experiment: Test sequence-verified human EYS preparations or controlled cell-surface assemblies for coating, deformation resistance and force response, alongside matched EYS-negative controls and separate cytoskeletal perturbations. Compare candidate partner conditions without assuming that fly Prominin binding transfers directly to human EYS. Couple any reproducible mechanical effect to product-specific rescue of photoreceptor architecture and longitudinal survival in a suitable retinal model.
Hypothesis: Human EYS may provide mechanical support through extracellular assembly or attachment, with native retinal partners determining the effective structural unit.
Type: Human structural activity and retinal maintenance coupling
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