{"gene":"MYOF","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2019,"finding":"A truncating frameshift variant in MYOF (c.[2576delG; 2575G>C], p.G859QfsTer8) causes limb-girdle muscular dystrophy and cardiomyopathy; functional studies in primary patient skeletal muscle mesenchymal progenitor cells (RNA sequencing and morphological studies) and in vivo zebrafish modeling confirmed the disease-causative role of MYOF loss-of-function.","method":"Whole exome sequencing, in vitro functional studies (RNA-seq, morphology) in patient-derived cells, and in vivo zebrafish phenotype rescue experiments","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell functional studies plus in vivo zebrafish model, single lab, two orthogonal methods","pmids":["31297131"],"is_preprint":false},{"year":2025,"finding":"MYOF recruits both OTUB1 (a deubiquitinase) and ILF3 to enhance their interaction, thereby preventing K48-linked ubiquitination and proteasomal degradation of ILF3; stabilized ILF3 then binds and increases LCN2 mRNA stability, promoting LCN2 expression and suppressing ferroptosis in pancreatic cancer cells.","method":"MYOF knockout (in vitro and in vivo xenograft), co-immunoprecipitation, ectopic LCN2 rescue experiments, proteasome inhibitor assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO with defined phenotype, rescue experiment, single lab","pmids":["40381229"],"is_preprint":false},{"year":2025,"finding":"The E3 ubiquitin ligase TRIM8 targets MYOF for K48-linked polyubiquitination, leading to proteasome-mediated degradation of MYOF; TRIM8-mediated MYOF degradation suppresses extracellular secretion of matrix metalloproteinases (MMPs) and lung cancer cell migration/invasion.","method":"Gain- and loss-of-function experiments in NSCLC cells, xenograft mouse model, MYOF rescue in TRIM8-overexpressing cells, ubiquitination assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue, ubiquitination assay, in vivo model, single lab","pmids":["39934162"],"is_preprint":false},{"year":2024,"finding":"hnRNPLL regulates MYOF alternative splicing; its depletion causes MYOF exon 17 retention, reducing the short isoform MYOFb and inhibiting pancreatic cancer cell migration and invasion. Conversely, hnRNPLL or MYOFb overexpression promotes migration and invasion, placing hnRNPLL upstream of MYOF isoform switching in metastasis.","method":"hnRNPLL knockdown with RNA-seq (exon-skipping analysis), overexpression of hnRNPLL and MYOFb isoform, migration and invasion assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD plus overexpression with functional readout, single lab, two orthogonal methods","pmids":["39742990"],"is_preprint":false},{"year":2024,"finding":"Myoferlin (MYOF) associates with influenza A virus (IAV) viral ribonucleoprotein (vRNP) complexes in the cytoplasm and colocalizes with Rab11a endosomal recycling vesicles during late-stage IAV infection; this role is conserved for RSV and Sendai virus (SeV). MYOF likely recruits EHD family proteins (involved in endosomal biogenesis) to these vRNP trafficking vesicles.","method":"Co-localization imaging, biochemical association assays, loss-of-function studies in viral infection models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization and co-association confirmed across multiple viruses, preprint, single lab","pmids":["bio_10.1101_2024.07.02.601679"],"is_preprint":true}],"current_model":"MYOF (myoferlin) is a membrane-associated ferlin family protein that functions in vesicle trafficking, endosomal recycling, and membrane repair; it stabilizes the deubiquitinase target ILF3 by scaffolding OTUB1–ILF3 complexes to promote LCN2 mRNA stability, is itself subject to TRIM8-mediated K48-linked polyubiquitination and proteasomal degradation, undergoes hnRNPLL-regulated alternative splicing to generate pro-migratory isoforms, associates with Rab11a/vRNP endosomal vesicles during RNA virus infection, and loss-of-function variants cause skeletal muscle and cardiac disease in humans."},"narrative":{"mechanistic_narrative":"MYOF (myoferlin) is a membrane-associated protein implicated in vesicle trafficking and tissue homeostasis whose loss of function causes human disease and whose levels and isoforms are tightly controlled in cancer and infection contexts [PMID:31297131, PMID:39934162]. A truncating frameshift variant in MYOF causes limb-girdle muscular dystrophy with cardiomyopathy, with the disease-causative role of MYOF loss-of-function confirmed in patient-derived skeletal muscle mesenchymal progenitor cells and zebrafish modeling [PMID:31297131]. In cancer, MYOF acts as a scaffold that recruits the deubiquitinase OTUB1 together with ILF3, preventing K48-linked ubiquitination and proteasomal degradation of ILF3; stabilized ILF3 binds and stabilizes LCN2 mRNA, promoting LCN2 expression and suppressing ferroptosis in pancreatic cancer cells [PMID:40381229]. MYOF protein abundance is itself constrained by the E3 ubiquitin ligase TRIM8, which directs K48-linked polyubiquitination and proteasomal degradation of MYOF, thereby restraining MMP secretion and tumor cell migration and invasion [PMID:39934162]. MYOF isoform composition is set by hnRNPLL-regulated alternative splicing, where hnRNPLL promotes inclusion that generates the pro-migratory short isoform MYOFb [PMID:39742990]. During RNA virus infection, MYOF associates with influenza viral ribonucleoprotein complexes and colocalizes with Rab11a endosomal recycling vesicles, a role conserved across RSV and Sendai virus [PMID:bio_10.1101_2024.07.02.601679].","teleology":[{"year":2019,"claim":"Established that MYOF loss-of-function is causative for human muscle and cardiac disease, moving MYOF from a candidate to a confirmed disease gene.","evidence":"Whole exome sequencing of a frameshift variant, RNA-seq and morphology in patient-derived muscle progenitor cells, and zebrafish phenotype modeling","pmids":["31297131"],"confidence":"Medium","gaps":["The molecular pathway connecting MYOF loss to dystrophic and cardiac phenotypes is not defined","Single family/variant; allelic spectrum not established","No mechanistic link to membrane repair or trafficking demonstrated in this study"]},{"year":2024,"claim":"Identified hnRNPLL-driven alternative splicing as the upstream switch generating the pro-migratory MYOFb isoform, explaining how MYOF isoform choice contributes to metastatic behavior.","evidence":"hnRNPLL knockdown with exon-skipping RNA-seq plus hnRNPLL and MYOFb overexpression with migration/invasion assays in pancreatic cancer cells","pmids":["39742990"],"confidence":"Medium","gaps":["Functional distinction between MYOFb and the full-length isoform at the protein level is not resolved","Direct binding of hnRNPLL to MYOF pre-mRNA not shown","Whether isoform switching operates outside pancreatic cancer is untested"]},{"year":2024,"claim":"Placed MYOF in viral RNA trafficking by showing it associates with viral ribonucleoprotein complexes and Rab11a recycling vesicles, suggesting a conserved role in RNA virus assembly/egress.","evidence":"Co-localization imaging, biochemical association, and loss-of-function in IAV, RSV, and SeV infection models (preprint)","pmids":["bio_10.1101_2024.07.02.601679"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Proposed EHD recruitment to vRNP vesicles not directly demonstrated","Mechanism of MYOF recruitment to vRNP/Rab11a vesicles unresolved"]},{"year":2025,"claim":"Defined a MYOF scaffolding function that stabilizes ILF3 via OTUB1 to sustain LCN2 expression and suppress ferroptosis, providing a molecular pathway for MYOF in tumor cell survival.","evidence":"MYOF knockout in vitro and in xenografts, co-immunoprecipitation, proteasome inhibitor assays, and ectopic LCN2 rescue in pancreatic cancer cells","pmids":["40381229"],"confidence":"Medium","gaps":["Structural basis of the MYOF–OTUB1–ILF3 ternary complex not determined","Whether this scaffolding activity relates to MYOF's trafficking/membrane functions is unknown","Direct vs indirect nature of the interactions rests on Co-IP without reciprocal structural validation"]},{"year":2025,"claim":"Showed MYOF protein levels are controlled by TRIM8-mediated K48 polyubiquitination and degradation, identifying a post-translational brake on MYOF-driven MMP secretion and invasion.","evidence":"Gain/loss-of-function and MYOF rescue in NSCLC cells, ubiquitination assays, and xenograft model","pmids":["39934162"],"confidence":"Medium","gaps":["TRIM8 ubiquitination site(s) on MYOF not mapped","How MMP secretion is mechanistically linked to MYOF is not detailed","Whether TRIM8 regulation applies to MYOF's muscle functions is untested"]},{"year":null,"claim":"How MYOF's vesicle-trafficking/membrane biology mechanistically unifies its disparate roles in muscle disease, cancer scaffolding, and viral RNA transport remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single mechanistic study connects the membrane/trafficking function to the cancer scaffolding role","No structural model of MYOF or its complexes in the corpus","Tissue-specific determinants of MYOF function not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[4]}],"complexes":[],"partners":["OTUB1","ILF3","TRIM8","HNRNPLL","RAB11A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZM1","full_name":"Myoferlin","aliases":["Fer-1-like protein 3"],"length_aa":2061,"mass_kda":234.7,"function":"Calcium/phospholipid-binding protein that plays a role in the plasmalemma repair mechanism of endothelial cells that permits rapid resealing of membranes disrupted by mechanical stress. Involved in endocytic recycling. Implicated in VEGF signal transduction by regulating the levels of the receptor KDR (By similarity)","subcellular_location":"Cell membrane; Nucleus membrane; Cytoplasmic vesicle membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZM1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYOF","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYOF","total_profiled":1310},"omim":[{"mim_id":"619366","title":"ANGIOEDEMA, HEREDITARY, 7; HAE7","url":"https://www.omim.org/entry/619366"},{"mim_id":"604603","title":"MYOFERLIN; MYOF","url":"https://www.omim.org/entry/604603"},{"mim_id":"603009","title":"DYSFERLIN; DYSF","url":"https://www.omim.org/entry/603009"},{"mim_id":"106100","title":"ANGIOEDEMA, HEREDITARY, 1; HAE1","url":"https://www.omim.org/entry/106100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Centriolar satellite","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYOF"},"hgnc":{"alias_symbol":["KIAA1207"],"prev_symbol":["FER1L3"]},"alphafold":{"accession":"Q9NZM1","domains":[{"cath_id":"2.60.40.150","chopping":"3-125","consensus_level":"high","plddt":87.5181,"start":3,"end":125},{"cath_id":"2.60.40.150","chopping":"198-331_339-354","consensus_level":"high","plddt":80.9095,"start":198,"end":354},{"cath_id":"2.60.40.150","chopping":"356-469_495-570","consensus_level":"medium","plddt":78.8629,"start":356,"end":570},{"cath_id":"-","chopping":"931-962_1017-1029","consensus_level":"medium","plddt":85.0922,"start":931,"end":1029},{"cath_id":"2.60.40.150","chopping":"1136-1299","consensus_level":"medium","plddt":86.2299,"start":1136,"end":1299},{"cath_id":"2.60.40.150","chopping":"1300-1417_1492-1534","consensus_level":"medium","plddt":81.8071,"start":1300,"end":1534},{"cath_id":"2.60.40.150","chopping":"1552-1653_1742-1773","consensus_level":"medium","plddt":87.8244,"start":1552,"end":1773},{"cath_id":"2.60.40.150","chopping":"1787-1928_1935-2006","consensus_level":"high","plddt":83.791,"start":1787,"end":2006},{"cath_id":"1.20.120","chopping":"652-714_718-766","consensus_level":"medium","plddt":87.0914,"start":652,"end":766},{"cath_id":"1.20.5","chopping":"2009-2049","consensus_level":"medium","plddt":69.439,"start":2009,"end":2049}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZM1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZM1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZM1-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYOF","jax_strain_url":"https://www.jax.org/strain/search?query=MYOF"},"sequence":{"accession":"Q9NZM1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZM1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZM1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZM1"}},"corpus_meta":[{"pmid":"12953059","id":"PMC_12953059","title":"Shared, unique and redundant functions of three members of the class I myosins (MyoA, MyoB and MyoF) in motility and chemotaxis in Dictyostelium.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12953059","citation_count":43,"is_preprint":false},{"pmid":"7787058","id":"PMC_7787058","title":"Molecular genetic analysis of myoF, a new Dictyostelium myosin I gene.","date":"1995","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/7787058","citation_count":16,"is_preprint":false},{"pmid":"34464754","id":"PMC_34464754","title":"Dynamics of the orphan myosin MyoF over Trypanosoma cruzi life cycle and along the endocytic pathway.","date":"2021","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/34464754","citation_count":12,"is_preprint":false},{"pmid":"31297131","id":"PMC_31297131","title":"Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy.","date":"2019","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31297131","citation_count":9,"is_preprint":false},{"pmid":"32552653","id":"PMC_32552653","title":"An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors.","date":"2020","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32552653","citation_count":8,"is_preprint":false},{"pmid":"39742990","id":"PMC_39742990","title":"hnRNPLL regulates MYOF alternative splicing and correlates with early metastasis in pancreatic ductal adenocarcinoma.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39742990","citation_count":6,"is_preprint":false},{"pmid":"40381229","id":"PMC_40381229","title":"Targeting MYOF suppresses pancreatic ductal adenocarcinoma progression by inhibiting ILF3-LCN2 signaling through disrupting OTUB1-mediated deubiquitination of ILF3.","date":"2025","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/40381229","citation_count":5,"is_preprint":false},{"pmid":"39934162","id":"PMC_39934162","title":"E3 ligase TRIM8 suppresses lung cancer metastasis by targeting MYOF degradation through K48-linked polyubiquitination.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39934162","citation_count":2,"is_preprint":false},{"pmid":"38054026","id":"PMC_38054026","title":"Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38054026","citation_count":1,"is_preprint":false},{"pmid":"38253296","id":"PMC_38253296","title":"A missense variant in MYOF is associated with ARVC and sudden cardiac death.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38253296","citation_count":1,"is_preprint":false},{"pmid":"39498317","id":"PMC_39498317","title":"Corrigendum: Chronic systemic capillary leak syndrome with lymphatic capillaries involvement and MYOF mutation: case report and literature review.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39498317","citation_count":0,"is_preprint":false},{"pmid":"40665025","id":"PMC_40665025","title":"In silico analysis of the oncogenic role of myoferlin (MYOF) and suggestion of folate as a potential therapeutic for brain cancer in the Caucasian population.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40665025","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.02.679852","title":"Molecular features of Myosin F adapted for driving actin flows in  <i>Toxoplasma 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disease","date":"2024-10-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.18.619080","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8660,"output_tokens":1422,"usd":0.023655,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8090,"output_tokens":2502,"usd":0.0515,"stage2_stop_reason":"end_turn"},"total_usd":0.075155,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"A truncating frameshift variant in MYOF (c.[2576delG; 2575G>C], p.G859QfsTer8) causes limb-girdle muscular dystrophy and cardiomyopathy; functional studies in primary patient skeletal muscle mesenchymal progenitor cells (RNA sequencing and morphological studies) and in vivo zebrafish modeling confirmed the disease-causative role of MYOF loss-of-function.\",\n      \"method\": \"Whole exome sequencing, in vitro functional studies (RNA-seq, morphology) in patient-derived cells, and in vivo zebrafish phenotype rescue experiments\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell functional studies plus in vivo zebrafish model, single lab, two orthogonal methods\",\n      \"pmids\": [\"31297131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYOF recruits both OTUB1 (a deubiquitinase) and ILF3 to enhance their interaction, thereby preventing K48-linked ubiquitination and proteasomal degradation of ILF3; stabilized ILF3 then binds and increases LCN2 mRNA stability, promoting LCN2 expression and suppressing ferroptosis in pancreatic cancer cells.\",\n      \"method\": \"MYOF knockout (in vitro and in vivo xenograft), co-immunoprecipitation, ectopic LCN2 rescue experiments, proteasome inhibitor assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO with defined phenotype, rescue experiment, single lab\",\n      \"pmids\": [\"40381229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The E3 ubiquitin ligase TRIM8 targets MYOF for K48-linked polyubiquitination, leading to proteasome-mediated degradation of MYOF; TRIM8-mediated MYOF degradation suppresses extracellular secretion of matrix metalloproteinases (MMPs) and lung cancer cell migration/invasion.\",\n      \"method\": \"Gain- and loss-of-function experiments in NSCLC cells, xenograft mouse model, MYOF rescue in TRIM8-overexpressing cells, ubiquitination assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue, ubiquitination assay, in vivo model, single lab\",\n      \"pmids\": [\"39934162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hnRNPLL regulates MYOF alternative splicing; its depletion causes MYOF exon 17 retention, reducing the short isoform MYOFb and inhibiting pancreatic cancer cell migration and invasion. Conversely, hnRNPLL or MYOFb overexpression promotes migration and invasion, placing hnRNPLL upstream of MYOF isoform switching in metastasis.\",\n      \"method\": \"hnRNPLL knockdown with RNA-seq (exon-skipping analysis), overexpression of hnRNPLL and MYOFb isoform, migration and invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD plus overexpression with functional readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"39742990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myoferlin (MYOF) associates with influenza A virus (IAV) viral ribonucleoprotein (vRNP) complexes in the cytoplasm and colocalizes with Rab11a endosomal recycling vesicles during late-stage IAV infection; this role is conserved for RSV and Sendai virus (SeV). MYOF likely recruits EHD family proteins (involved in endosomal biogenesis) to these vRNP trafficking vesicles.\",\n      \"method\": \"Co-localization imaging, biochemical association assays, loss-of-function studies in viral infection models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization and co-association confirmed across multiple viruses, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.07.02.601679\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MYOF (myoferlin) is a membrane-associated ferlin family protein that functions in vesicle trafficking, endosomal recycling, and membrane repair; it stabilizes the deubiquitinase target ILF3 by scaffolding OTUB1–ILF3 complexes to promote LCN2 mRNA stability, is itself subject to TRIM8-mediated K48-linked polyubiquitination and proteasomal degradation, undergoes hnRNPLL-regulated alternative splicing to generate pro-migratory isoforms, associates with Rab11a/vRNP endosomal vesicles during RNA virus infection, and loss-of-function variants cause skeletal muscle and cardiac disease in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYOF (myoferlin) is a membrane-associated protein implicated in vesicle trafficking and tissue homeostasis whose loss of function causes human disease and whose levels and isoforms are tightly controlled in cancer and infection contexts [#0, #2]. A truncating frameshift variant in MYOF causes limb-girdle muscular dystrophy with cardiomyopathy, with the disease-causative role of MYOF loss-of-function confirmed in patient-derived skeletal muscle mesenchymal progenitor cells and zebrafish modeling [#0]. In cancer, MYOF acts as a scaffold that recruits the deubiquitinase OTUB1 together with ILF3, preventing K48-linked ubiquitination and proteasomal degradation of ILF3; stabilized ILF3 binds and stabilizes LCN2 mRNA, promoting LCN2 expression and suppressing ferroptosis in pancreatic cancer cells [#1]. MYOF protein abundance is itself constrained by the E3 ubiquitin ligase TRIM8, which directs K48-linked polyubiquitination and proteasomal degradation of MYOF, thereby restraining MMP secretion and tumor cell migration and invasion [#2]. MYOF isoform composition is set by hnRNPLL-regulated alternative splicing, where hnRNPLL promotes inclusion that generates the pro-migratory short isoform MYOFb [#3]. During RNA virus infection, MYOF associates with influenza viral ribonucleoprotein complexes and colocalizes with Rab11a endosomal recycling vesicles, a role conserved across RSV and Sendai virus [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that MYOF loss-of-function is causative for human muscle and cardiac disease, moving MYOF from a candidate to a confirmed disease gene.\",\n      \"evidence\": \"Whole exome sequencing of a frameshift variant, RNA-seq and morphology in patient-derived muscle progenitor cells, and zebrafish phenotype modeling\",\n      \"pmids\": [\"31297131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular pathway connecting MYOF loss to dystrophic and cardiac phenotypes is not defined\",\n        \"Single family/variant; allelic spectrum not established\",\n        \"No mechanistic link to membrane repair or trafficking demonstrated in this study\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified hnRNPLL-driven alternative splicing as the upstream switch generating the pro-migratory MYOFb isoform, explaining how MYOF isoform choice contributes to metastatic behavior.\",\n      \"evidence\": \"hnRNPLL knockdown with exon-skipping RNA-seq plus hnRNPLL and MYOFb overexpression with migration/invasion assays in pancreatic cancer cells\",\n      \"pmids\": [\"39742990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional distinction between MYOFb and the full-length isoform at the protein level is not resolved\",\n        \"Direct binding of hnRNPLL to MYOF pre-mRNA not shown\",\n        \"Whether isoform switching operates outside pancreatic cancer is untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed MYOF in viral RNA trafficking by showing it associates with viral ribonucleoprotein complexes and Rab11a recycling vesicles, suggesting a conserved role in RNA virus assembly/egress.\",\n      \"evidence\": \"Co-localization imaging, biochemical association, and loss-of-function in IAV, RSV, and SeV infection models (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.02.601679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, single lab, not peer-reviewed\",\n        \"Proposed EHD recruitment to vRNP vesicles not directly demonstrated\",\n        \"Mechanism of MYOF recruitment to vRNP/Rab11a vesicles unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a MYOF scaffolding function that stabilizes ILF3 via OTUB1 to sustain LCN2 expression and suppress ferroptosis, providing a molecular pathway for MYOF in tumor cell survival.\",\n      \"evidence\": \"MYOF knockout in vitro and in xenografts, co-immunoprecipitation, proteasome inhibitor assays, and ectopic LCN2 rescue in pancreatic cancer cells\",\n      \"pmids\": [\"40381229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of the MYOF–OTUB1–ILF3 ternary complex not determined\",\n        \"Whether this scaffolding activity relates to MYOF's trafficking/membrane functions is unknown\",\n        \"Direct vs indirect nature of the interactions rests on Co-IP without reciprocal structural validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MYOF protein levels are controlled by TRIM8-mediated K48 polyubiquitination and degradation, identifying a post-translational brake on MYOF-driven MMP secretion and invasion.\",\n      \"evidence\": \"Gain/loss-of-function and MYOF rescue in NSCLC cells, ubiquitination assays, and xenograft model\",\n      \"pmids\": [\"39934162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"TRIM8 ubiquitination site(s) on MYOF not mapped\",\n        \"How MMP secretion is mechanistically linked to MYOF is not detailed\",\n        \"Whether TRIM8 regulation applies to MYOF's muscle functions is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYOF's vesicle-trafficking/membrane biology mechanistically unifies its disparate roles in muscle disease, cancer scaffolding, and viral RNA transport remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No single mechanistic study connects the membrane/trafficking function to the cancer scaffolding role\",\n        \"No structural model of MYOF or its complexes in the corpus\",\n        \"Tissue-specific determinants of MYOF function not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OTUB1\", \"ILF3\", \"TRIM8\", \"hnRNPLL\", \"Rab11a\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}