Dysferlin is a ferlin-family membrane protein whose C2 domains bind calcium and acidic phospholipids. It participates in skeletal-muscle membrane maintenance and repair and is found at the sarcolemma, T-tubules and internal membrane compartments, with trafficking between the cell surface and endosomes. Alternative splicing changes its N-terminal calcium/lipid coupling, and one truncated product lacks the canonical C-terminal membrane anchor.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002280 monocyte activation involved in immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The automated monocyte-activation assertion is biologically supported but contextual. Reason: The literal ARBA00089298 rule contains the vertebrate FunFam condition associated with the target and predicts this term. The complete original reports activated mononuclear infiltrates in human dysferlin-deficient muscle and increased activation markers in dysferlin-deficient mouse macrophages. This supports the curated immune context, but does not establish a primary immune-receptor or cytokine-signaling activity of dysferlin. The human basal phagocytosis difference was not statistically significant; the significant human comparison was after TNF treatment. Controlled dysferlin knockdown and increased phagocytosis were demonstrated in mouse J774 cells. Preserve the positive disease/cell context as non-core without treating all these assays as human or as one activation mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00089298 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0002280 monocyte activation involved in immune response | IMP PMID:18276788 Dysferlin deficiency enhances monocyte phagocytosis: a model... | KEEP AS NON CORE | Summary: Monocyte activation is a supported contextual phenotype. Reason: The complete original reports activated mononuclear infiltrates in human dysferlin-deficient muscle and increased activation markers in dysferlin-deficient mouse macrophages. This supports the curated immune context, but does not establish a primary immune-receptor or cytokine-signaling activity of dysferlin. The human basal phagocytosis difference was not statistically significant; the significant human comparison was after TNF treatment. Controlled dysferlin knockdown and increased phagocytosis were demonstrated in mouse J774 cells. Preserve the positive disease/cell context as non-core without treating all these assays as human or as one activation mechanism. |
| GO:0002281 macrophage activation involved in immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The automated macrophage-activation assertion is contextual. Reason: The literal ARBA00089297 rule includes the relevant vertebrate FunFam arm; its other taxonomic/sequence arms are not all asserted to match DYSF. The complete original reports activated mononuclear infiltrates in human dysferlin-deficient muscle and increased activation markers in dysferlin-deficient mouse macrophages. This supports the curated immune context, but does not establish a primary immune-receptor or cytokine-signaling activity of dysferlin. The human basal phagocytosis difference was not statistically significant; the significant human comparison was after TNF treatment. Controlled dysferlin knockdown and increased phagocytosis were demonstrated in mouse J774 cells. Preserve the positive disease/cell context as non-core without treating all these assays as human or as one activation mechanism. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00089297 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0002281 macrophage activation involved in immune response | IMP PMID:18276788 Dysferlin deficiency enhances monocyte phagocytosis: a model... | KEEP AS NON CORE | Summary: Macrophage activation is retained as a contextual immune function. Reason: The complete original reports activated mononuclear infiltrates in human dysferlin-deficient muscle and increased activation markers in dysferlin-deficient mouse macrophages. This supports the curated immune context, but does not establish a primary immune-receptor or cytokine-signaling activity of dysferlin. The human basal phagocytosis difference was not statistically significant; the significant human comparison was after TNF treatment. Controlled dysferlin knockdown and increased phagocytosis were demonstrated in mouse J774 cells. Preserve the positive disease/cell context as non-core without treating all these assays as human or as one activation mechanism. |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium binding is experimentally grounded on DYSF and phylogenetically inherited. Reason: The literal IBD at PTN002473508 is on the exact O75923 leaf path in the authenticated PANTHER tree, and its MSA sequence matches the displayed 2,080-aa protein. DYSF itself is a legitimate descendant experimental source alongside MCTP-family evidence, not circular support. Direct human canonical C2A work and independent measurements on seven human DYSF C2 domains support calcium binding. Alternative exon-1 C2A constructs have different calcium responses, so this gene-level annotation is not a claim of equivalent binding by every natural product. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0034389 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. PANTHER:PTN002473508 SUPPORTS TRANSFER Literal IBD and target descent are verified in the authentic tree/MSA; this is not a donor-count or node-validity challenge. UniProtKB:O75923 SUPPORTS TRANSFER Target experimental grounding is a legitimate descendant source for the IBD, not circular evidence. UniProtKB:Q6DN12 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. UniProtKB:Q6DN14 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0005509 calcium ion binding | IDA PMID:24239457 Alternate splicing of dysferlin C2A confers Ca²⁺-dependent a... | ACCEPT | Summary: The canonical human C2A domain directly binds calcium. Reason: The original study assays human canonical C2A residues 1–125 and the alternative N-terminal C2Av1 class as bacterial recombinant fragments. Canonical C2A binds calcium; the variant lacks measurable binding in solution but gains a lipid-exposed calcium site with different effects on membrane avidity. Retain the positive gene-level IDA assertion without applying canonical behavior to all 15 products or treating the Cys2Ala variant reagent as an unmodified natural full-length isoform. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17185750 AHNAK, a novel component of the dysferlin protein complex, r... | KEEP AS NON CORE | Summary: The positive AHNAK association is retained without an unsupported functional subclass. Reason: The authentic abstract reports dysferlin–AHNAK co-immunoprecipitation/mass spectrometry and GST-pull-down mapping of dysferlin C2A to the AHNAK carboxy terminus. Current official records independently retain the pair. The full original was not recovered after bounded publisher/repository attempts, so finer construct and partner-mechanism claims are not made. AHNAK is a large scaffold with multiple contexts; the inspected evidence does not establish a sufficiently precise binding subclass here. Supported generic binding is retained under the CLINGEN project exception. |
| GO:0005515 protein binding | IPI PMID:17185750 AHNAK, a novel component of the dysferlin protein complex, r... | KEEP AS NON CORE | Summary: The curated AHNAK2 association is retained with explicit access limits. Reason: The imported experimental pair and current official AHNAK2/DYSF interaction records support the gene-level association. The normal abstract foregrounds AHNAK and does not resolve the AHNAK2-specific assay; bounded full-original recovery failed. This is a limitation of independent assay attribution, not evidence of a wrong partner or a negative result. Retain the positive generic association under the project exception without claiming a newly inspected AHNAK2 figure, exact construct, or a more specific biochemical binding class. |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: Nebulin binding has a supported cytoskeletal partner class. Reason: The human muscle-library study reports the DYSF–NEB pair with PBS category A and positive proximity ligation in its original supplementary interaction table. Literal IntAct records preserve the DYSF and nebulin fragments, including the P20929-1 participant; the reference-sequence ROGID independently matches that official isoform. Nebulin is an independently established F-actin-associated structural sarcomere protein. Refine the binding class without transferring nebulin structural activity to DYSF, equating PLA proximity with purified contact, or claiming that the full natural proteins were assayed in every record. Proposed replacements: cytoskeletal protein binding |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: Myomesin-1 is an established cytoskeletal structural partner. Reason: The source supplementary table records the DYSF–MYOM1 pair as category A with positive co-IP and proximity ligation, while colocalization was negative. The assays have different scopes: human fragment-library Y2H, mouse co-IP contexts and human-tissue PLA are not all a purified human binary interface. Official MYOM1 annotation establishes a structural component of the myofibrillar M band. Cytoskeletal protein binding captures the independently known partner class while preserving the mixed validation results. Proposed replacements: cytoskeletal protein binding |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: The MYOM2 association supports a cytoskeletal binding refinement. Reason: MYOM2 is independently established as a structural M-band protein. The source table explicitly reports a category D DYSF–MYOM2 Y2H pair with positive proximity ligation and negative colocalization. Category D was a putative network edge unless independently validated; the positive PLA is recorded, without calling it purified direct contact or silently upgrading the initial Y2H score. Literal fragment records and partner identity support cytoskeletal protein binding at this limited assay resolution. Proposed replacements: cytoskeletal protein binding |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: The MYBPC1 pair supports cytoskeletal protein binding. Reason: The original interaction table records the human muscle-library DYSF–MYBPC1 pair as PBS category A; it does not list an orthogonal validation for this particular pair. IntAct preserves the assayed binding regions and reference-sequence identities. MYBPC1 is a thick-filament-associated structural sarcomere protein that binds actin and myosin. This justifies the partner-class refinement from the positive fragment assay without requiring an unperformed native assay or attributing MYBPC1 contractile regulation to DYSF. Proposed replacements: cytoskeletal protein binding |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | KEEP AS NON CORE | Summary: The SGCG association is retained as positive generic binding. Reason: The original table reports the SGCG-bait/DYSF-prey pair as category A with positive proximity ligation; literal records include the SGCG N-terminal 1–36 fragment. SGCG is an independently established membrane sarcoglycan/DGC component linking the actin cytoskeleton to the extracellular matrix, with a cytoskeletal location also recorded by similarity. The inspected evidence most directly establishes this membrane-subcomplex identity, rather than an unambiguous actin, microtubule or intermediate-filament structural protein class. Retain generic binding conservatively; membrane topology itself does not exclude cytoskeletal association, and no purified-contact requirement is imposed. |
| GO:0005515 protein binding | IPI PMID:23414517 A human skeletal muscle interactome centered on proteins inv... | MODIFY | Summary: The recorded titin interaction supports titin binding. Reason: The human muscle-library study records DYSF–TTN as PBS category A with positive PLA in its supplementary table. GO:0031432 names the independently identified partner and is a current child of cytoskeletal protein binding. Fragment Y2H and tissue proximity support this refinement with their original assay scope; the multiple fragment pairs are not independent full-length interface measurements. Proposed replacements: titin binding |
| GO:0005515 protein binding | IPI PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin pro... | MODIFY | Summary: The endogenous HDAC6 association supports histone deacetylase binding. Reason: The complete original shows reciprocal dysferlin/HDAC6 co-IP during differentiation of primary human fetal myogenic cells, alongside FAM65B/RIPOR2 association. It explicitly allows direct or indirect association in this complex. HDAC6 is independently established as a deacetylase, and the study also assays immunoprecipitated HDAC activity. GO:0042826 names the partner class; it does not assert that DYSF is a deacetylase, a purified direct interface, or a chromatin mechanism. The transient myogenic context remains explicit. Proposed replacements: histone deacetylase binding |
| GO:0005515 protein binding | IPI PMID:24687993 Fam65b is important for formation of the HDAC6-dysferlin pro... | KEEP AS NON CORE | Summary: RIPOR2/FAM65B is a supported myogenic interaction partner. Reason: The complete original reports endogenous reciprocal co-IP of dysferlin with FAM65B/RIPOR2 in differentiating primary human fetal myogenic cells and discusses a transient complex with HDAC6. The paper does not establish a purified binary interface. RIPOR2 is a RHOA regulator with cytoskeletal and differentiation contexts, but binding a regulator is not small-GTPase binding and does not transfer its signaling activity to DYSF. Retain this supported contextual association as generic non-core binding; no better evidenced molecular subclass is established by the inspected pair. |
| GO:0005543 phospholipid binding | IDA PMID:24239457 Alternate splicing of dysferlin C2A confers Ca²⁺-dependent a... | ACCEPT | Summary: Phospholipid binding is a central demonstrated DYSF activity. Reason: Human canonical and alternative-exon C2A fragments bind lipid membranes with different calcium dependence in the cited original. Independent human DYSF domain assays show binding to POPC/POPS liposomes even in EDTA and enhancement by calcium, with no significant binding to pure POPC. Retain broad phospholipid binding because universal absolute calcium dependence would misdescribe the observed domain behavior. Neither study assays all 15 natural full-length products. Supporting Evidence: |
| GO:0005544 calcium-dependent phospholipid binding | IMP PMID:11959863 Calcium-sensitive phospholipid binding properties of normal ... | ACCEPT | Summary: Calcium-dependent phospholipid binding is positively supported. Reason: The authentic cited abstract directly reports calcium-sensitive phospholipid binding by dysferlin C2A and reduced binding with the pathogenic V67D substitution. Full-text retrieval failed, so unseen experimental details are not supplied. Independent human C2-domain assays corroborate calcium-enhanced anionic-lipid binding. Preserve the original experimental assertion and qualifier while distinguishing the canonical C2A result from alternative-exon C2A behavior and basal calcium-independent binding. |
| GO:0005768 endosome | IDA PMID:20595382 Reduced plasma membrane expression of dysferlin mutants is a... | MODIFY | Summary: The demonstrated endosomal itinerary resolves early and late compartments. Reason: The complete original tracks surface-labeled full-length dysferlin and deletion constructs in C2C12 myotubes through EEA1/Rab5-positive early endosomes and later dextran/LDL-positive compartments. Full-length protein participates, although some mutant constructs internalize much faster. Refine the broad endosome term to the two independently observed stages, preserving their shared source and without equating construct overexpression with quantitative endogenous human occupancy. Proposed replacements: early endosome late endosome |
| GO:0005769 early endosome | IDA PMID:20595382 Reduced plasma membrane expression of dysferlin mutants is a... | ACCEPT | Summary: Early-endosome localization is directly observed in the trafficking study. Reason: Surface-label internalization and colocalization with early-endosome markers support the positive source assertion in transfected C2C12 myotubes. Full-length dysferlin is included; the larger vesicular burden of selected deletion/pathogenic constructs is a quantitative difference, not evidence that only mutants enter the pathway. The inspected Methods identify the supplied expression plasmid but do not independently authenticate a complete natural human isoform sequence. Supporting Evidence: |
| GO:0005770 late endosome | IDA PMID:20595382 Reduced plasma membrane expression of dysferlin mutants is a... | ACCEPT | Summary: Late-endosome localization is part of the observed dysferlin itinerary. Reason: The source follows internalized full-length and deletion constructs into late endosomal/lysosomal tracer-positive compartments in C2C12 myotubes. Its mutant-enriched vesicular signal does not eliminate the positive full-length result. Independent human-ferlin expression experiments distinguish a substantial Rab7-positive late-endosome pool from more occasional LAMP1 colocalization. Retain the original late-endosome assertion without treating all tracer-positive structures as exclusively lysosomes. Supporting Evidence: |
| GO:0005886 plasma membrane | EXP PMID:10196375 Dysferlin is a plasma membrane protein and is expressed earl... | ACCEPT | Summary: Plasma-membrane localization is directly supported in muscle. Reason: The authentic cited abstract reports an approximately 230-kDa dysferlin band recognized by NCL-Hamlet and plasma-membrane localization by light and electron microscopy in normal muscle fibers, with specific loss in affected patients. This positive experimental result is independently concordant with the other localization studies. The full original was not independently recovered, so details beyond that abstract and the preserved curated EXP assertion are not invented. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA specifically supports a plasma-membrane pool. Reason: The exact DYSF HPA target page reports plasma membrane as supported, while centriolar satellite and mid-piece locations are uncertain; the overall assay reliability is approved. HPA017071 staining in human Rh30 cells includes the plasma membrane, with U2OS showing no staining. This positive, location-specific evidence supports the imported IDA assertion. The XML/HTML metadata were inspected, not image pixels, and neither uncertain additional locations nor a muscle-specific sarcolemma assignment are inferred from this assay. |
| GO:0005886 plasma membrane | IDA PMID:20595382 Reduced plasma membrane expression of dysferlin mutants is a... | ACCEPT | Summary: The trafficking study directly observes surface dysferlin. Reason: Full-length tagged dysferlin reaches the plasma membrane in C2C12 myotubes and is subsequently endocytosed. Extracellular-tag antibody uptake distinguishes the surface-accessible starting population from internal vesicles. Selected mutant constructs redistribute more strongly to vesicles, but the positive full-length surface result is preserved. This is a defined expression-system result, not an isoform-universal native distribution. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:24239457 Alternate splicing of dysferlin C2A confers Ca²⁺-dependent a... | ACCEPT | Summary: Both tested N-terminal classes can reach the plasma membrane. Reason: The cited full original shows surface epitope labeling of full-length EGFP dysferlin constructs containing canonical or alternative exon-1 N-terminal classes in mouse C2C12 cells. An identical HEK293 result is stated without displayed data. This supports the positive location annotation, but the construct class cannot be assigned to one unique current natural isoform from the N terminus alone, and surface targeting does not establish equal repair function for all products. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:26707827 Ferlins Show Tissue-Specific Expression and Segregate as Pla... | ACCEPT | Summary: The human-ferlin localization study supports plasma-membrane residence. Reason: The separately recovered indexed original reports surface antibody labeling, flow analysis and three-dimensional SIM/WGA comparison for tagged dysferlin in HEK293 cells, with similar distribution in C2C12 cells. Plasma-membrane and intracellular endosomal pools coexist. The operative Results were read; the complete Methods and figure pixels were not independently recovered, so no more detailed construct authentication or native occupancy is claimed. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt plasma-membrane mapping agrees with direct localization. Reason: The literal SL-0039 source location is present in the official record and is independently supported by muscle localization, HPA and surface-label trafficking experiments. Retain the general plasma-membrane assignment because positive non-muscle human-cell and placental pools make a universal narrowing to sarcolemma inappropriate. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0005886 plasma membrane | TAS PMID:10496277 Dysferlin is a surface membrane-associated protein that is a... | ACCEPT | Summary: The historical TAS plasma-membrane annotation is supported. Reason: The authentic cited abstract describes dysferlin at muscle membranes, with absent staining in Miyoshi myopathy/LGMD2B while dystrophin-associated proteins remain normal. This statement agrees with independent direct localization. Retain the TAS provenance rather than converting it to a different evidence code or asserting that DYSF is an integral member of the dystrophin-associated glycoprotein complex. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The broad membrane mapping can be resolved to two demonstrated pools. Reason: The literal IPR006614, IPR012560 and IPR012561 entries map to membrane and match ferlin-domain annotations in the target. These domain rules do not by themselves identify a compartment. Independent positive evidence supports plasma membrane and cytoplasmic vesicle membrane, so use both as replacements rather than selecting only the muscle surface or only an endosome subtype. The refinement is gene-level and does not assign the canonical transmembrane anchor to the truncated O75923-15 product. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR006614 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. InterPro:IPR012560 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. InterPro:IPR012561 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. Proposed replacements: plasma membrane cytoplasmic vesicle membrane |
| GO:0030139 endocytic vesicle | IDA PMID:20595382 Reduced plasma membrane expression of dysferlin mutants is a... | ACCEPT | Summary: Endocytic-vesicle localization is directly supported. Reason: The complete original labels the extracellular tag at the cell surface and follows its uptake into vesicles in C2C12 myotubes. Full-length protein and several deletion constructs share the endocytic route, although their rates differ. This establishes the source compartment and does not require the stronger claim that all intracellular dysferlin vesicles are endocytic or that DYSF itself catalyzes endocytosis. Supporting Evidence: |
| GO:0030315 T-tubule | IDA PMID:17185750 AHNAK, a novel component of the dysferlin protein complex, r... | ACCEPT | Summary: T-tubule localization is a supported muscle context. Reason: The cited authentic abstract reports dysferlin and AHNAK together at sarcolemma and T-tubules in normal muscle, while specifically identifying the regeneration experiment as rat. The full localization Methods were not recovered, so the normal-muscle species is not inferred from affiliation or gene names. Independent muscle-cell work reports dysferlin colocalization with the T-tubule system. Retain the positive curated IDA and its scope rather than treating incomplete access as contrary evidence. |
| GO:0030315 T-tubule | IEA GO_REF:0000117 | ACCEPT | Summary: The automated T-tubule mapping is independently supported. Reason: ARBA00087396 contains the target-associated ferlin FunFam condition among several independent rule arms. The positive muscle-localization literature supports the T-tubule term, with normal-muscle and regenerating-rat observations kept distinct and without inferring every rule arm matches DYSF. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00087396 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: A cytoplasmic-vesicle membrane pool is well supported. Reason: The literal SL-0089 location is present in the official record. Surface-label internalization, late-endosome localization and the explicitly identified DYSF Reactome input entity support this membrane pool. It is not a claim that all vesicles are synaptic or that all 15 splice products retain the canonical membrane anchor. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0089 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0030659 cytoplasmic vesicle membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse-ortholog vesicle-membrane inference is supported. Reason: The current Q9ESD7 donor record has an experimental vesicle-membrane annotation attributed to PMID:12736685, and its official location statement identifies dysferlin at fusion vesicles during membrane repair. That original was not independently read in this lane. The ortholog inference is nevertheless concordant with independently inspected target-related surface/internal-vesicle and late-endosome evidence. Preserve the ISS source rather than mislabeling the donor as entirely inferred or inventing a donor assay read. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9ESD7 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0030659 cytoplasmic vesicle membrane | TAS Reactome:R-HSA-5263633 | ACCEPT | Summary: The Reactome location is resolved to the exact human DYSF entity. Reason: The curated event R-HSA-5263633 has input R-HSA-5263626, whose reference entity is UniProt O75923, human DYSF residues 1–2080, in GO:0030659 cytoplasmic vesicle membrane. This is a literal target/compartment join rather than a pathway-title inference. The event models association with CAV3/TRIM72 and transition toward a plasma-membrane complex; it does not establish a purified ternary interface or a measured transport rate. |
| GO:0030672 synaptic vesicle membrane | IBA GO_REF:0000033 | UNDECIDED | Summary: The synaptic-vesicle inference remains biologically unresolved despite a valid PAINT path. Reason: The exact PTN000413636 IBD for GO:0030672 is inherited by the authenticated DYSF leaf; the literal donor RGD:1305199 resolves to rat Mctp1, not a dysferlin ortholog. Its current experimental annotation cites PMID:26195140, whose authentic abstract reports neuronal vesicle/presynaptic localization; full-original access was not recovered. DYSF is a ferlin with a different domain/membrane architecture, while the donor is an MCTP protein. This raises an unresolved functional-specialization question but does not demonstrate target-specific loss or invalidate the node. Preserve the source assertion without asserting that generic DYSF trafficking proves a synaptic pool. Donor count and ordinary is_active_in wording are not reasons for rejection. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000413636 UNRESOLVED Literal IBD and target descent are verified in the authentic tree/MSA; this is not a donor-count or node-validity challenge. RGD:1305199 UNRESOLVED The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0031902 late endosome membrane | IDA PMID:26707827 Ferlins Show Tissue-Specific Expression and Segregate as Pla... | ACCEPT | Summary: Late-endosome membrane localization is supported in the expression assay. Reason: The indexed original Results describe human dysferlin expression with substantial Rab5/Rab7-positive endosomal localization and large Rab7-positive structures usually distinct from LAMP1-positive lysosomes. The tagged human-ferlin study uses HEK293 and C2C12 contexts; its positive late-endosomal membrane pool is retained without treating occasional LAMP1 overlap as an exclusive lysosomal assignment. Complete Methods and figure pixels were not independently inspected. |
| GO:0031902 late endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic late-endosome membrane mapping is concordant with primary evidence. Reason: The official source contains SL-0151, and the current ARBA00033481 rule includes a relevant ferlin FunFam/Catarrhini arm. The independent indexed primary Results support the late-endosomal pool. Retain both literal source identifiers without claiming all eight rule arms match DYSF or that the automated rule itself supplies a new experiment. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00033481 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. UniProtKB-SubCell:SL-0151 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0042383 sarcolemma | IDA PMID:17185750 AHNAK, a novel component of the dysferlin protein complex, r... | ACCEPT | Summary: Sarcolemmal localization is a directly supported muscle pool. Reason: The authentic source abstract reports dysferlin and AHNAK at the sarcolemma in normal muscle and their redistribution during rat muscle regeneration. This agrees with other direct muscle-membrane studies. Preserve the sarcolemma annotation with source-specific normal/regenerating context and the full-original access limitation; do not infer that all plasma-membrane observations in other cell types are sarcolemmal. |
| GO:0042383 sarcolemma | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt sarcolemma mapping is supported. Reason: The literal SL-0238 location is present in the official DYSF record and agrees with the positive muscle-localization literature. This muscle-specific pool coexists with endosomal and non-muscle plasma-membrane pools. Retain the source mapping without equating sarcolemma with every general plasma-membrane assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0238 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0046928 regulation of neurotransmitter secretion | IBA GO_REF:0000033 | UNDECIDED | Summary: Conservation of the MCTP presynaptic regulatory function in DYSF remains unresolved. Reason: The literal PTN000413636 IBD is on the DYSF target path and is grounded by fly Mctp, FBgn0034389/A1ZBD6. The complete donor original PMID:28485711 demonstrates neuronal rescue, altered transmitter release and an ER-localized calcium-sensor mechanism in Drosophila; the fly protein is not dysferlin. The authentic tree and MSA support inherited relatedness, while the distinct MCTP/ferlin architecture and source-specific mechanism leave retention of this presynaptic function in DYSF unresolved. Do not call the source circular, count a single donor as weak, or infer a proven loss from absence of a native DYSF synaptic assay. Propagation Review Root cause: UNRESOLVED Sources checked: FB:FBgn0034389 UNRESOLVED The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. PANTHER:PTN000413636 UNRESOLVED Literal IBD and target descent are verified in the authentic tree/MSA; this is not a donor-count or node-validity challenge. |
| GO:0050765 negative regulation of phagocytosis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: The automated negative-phagocytosis annotation is contextual but supported. Reason: ARBA00089681 contains a target-associated FunFam arm; other rule alternatives are not all claimed to match. The complete original supports a negative relationship between dysferlin function and phagocytosis: controlled mouse J774 knockdown increases uptake, and human patient monocytes show a significant difference after TNF treatment. The untreated human baseline difference was not significant. Preserve the experimental/contextual function as non-core; neither a universal human-cell effect nor a defined Rho-GTPase mechanism is established. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00089681 SUPPORTS TRANSFER The exact source identifier was inspected; see the source-specific reason and saved raw-derived projection. |
| GO:0050765 negative regulation of phagocytosis | IMP PMID:18276788 Dysferlin deficiency enhances monocyte phagocytosis: a model... | KEEP AS NON CORE | Summary: Negative regulation of phagocytosis is retained as a contextual function. Reason: The complete original supports a negative relationship between dysferlin function and phagocytosis: controlled mouse J774 knockdown increases uptake, and human patient monocytes show a significant difference after TNF treatment. The untreated human baseline difference was not significant. Preserve the experimental/contextual function as non-core; neither a universal human-cell effect nor a defined Rho-GTPase mechanism is established. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Urinary-exosome detection is a positive contextual location. Reason: The full original Table 1 explicitly lists DYSF with one unique peptide and one spectrum. Methods describe pooled urine from eight healthy humans, differential ultracentrifugation and LC-MS/MS, with target-decoy filtering, manual checks of single-peptide spectra and disambiguation across genes. The linked NHLBI table identifies NP_003485. Retain this gene-level high-throughput extracellular-vesicle detection as non-core; the measurement does not discriminate all isoforms or demonstrate an active extracellular function, and one peptide or membrane topology alone is not a reason to reject it. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: EPS-urine exosome annotation is retained with explicit target-table access limits. Reason: The full original describes differential-ultracentrifugation exosome preparations from pooled expressed-prostatic-secretion urine, followed by duplicate UHPLC-MS analyses and MaxQuant identification. Its target list is in Supplementary Table 2, whose attempted publisher/PMC/EuropePMC downloads did not yield a valid workbook in this lane. Preserve the positive curator HDA assertion because independent PMID:19056867 directly establishes gene-level urinary-exosome detection; do not claim that the DYSF-specific EPS measurement was independently inspected or that exosome association is a core extracellular activity. |
| GO:0001778 plasma membrane repair | IMP PMID:24967968 Dysferlin regulates cell membrane repair by facilitating inj... | NEW | Summary: Dysferlin contributes directly to plasma membrane resealing. Reason: Patient-derived dysferlin-deficient myoblasts show impaired repair after focal laser injury (PMID:24967968). Human dysferlin constructs also promote calcium-dependent SNARE assembly and lipid mixing in a reconstituted system (PMID:27226605), identifying work performed by the protein. The comparator audit finds membrane-fusion machinery SYT7 and MYOF annotated to this process, plus experimental ANO5 and CHMP3 precedents. Current term ancestry, all 45 imported assertions and the GO-CAM index show no redundant process or contrary modeled role. This combined evidence supports participation; the human-cell phenotype alone would establish necessity. Supporting Evidence: Reactome:R-HSA-5263633 file:human/DYSF/DYSF-bioinformatics/repair-audit/README.md |
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Download this section (compressed HTML)Q: Which full-length products carrying alternative exon 1 reproduce the isolated C2Av1 calcium/lipid response, and how does the membrane-anchor-deficient product localize and function?
Q: Do the inherited synaptic annotations reflect a conserved human dysferlin function or a specialization of experimentally characterized MCTP donors?
Experiment: Compare sequence-authenticated full-length products in matched cell backgrounds using calcium-controlled lipid association, surface/endosomal imaging and damage-repair assays, including expression and trafficking controls.
Hypothesis: The alternative N terminus and loss of the C-terminal anchor have separable effects on full-length dysferlin membrane engagement.
Type: Matched full-length isoform biochemistry and cell imaging
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