{"gene":"DYSF","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2001,"finding":"Mouse dysferlin (ortholog of human DYSF) contains six C2 domains and a C-terminal transmembrane anchoring domain; the SJL mouse strain harbors a splice-site mutation causing exon skipping and dysferlin deficiency, establishing it as a natural model of dysferlinopathy.","method":"cDNA cloning, genomic sequencing, sequence analysis of SJL mutation","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and genomic characterization with identification of splice-site mutation; single lab, two orthogonal methods (cDNA sequencing + genomic analysis)","pmids":["11234777"],"is_preprint":false},{"year":2003,"finding":"Dysferlin has a role in calcium-induced membrane fusion and repair in skeletal muscle, as inferred from functional studies in dysferlin-deficient patient cells.","method":"Functional analysis in dysferlin-deficient patient muscle cells","journal":"Neuromuscular disorders : NMD","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cited as an established role without detailed experimental description in abstract; single mention","pmids":["14678801"],"is_preprint":false},{"year":2003,"finding":"Dysferlin and caveolin-3 interact in human skeletal muscle; secondary reduction of caveolin-3 was detected in dysferlin-deficient (LGMD2B/MM) patients, providing evidence for a dysferlin–caveolin-3 interaction.","method":"Clinical morphological analysis, immunohistochemistry, electron microscopy in patient muscle biopsies","journal":"Journal of neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — secondary caveolin-3 reduction in multiple patients with confirmed dysferlin deficiency; replicated finding across patients but no direct biochemical pulldown described in abstract","pmids":["14673575"],"is_preprint":false},{"year":2008,"finding":"The inner DysF domain of the ferlin family (solved by NMR for myoferlin as structural proxy for dysferlin) has a unique fold stabilized by stacking interactions between arginine and tryptophan residues; pathogenic mutations in dysferlin disrupt this stacking, explaining their disease-causing mechanism.","method":"NMR solution structure determination of inner DysF domain of myoferlin (dysferlin paralogue) with comparison to dysferlin pathogenic mutations","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure with mechanistic interpretation of pathogenic mutations, but structure is of the paralogue myoferlin, not dysferlin itself; single lab","pmids":["18495154"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the human dysferlin inner DysF domain at 1.9 Å resolution shows that the domain is held in a folded conformation by aromatic/arginine stacks (parallel ring/guanidinium stacking, perpendicular H-bond stacking, and aliphatic chain packing); most pathogenic point mutations disrupt these stacking interactions.","method":"X-ray crystallography (1.9 Å resolution crystal structure)","journal":"BMC structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure of human dysferlin inner DysF domain with structural interpretation of pathogenic mutations; single lab but rigorous Tier 1 method","pmids":["24438169"],"is_preprint":false},{"year":2016,"finding":"Pathogenic mutation R959W in the dysferlin inner DysF domain does not cause local unfolding but instead inhibits a 'pincer motion' of a predicted protein-binding site (residues T958–I966 and E1031–H1037), locking the domain in an open state and altering its recognition dynamics, suggesting the inner DysF domain recruits dysferlin to the plasma membrane for membrane repair.","method":"Microsecond molecular dynamics (MD) simulations, protein binding-site prediction, Cartesian principal component analysis","journal":"Molecular bioSystems","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation; single study","pmids":["26806107"],"is_preprint":false},{"year":2018,"finding":"Plasma membrane resealing function of dysferlin can be partially maintained by in-frame deletion of exons 26–27 or 28–29; antisense oligonucleotide-mediated multi-exon skipping of these exons rescues membrane repair in patient cells, demonstrating these regions are dispensable for core membrane-resealing activity.","method":"Membrane wounding assay, antisense oligonucleotide exon skipping, plasmid constructs with mutant DYSF in patient cells","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional membrane-wounding assay with multiple exon-skipping constructs tested in patient cells; single lab, two orthogonal approaches (plasmid constructs + ASOs)","pmids":["30439648"],"is_preprint":false},{"year":2018,"finding":"A missense mutation in dysferlin exon 38 (analogous to human DYSF p.Leu1341Pro) causes dysferlin aggregation and amyloid formation in addition to defects in sarcolemmal membrane repair and progressive muscle wasting; exon 37/38 skipping via U7 snRNA-based splice switching partially rescues the phenotype in vivo.","method":"Knock-in mouse model (MMex38), membrane repair assay, amyloid staining, U7 snRNA exon skipping in vivo","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetically defined mouse model with multiple phenotypic readouts plus in vivo exon-skipping rescue; single lab","pmids":["30292141"],"is_preprint":false},{"year":2022,"finding":"DYSF promoter hypermethylation upregulates DYSF expression; elevated dysferlin in monocytes/macrophages enhances phagocytosis, migration, and adhesion of THP-1 cells, and promotes monocyte activation; SELL was identified as a downstream target of DYSF in this pathway.","method":"Methylation analysis of peripheral blood leukocytes, THP-1 DYSF knockdown and overexpression, phagocytosis/transwell/adhesion assays, WGCNA, Apoe−/− mouse model","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (phagocytosis, migration, adhesion) in knockdown and overexpression conditions plus in vivo validation; single lab","pmids":["35460889"],"is_preprint":false},{"year":2024,"finding":"Dysferlin regulates membrane resealing, calcium homeostasis, and lipid metabolism in skeletal muscle; loss of dysferlin in hiPSC-derived 3D myobundles results in compromised contractile function, impaired calcium handling, defective membrane repair, mitochondrial dysfunction, and lipid droplet accumulation; intracellular Ca²⁺ leak via ryanodine receptor (RyR) is a critical driver of dysferlinopathic contractile and metabolic phenotypes, as RyR inhibition with dantrolene restores contractility, improves membrane repair, and reduces lipid accumulation.","method":"3D tissue-engineered hiPSC-derived skeletal muscle myobundle model, Ca²⁺ imaging, contractility assays, membrane repair assay, transcriptomics, RyR inhibitor (dantrolene) treatment, vamorolone treatment","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays in a human disease model with pharmacological rescue experiments; single lab but broad mechanistic validation","pmids":["38887849"],"is_preprint":false},{"year":2024,"finding":"Loss of dysferlin in cardiomyocytes reduces T-tubule density, decreases systolic Ca²⁺ transient amplitude and rate of decay, and narrows the dyadic cleft; dysferlin-knockout hearts are more susceptible to ventricular arrhythmias; dysferlin is required for T-tubule integrity during hypo-osmotic stress, and cardiac dysferlin abundance declines naturally with age.","method":"Global dysferlin knockout mouse, T-tubule imaging, Ca²⁺ transient measurements, electrical mapping of ex vivo hearts, hypo-osmotic shock injury in vitro","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in KO mouse model with functional cardiac readouts; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"DYSF overexpression in macrophages promotes M1-type polarization, inflammatory cytokine secretion, and cell invasion via regulation of Ca²⁺ influx and activation of the STAT1 signaling pathway; DYSF deficiency suppresses Ca²⁺ influx and STAT1 activation; macrophages overexpressing DYSF inhibit myoblast differentiation in co-culture.","method":"DYSF overexpression and knockdown in macrophages, Ca²⁺ influx measurement, STAT1 activation assay, co-culture of macrophages and myoblasts, cytokine secretion assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (Ca²⁺ influx, STAT1 signaling, co-culture myogenesis) with gain- and loss-of-function; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"Two adjacent homozygous missense mutations in DYSF exon 50 (c.5628C>A p.D1876E and c.5633A>T p.Y1878F) cause exon 50 skipping, resulting in a 32-amino acid deletion in the protein; in vivo splicing assay and in vitro minigene assay demonstrated that c.5628C>A specifically disrupts splicing while c.5633A>T does not.","method":"In vivo splicing assay, in vitro minigene assay, whole-exome sequencing, Sanger sequencing, bioinformatics splice prediction","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vivo and in vitro splicing assays orthogonally confirm the splicing mechanism; single lab","pmids":["38903757"],"is_preprint":false}],"current_model":"Dysferlin (DYSF) is a large, C-terminally membrane-anchored protein containing multiple C2 domains and a nested DysF domain whose fold is stabilized by aromatic/arginine stacking interactions; it functions as a key regulator of plasma membrane resealing in skeletal muscle (requiring its C2 domains for calcium-dependent membrane fusion), maintains T-tubule integrity and excitation-contraction coupling in cardiomyocytes, controls intracellular Ca²⁺ homeostasis through ryanodine receptor-dependent pathways that also affect lipid metabolism and mitochondrial function, interacts with caveolin-3 at the sarcolemma, and in macrophages regulates Ca²⁺ influx and STAT1 signaling to modulate inflammatory polarization and myogenesis; pathogenic missense mutations predominantly disrupt the DysF domain stacking network or disrupt splicing, leading to protein misfolding or loss-of-function."},"narrative":{"mechanistic_narrative":"Dysferlin (DYSF) is a C-terminally membrane-anchored, multi-C2-domain protein that governs calcium-dependent plasma membrane resealing in striated muscle and is the gene mutated in dysferlinopathy [PMID:11234777, PMID:14678801]. Its architecture includes an inner DysF domain whose fold is held in a defined conformation by parallel ring/guanidinium stacking, perpendicular H-bond stacking, and aliphatic packing of aromatic and arginine residues, as resolved by crystallography of the human domain; most pathogenic point mutations cluster here and disrupt these stabilizing stacks [PMID:24438169]. Beyond local folding, the membrane-resealing function tolerates removal of certain regions: in-frame deletion of exons 26–27 or 28–29 by antisense oligonucleotide skipping preserves core repair activity in patient cells [PMID:30439648], whereas an exon-38 missense lesion drives dysferlin aggregation, amyloid formation, and progressive muscle wasting that is partially rescued by splice-switching exon skipping in vivo [PMID:30292141]. In human iPSC-derived 3D myobundles, dysferlin loss compromises contractility, calcium handling, membrane repair, mitochondrial function and lipid handling, with ryanodine-receptor-mediated Ca²⁺ leak identified as a central driver since RyR inhibition by dantrolene restores these phenotypes [PMID:38887849]. Dysferlin also maintains cardiomyocyte T-tubule integrity and excitation–contraction coupling, with knockout hearts showing reduced T-tubule density, blunted Ca²⁺ transients and arrhythmia susceptibility. In myeloid cells, dysferlin enhances monocyte/macrophage phagocytosis, migration and activation [PMID:35460889]. Multiple pathogenic alleles act not by direct coding change but by disrupting splicing, including exon-50 missense variants that induce exon skipping and an in-frame deletion [PMID:38903757].","teleology":[{"year":2001,"claim":"Establishing dysferlin's domain architecture and a natural deficiency model anchored the gene to muscle disease and defined its multi-C2/transmembrane organization.","evidence":"cDNA cloning and genomic sequencing of mouse dysferlin and the SJL splice-site mutation","pmids":["11234777"],"confidence":"Medium","gaps":["Does not define the molecular function of individual C2 domains","Ortholog characterization; human protein function not directly tested here"]},{"year":2003,"claim":"Linking dysferlin to calcium-induced membrane fusion gave the gene a candidate cellular function in sarcolemmal repair.","evidence":"Functional analysis in dysferlin-deficient patient muscle cells","pmids":["14678801"],"confidence":"Low","gaps":["Role asserted without detailed mechanistic assay in the record","Does not identify the fusion machinery dysferlin engages"]},{"year":2003,"claim":"Identifying a dysferlin–caveolin-3 relationship placed dysferlin in a sarcolemmal protein network.","evidence":"Morphological, immunohistochemical and EM analysis of patient muscle biopsies showing secondary caveolin-3 reduction","pmids":["14673575"],"confidence":"Medium","gaps":["No direct biochemical pulldown described","Cannot distinguish direct interaction from secondary co-regulation"]},{"year":2008,"claim":"NMR of the ferlin inner DysF domain provided the first structural rationale for how pathogenic mutations destabilize the fold.","evidence":"NMR solution structure of the myoferlin inner DysF domain used as a proxy for dysferlin","pmids":["18495154"],"confidence":"Medium","gaps":["Structure is of the paralogue myoferlin, not dysferlin","Does not test mutation effects experimentally"]},{"year":2014,"claim":"A high-resolution human dysferlin DysF structure defined the precise stacking interactions whose disruption explains disease-causing point mutations.","evidence":"1.9 Å X-ray crystal structure of the human dysferlin inner DysF domain","pmids":["24438169"],"confidence":"High","gaps":["Single-domain structure; full-length architecture unresolved","Functional consequence of stacking loss not assayed in cells"]},{"year":2016,"claim":"Simulations reframed R959W as altering a binding-site 'pincer' motion rather than causing unfolding, proposing the DysF domain mediates membrane recruitment.","evidence":"Microsecond molecular dynamics, binding-site prediction and principal component analysis","pmids":["26806107"],"confidence":"Low","gaps":["Computational only, no experimental validation","Predicted binding partner unidentified"]},{"year":2018,"claim":"Functional mapping showed core membrane-resealing activity is preserved when specific exons are removed, defining dispensable regions and a therapeutic exon-skipping strategy.","evidence":"Membrane-wounding assays with exon-skipping ASOs and mutant DYSF constructs in patient cells","pmids":["30439648"],"confidence":"Medium","gaps":["Does not quantify long-term in vivo efficacy","Other dysferlin functions of these exons untested"]},{"year":2018,"claim":"An exon-38 missense knock-in revealed that some mutations cause dysferlin aggregation/amyloid in addition to repair failure, expanding the disease mechanism beyond simple loss-of-function.","evidence":"MMex38 knock-in mouse with membrane repair and amyloid readouts plus U7 snRNA exon skipping in vivo","pmids":["30292141"],"confidence":"Medium","gaps":["Mechanism of aggregation toxicity not resolved","Single model and lab"]},{"year":2022,"claim":"Demonstrating that dysferlin drives monocyte/macrophage phagocytosis, migration and activation established a myeloid role beyond muscle.","evidence":"Methylation analysis, THP-1 knockdown/overexpression functional assays, WGCNA and Apoe−/− mouse","pmids":["35460889"],"confidence":"Medium","gaps":["SELL identified as downstream target but mechanism of regulation unclear","Relationship to muscle function not addressed"]},{"year":2024,"claim":"A human iPSC myobundle model identified RyR-mediated Ca²⁺ leak as a central, pharmacologically reversible driver linking dysferlin loss to contractile, mitochondrial and lipid defects.","evidence":"3D hiPSC skeletal myobundles with Ca²⁺ imaging, contractility, repair assays, transcriptomics and dantrolene/vamorolone rescue","pmids":["38887849"],"confidence":"High","gaps":["How dysferlin loss triggers RyR leak mechanistically is undefined","Long-term and in vivo translation not established"]},{"year":2024,"claim":"Cardiomyocyte studies extended dysferlin's role to T-tubule maintenance and excitation-contraction coupling, with arrhythmia susceptibility on knockout.","evidence":"Global dysferlin-KO mouse with T-tubule imaging, Ca²⁺ transients, ex vivo electrical mapping and hypo-osmotic stress (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Molecular basis of T-tubule maintenance unresolved"]},{"year":2024,"claim":"Splicing assays of exon-50 variants showed pathogenicity can arise from disrupted splicing rather than coding change, refining genotype interpretation.","evidence":"In vivo splicing and in vitro minigene assays with WES/Sanger confirmation","pmids":["38903757"],"confidence":"Medium","gaps":["Functional consequence of the 32-aa deletion on protein activity not assayed","Limited to two adjacent variants"]},{"year":2025,"claim":"Macrophage gain/loss-of-function work tied dysferlin to M1 polarization and STAT1 signaling, connecting its myeloid role to inflammation and inhibition of myogenesis.","evidence":"DYSF overexpression/knockdown in macrophages with Ca²⁺ influx, STAT1 assays and macrophage–myoblast co-culture (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Direct molecular link between dysferlin and STAT1 not established"]},{"year":null,"claim":"How dysferlin's C2 domains and DysF domain mechanistically couple Ca²⁺ sensing to membrane fusion, partner recruitment, and RyR-dependent calcium control remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length structure or defined fusion machinery","Direct binding partners of the DysF domain unidentified","Mechanism connecting dysferlin loss to RyR Ca²⁺ leak unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,10]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,11]}],"complexes":[],"partners":["CAV3","RYR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75923","full_name":"Dysferlin","aliases":["Dystrophy-associated fer-1-like protein","Fer-1-like protein 1"],"length_aa":2080,"mass_kda":237.3,"function":"Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity)","subcellular_location":"Cell membrane, sarcolemma; Cytoplasmic vesicle membrane; Cell membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/O75923/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DYSF","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DYSF","total_profiled":1310},"omim":[{"mim_id":"620884","title":"FER1-LIKE FAMILY, MEMBER 6; FER1L6","url":"https://www.omim.org/entry/620884"},{"mim_id":"620883","title":"FER1-LIKE FAMILY, MEMBER 5; FER1L5","url":"https://www.omim.org/entry/620883"},{"mim_id":"614321","title":"MYOPATHY, DISTAL, TATEYAMA TYPE; MPDT","url":"https://www.omim.org/entry/614321"},{"mim_id":"613319","title":"MIYOSHI MUSCULAR DYSTROPHY 3; MMD3","url":"https://www.omim.org/entry/613319"},{"mim_id":"606768","title":"MYOPATHY, DISTAL, WITH ANTERIOR TIBIAL ONSET; DMAT","url":"https://www.omim.org/entry/606768"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":49.3},{"tissue":"skeletal muscle","ntpm":119.0}],"url":"https://www.proteinatlas.org/search/DYSF"},"hgnc":{"alias_symbol":["FER1L1"],"prev_symbol":["LGMD2B"]},"alphafold":{"accession":"O75923","domains":[{"cath_id":"2.60.40.150","chopping":"3-124","consensus_level":"high","plddt":85.2258,"start":3,"end":124},{"cath_id":"2.60.40.150","chopping":"219-349","consensus_level":"high","plddt":84.1361,"start":219,"end":349},{"cath_id":"2.60.40.150","chopping":"377-405_414-489_515-534_542-588","consensus_level":"medium","plddt":82.6452,"start":377,"end":588},{"cath_id":"-","chopping":"943-1057","consensus_level":"high","plddt":79.9812,"start":943,"end":1057},{"cath_id":"2.60.40.150","chopping":"1151-1290_1314-1320","consensus_level":"high","plddt":85.9344,"start":1151,"end":1320},{"cath_id":"2.60.40.150","chopping":"1330-1433_1519-1554","consensus_level":"high","plddt":84.0213,"start":1330,"end":1554},{"cath_id":"2.60.40.150","chopping":"1807-2022","consensus_level":"medium","plddt":82.4391,"start":1807,"end":2022},{"cath_id":"1.20.120","chopping":"670-732_736-784","consensus_level":"high","plddt":87.9294,"start":670,"end":784},{"cath_id":"1.20.5","chopping":"2026-2066","consensus_level":"medium","plddt":71.5195,"start":2026,"end":2066}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75923","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75923-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75923-F1-predicted_aligned_error_v6.png","plddt_mean":78.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DYSF","jax_strain_url":"https://www.jax.org/strain/search?query=DYSF"},"sequence":{"accession":"O75923","fasta_url":"https://rest.uniprot.org/uniprotkb/O75923.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75923/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75923"}},"corpus_meta":[{"pmid":"16010686","id":"PMC_16010686","title":"Dysferlin 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the SJL mouse strain harbors a splice-site mutation causing exon skipping and dysferlin deficiency, establishing it as a natural model of dysferlinopathy.\",\n      \"method\": \"cDNA cloning, genomic sequencing, sequence analysis of SJL mutation\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and genomic characterization with identification of splice-site mutation; single lab, two orthogonal methods (cDNA sequencing + genomic analysis)\",\n      \"pmids\": [\"11234777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Dysferlin has a role in calcium-induced membrane fusion and repair in skeletal muscle, as inferred from functional studies in dysferlin-deficient patient cells.\",\n      \"method\": \"Functional analysis in dysferlin-deficient patient muscle cells\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cited as an established role without detailed experimental description in abstract; single mention\",\n      \"pmids\": [\"14678801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Dysferlin and caveolin-3 interact in human skeletal muscle; secondary reduction of caveolin-3 was detected in dysferlin-deficient (LGMD2B/MM) patients, providing evidence for a dysferlin–caveolin-3 interaction.\",\n      \"method\": \"Clinical morphological analysis, immunohistochemistry, electron microscopy in patient muscle biopsies\",\n      \"journal\": \"Journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — secondary caveolin-3 reduction in multiple patients with confirmed dysferlin deficiency; replicated finding across patients but no direct biochemical pulldown described in abstract\",\n      \"pmids\": [\"14673575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The inner DysF domain of the ferlin family (solved by NMR for myoferlin as structural proxy for dysferlin) has a unique fold stabilized by stacking interactions between arginine and tryptophan residues; pathogenic mutations in dysferlin disrupt this stacking, explaining their disease-causing mechanism.\",\n      \"method\": \"NMR solution structure determination of inner DysF domain of myoferlin (dysferlin paralogue) with comparison to dysferlin pathogenic mutations\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure with mechanistic interpretation of pathogenic mutations, but structure is of the paralogue myoferlin, not dysferlin itself; single lab\",\n      \"pmids\": [\"18495154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the human dysferlin inner DysF domain at 1.9 Å resolution shows that the domain is held in a folded conformation by aromatic/arginine stacks (parallel ring/guanidinium stacking, perpendicular H-bond stacking, and aliphatic chain packing); most pathogenic point mutations disrupt these stacking interactions.\",\n      \"method\": \"X-ray crystallography (1.9 Å resolution crystal structure)\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure of human dysferlin inner DysF domain with structural interpretation of pathogenic mutations; single lab but rigorous Tier 1 method\",\n      \"pmids\": [\"24438169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pathogenic mutation R959W in the dysferlin inner DysF domain does not cause local unfolding but instead inhibits a 'pincer motion' of a predicted protein-binding site (residues T958–I966 and E1031–H1037), locking the domain in an open state and altering its recognition dynamics, suggesting the inner DysF domain recruits dysferlin to the plasma membrane for membrane repair.\",\n      \"method\": \"Microsecond molecular dynamics (MD) simulations, protein binding-site prediction, Cartesian principal component analysis\",\n      \"journal\": \"Molecular bioSystems\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation; single study\",\n      \"pmids\": [\"26806107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plasma membrane resealing function of dysferlin can be partially maintained by in-frame deletion of exons 26–27 or 28–29; antisense oligonucleotide-mediated multi-exon skipping of these exons rescues membrane repair in patient cells, demonstrating these regions are dispensable for core membrane-resealing activity.\",\n      \"method\": \"Membrane wounding assay, antisense oligonucleotide exon skipping, plasmid constructs with mutant DYSF in patient cells\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional membrane-wounding assay with multiple exon-skipping constructs tested in patient cells; single lab, two orthogonal approaches (plasmid constructs + ASOs)\",\n      \"pmids\": [\"30439648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A missense mutation in dysferlin exon 38 (analogous to human DYSF p.Leu1341Pro) causes dysferlin aggregation and amyloid formation in addition to defects in sarcolemmal membrane repair and progressive muscle wasting; exon 37/38 skipping via U7 snRNA-based splice switching partially rescues the phenotype in vivo.\",\n      \"method\": \"Knock-in mouse model (MMex38), membrane repair assay, amyloid staining, U7 snRNA exon skipping in vivo\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetically defined mouse model with multiple phenotypic readouts plus in vivo exon-skipping rescue; single lab\",\n      \"pmids\": [\"30292141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DYSF promoter hypermethylation upregulates DYSF expression; elevated dysferlin in monocytes/macrophages enhances phagocytosis, migration, and adhesion of THP-1 cells, and promotes monocyte activation; SELL was identified as a downstream target of DYSF in this pathway.\",\n      \"method\": \"Methylation analysis of peripheral blood leukocytes, THP-1 DYSF knockdown and overexpression, phagocytosis/transwell/adhesion assays, WGCNA, Apoe−/− mouse model\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (phagocytosis, migration, adhesion) in knockdown and overexpression conditions plus in vivo validation; single lab\",\n      \"pmids\": [\"35460889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dysferlin regulates membrane resealing, calcium homeostasis, and lipid metabolism in skeletal muscle; loss of dysferlin in hiPSC-derived 3D myobundles results in compromised contractile function, impaired calcium handling, defective membrane repair, mitochondrial dysfunction, and lipid droplet accumulation; intracellular Ca²⁺ leak via ryanodine receptor (RyR) is a critical driver of dysferlinopathic contractile and metabolic phenotypes, as RyR inhibition with dantrolene restores contractility, improves membrane repair, and reduces lipid accumulation.\",\n      \"method\": \"3D tissue-engineered hiPSC-derived skeletal muscle myobundle model, Ca²⁺ imaging, contractility assays, membrane repair assay, transcriptomics, RyR inhibitor (dantrolene) treatment, vamorolone treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays in a human disease model with pharmacological rescue experiments; single lab but broad mechanistic validation\",\n      \"pmids\": [\"38887849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of dysferlin in cardiomyocytes reduces T-tubule density, decreases systolic Ca²⁺ transient amplitude and rate of decay, and narrows the dyadic cleft; dysferlin-knockout hearts are more susceptible to ventricular arrhythmias; dysferlin is required for T-tubule integrity during hypo-osmotic stress, and cardiac dysferlin abundance declines naturally with age.\",\n      \"method\": \"Global dysferlin knockout mouse, T-tubule imaging, Ca²⁺ transient measurements, electrical mapping of ex vivo hearts, hypo-osmotic shock injury in vitro\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in KO mouse model with functional cardiac readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DYSF overexpression in macrophages promotes M1-type polarization, inflammatory cytokine secretion, and cell invasion via regulation of Ca²⁺ influx and activation of the STAT1 signaling pathway; DYSF deficiency suppresses Ca²⁺ influx and STAT1 activation; macrophages overexpressing DYSF inhibit myoblast differentiation in co-culture.\",\n      \"method\": \"DYSF overexpression and knockdown in macrophages, Ca²⁺ influx measurement, STAT1 activation assay, co-culture of macrophages and myoblasts, cytokine secretion assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (Ca²⁺ influx, STAT1 signaling, co-culture myogenesis) with gain- and loss-of-function; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Two adjacent homozygous missense mutations in DYSF exon 50 (c.5628C>A p.D1876E and c.5633A>T p.Y1878F) cause exon 50 skipping, resulting in a 32-amino acid deletion in the protein; in vivo splicing assay and in vitro minigene assay demonstrated that c.5628C>A specifically disrupts splicing while c.5633A>T does not.\",\n      \"method\": \"In vivo splicing assay, in vitro minigene assay, whole-exome sequencing, Sanger sequencing, bioinformatics splice prediction\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo and in vitro splicing assays orthogonally confirm the splicing mechanism; single lab\",\n      \"pmids\": [\"38903757\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Dysferlin (DYSF) is a large, C-terminally membrane-anchored protein containing multiple C2 domains and a nested DysF domain whose fold is stabilized by aromatic/arginine stacking interactions; it functions as a key regulator of plasma membrane resealing in skeletal muscle (requiring its C2 domains for calcium-dependent membrane fusion), maintains T-tubule integrity and excitation-contraction coupling in cardiomyocytes, controls intracellular Ca²⁺ homeostasis through ryanodine receptor-dependent pathways that also affect lipid metabolism and mitochondrial function, interacts with caveolin-3 at the sarcolemma, and in macrophages regulates Ca²⁺ influx and STAT1 signaling to modulate inflammatory polarization and myogenesis; pathogenic missense mutations predominantly disrupt the DysF domain stacking network or disrupt splicing, leading to protein misfolding or loss-of-function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Dysferlin (DYSF) is a C-terminally membrane-anchored, multi-C2-domain protein that governs calcium-dependent plasma membrane resealing in striated muscle and is the gene mutated in dysferlinopathy [#0, #1]. Its architecture includes an inner DysF domain whose fold is held in a defined conformation by parallel ring/guanidinium stacking, perpendicular H-bond stacking, and aliphatic packing of aromatic and arginine residues, as resolved by crystallography of the human domain; most pathogenic point mutations cluster here and disrupt these stabilizing stacks [#4]. Beyond local folding, the membrane-resealing function tolerates removal of certain regions: in-frame deletion of exons 26\\u201327 or 28\\u201329 by antisense oligonucleotide skipping preserves core repair activity in patient cells [#6], whereas an exon-38 missense lesion drives dysferlin aggregation, amyloid formation, and progressive muscle wasting that is partially rescued by splice-switching exon skipping in vivo [#7]. In human iPSC-derived 3D myobundles, dysferlin loss compromises contractility, calcium handling, membrane repair, mitochondrial function and lipid handling, with ryanodine-receptor-mediated Ca\\u00b2\\u207a leak identified as a central driver since RyR inhibition by dantrolene restores these phenotypes [#9]. Dysferlin also maintains cardiomyocyte T-tubule integrity and excitation\\u2013contraction coupling, with knockout hearts showing reduced T-tubule density, blunted Ca\\u00b2\\u207a transients and arrhythmia susceptibility [#10]. In myeloid cells, dysferlin enhances monocyte/macrophage phagocytosis, migration and activation [#8]. Multiple pathogenic alleles act not by direct coding change but by disrupting splicing, including exon-50 missense variants that induce exon skipping and an in-frame deletion [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing dysferlin's domain architecture and a natural deficiency model anchored the gene to muscle disease and defined its multi-C2/transmembrane organization.\",\n      \"evidence\": \"cDNA cloning and genomic sequencing of mouse dysferlin and the SJL splice-site mutation\",\n      \"pmids\": [\"11234777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular function of individual C2 domains\", \"Ortholog characterization; human protein function not directly tested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linking dysferlin to calcium-induced membrane fusion gave the gene a candidate cellular function in sarcolemmal repair.\",\n      \"evidence\": \"Functional analysis in dysferlin-deficient patient muscle cells\",\n      \"pmids\": [\"14678801\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Role asserted without detailed mechanistic assay in the record\", \"Does not identify the fusion machinery dysferlin engages\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying a dysferlin\\u2013caveolin-3 relationship placed dysferlin in a sarcolemmal protein network.\",\n      \"evidence\": \"Morphological, immunohistochemical and EM analysis of patient muscle biopsies showing secondary caveolin-3 reduction\",\n      \"pmids\": [\"14673575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical pulldown described\", \"Cannot distinguish direct interaction from secondary co-regulation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"NMR of the ferlin inner DysF domain provided the first structural rationale for how pathogenic mutations destabilize the fold.\",\n      \"evidence\": \"NMR solution structure of the myoferlin inner DysF domain used as a proxy for dysferlin\",\n      \"pmids\": [\"18495154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structure is of the paralogue myoferlin, not dysferlin\", \"Does not test mutation effects experimentally\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A high-resolution human dysferlin DysF structure defined the precise stacking interactions whose disruption explains disease-causing point mutations.\",\n      \"evidence\": \"1.9 \\u00c5 X-ray crystal structure of the human dysferlin inner DysF domain\",\n      \"pmids\": [\"24438169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-domain structure; full-length architecture unresolved\", \"Functional consequence of stacking loss not assayed in cells\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Simulations reframed R959W as altering a binding-site 'pincer' motion rather than causing unfolding, proposing the DysF domain mediates membrane recruitment.\",\n      \"evidence\": \"Microsecond molecular dynamics, binding-site prediction and principal component analysis\",\n      \"pmids\": [\"26806107\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational only, no experimental validation\", \"Predicted binding partner unidentified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Functional mapping showed core membrane-resealing activity is preserved when specific exons are removed, defining dispensable regions and a therapeutic exon-skipping strategy.\",\n      \"evidence\": \"Membrane-wounding assays with exon-skipping ASOs and mutant DYSF constructs in patient cells\",\n      \"pmids\": [\"30439648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not quantify long-term in vivo efficacy\", \"Other dysferlin functions of these exons untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An exon-38 missense knock-in revealed that some mutations cause dysferlin aggregation/amyloid in addition to repair failure, expanding the disease mechanism beyond simple loss-of-function.\",\n      \"evidence\": \"MMex38 knock-in mouse with membrane repair and amyloid readouts plus U7 snRNA exon skipping in vivo\",\n      \"pmids\": [\"30292141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of aggregation toxicity not resolved\", \"Single model and lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that dysferlin drives monocyte/macrophage phagocytosis, migration and activation established a myeloid role beyond muscle.\",\n      \"evidence\": \"Methylation analysis, THP-1 knockdown/overexpression functional assays, WGCNA and Apoe\\u2212/\\u2212 mouse\",\n      \"pmids\": [\"35460889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SELL identified as downstream target but mechanism of regulation unclear\", \"Relationship to muscle function not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A human iPSC myobundle model identified RyR-mediated Ca\\u00b2\\u207a leak as a central, pharmacologically reversible driver linking dysferlin loss to contractile, mitochondrial and lipid defects.\",\n      \"evidence\": \"3D hiPSC skeletal myobundles with Ca\\u00b2\\u207a imaging, contractility, repair assays, transcriptomics and dantrolene/vamorolone rescue\",\n      \"pmids\": [\"38887849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dysferlin loss triggers RyR leak mechanistically is undefined\", \"Long-term and in vivo translation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiomyocyte studies extended dysferlin's role to T-tubule maintenance and excitation-contraction coupling, with arrhythmia susceptibility on knockout.\",\n      \"evidence\": \"Global dysferlin-KO mouse with T-tubule imaging, Ca\\u00b2\\u207a transients, ex vivo electrical mapping and hypo-osmotic stress (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Molecular basis of T-tubule maintenance unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Splicing assays of exon-50 variants showed pathogenicity can arise from disrupted splicing rather than coding change, refining genotype interpretation.\",\n      \"evidence\": \"In vivo splicing and in vitro minigene assays with WES/Sanger confirmation\",\n      \"pmids\": [\"38903757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the 32-aa deletion on protein activity not assayed\", \"Limited to two adjacent variants\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Macrophage gain/loss-of-function work tied dysferlin to M1 polarization and STAT1 signaling, connecting its myeloid role to inflammation and inhibition of myogenesis.\",\n      \"evidence\": \"DYSF overexpression/knockdown in macrophages with Ca\\u00b2\\u207a influx, STAT1 assays and macrophage\\u2013myoblast co-culture (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct molecular link between dysferlin and STAT1 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How dysferlin's C2 domains and DysF domain mechanistically couple Ca\\u00b2\\u207a sensing to membrane fusion, partner recruitment, and RyR-dependent calcium control remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length structure or defined fusion machinery\", \"Direct binding partners of the DysF domain unidentified\", \"Mechanism connecting dysferlin loss to RyR Ca\\u00b2\\u207a leak unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAV3\", \"RYR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}