{"gene":"MYOM2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2020,"finding":"MYOM2 is a major structural component of the myofibrillar M-band of the sarcomere. Patient-derived cardiomyocytes with MYOM2 mutations exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. In Drosophila, the putative ortholog CG14964 (dMnM) partial loss-of-function or cardiac knockdown results in cardiac dilation, while more severely reduced function causes a constricted phenotype and increased sarcomere myosin protein. Compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions.","method":"Patient-derived cardiomyocyte force measurements, Drosophila cardiac knockdown genetics, genetic epistasis with Mhc/MYH6/7","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (human patient cardiomyocyte functional assays, Drosophila loss-of-function, genetic epistasis), single focused study on MYOM2","pmids":["33033063"],"is_preprint":false},{"year":2022,"finding":"ALPK3 (alpha-kinase 3) colocalizes with MYOM2 (myomesin-2) at both the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes MYOM2 to mislocalize, disrupting M-band architecture and impairing cardiomyocyte structure and function.","method":"Immunofluorescence colocalization in iPSC-derived cardiomyocytes and patient tissues, ALPK3 loss-of-function experiments in isogenic hiPSC-CMs and mice","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal colocalization, loss-of-function with defined phenotype, multiple model systems (iPSC-CMs, mice, human tissue)","pmids":["36321451"],"is_preprint":false},{"year":2013,"finding":"Dysferlin directly interacts with myomesin-2 (MYOM2) in human skeletal muscle, as demonstrated by fluorescence lifetime imaging-FRET (FLIM-FRET) analysis in healthy myotubes. MYOM2 is a component of the dysferlin protein complex.","method":"Immunoprecipitation, blue native gel electrophoresis, FLIM-FRET in human skeletal muscle and myotubes","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — FLIM-FRET establishes direct interaction (not just complex membership), combined with Co-IP and blue native electrophoresis, single lab","pmids":["23792176"],"is_preprint":false},{"year":2008,"finding":"The bHLH/PAS transcription factor SIM2, when heterodimerized with ARNT1, directly binds a non-canonical E-box sequence (5'-AACGTG-3') in the MYOM2 promoter and activates MYOM2 transcription in HEK293 cells. In immortalized human myoblasts, SIM2 knockdown increases MYOM2 RNA levels, indicating context-dependent repressor activity.","method":"Microarray, promoter truncation/mutation assays, chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, promoter mutagenesis, reporter assay, siRNA), direct binding site identified","pmids":["18480125"],"is_preprint":false},{"year":2016,"finding":"The LIM domain protein nTRIP6 acts as a co-repressor for MEF2C by interacting with MEF2C and being co-recruited to MEF2-binding regions of the MYOM2 promoter (among other MEF2C target gene promoters) in proliferating myoblasts. nTRIP6 mediates recruitment of class IIa histone deacetylase HDAC5 to these promoters. Silencing nTRIP6 or preventing its interaction with MEF2C increases MYOM2 expression.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression analysis in myoblasts","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP at MYOM2 promoter, functional knockdown with gene expression readout, multiple orthogonal methods","pmids":["27292777"],"is_preprint":false},{"year":2007,"finding":"MYOM2 (M-protein) and MYOM1 show layer-specific differential expression in extraocular muscle (EOM): MYOM2 is expressed at higher levels in the global layer than the orbital layer. This differential M-band composition is associated with differences in thick filament lattice order and predicted to confer increased elasticity but reduced force in EOMs compared to tibialis anterior muscle.","method":"Semi-quantitative PCR, qPCR, immunohistochemistry, confocal microscopy, electron microscopy with inter-thick-filament distance quantification","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EM, qPCR, IHC) in single lab; functional inference is modeled rather than directly tested","pmids":["17325154"],"is_preprint":false},{"year":2020,"finding":"Myom2 expression is upregulated postnatally in cardiomyocytes, and Myom2-RFP+ PSC-derived cardiomyocytes exhibit more mature phenotypes (morphology, function, transcriptomics) than RFP- cells. Laminin-511/521 were identified as potent enhancers of cardiomyocyte maturation using this Myom2 reporter system.","method":"Myom2 locus knock-in fluorescent reporter in mouse ESCs, flow cytometry, sarcomere shortening assay, transcriptional profiling","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous locus tagging with functional validation via multiple assays, single lab","pmids":["32144297"],"is_preprint":false},{"year":2022,"finding":"Knockdown of dMnM (MYOM2 Drosophila homolog) in cardiomyocytes results in diastolic cardiac defects (diastolic dysfunction and arrhythmias) and increased cardiac oxidative stress. Knockdown in indirect flight muscle reduces climbing ability and shortens lifespan. Regular exercise ameliorates these defects and upregulates cardiomyocyte dMnM expression.","method":"Drosophila cardiac-specific and muscle-specific RNAi knockdown, cardiac functional assays (diastolic diameter, arrhythmia index), oxidative stress markers, climbing assay, lifespan analysis","journal":"International journal of environmental research and public health","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific loss-of-function with multiple phenotypic readouts in Drosophila model, single lab","pmids":["36554435"],"is_preprint":false},{"year":2023,"finding":"CaMKII regulates MYOM2 protein expression in cardiomyocytes. Diacetylmorphine increases autophosphorylation of CaMKII at Thr287, which is accompanied by altered MYOM2 and TPM1 expression and myocardial rhythm abnormalities. CaMKII inhibitor KN-93 rescues the toxic effects on MYOM2 expression and normalizes ECG changes.","method":"In vitro cardiomyocyte treatment, TMT relative quantitative proteomics, CaMKII inhibitor (KN-93) rescue experiment, rat ECG recording","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics with pharmacological rescue, single lab, mechanistic link between CaMKII phosphorylation and MYOM2 regulation demonstrated","pmids":["37037889"],"is_preprint":false},{"year":2025,"finding":"GATA4 regulates MYOM2 expression during cardiomyocyte differentiation. Overexpression of GATA4 reverses the low expression of MYOM2 caused by sodium arsenite exposure. Sodium arsenite reduces both GATA4 and MYOM2 protein/mRNA levels, and folic acid treatment restores their expression in hiPSC cells.","method":"Bioinformatics of hiPSC differentiation dataset (GSE85623), animal experiments (immunohistochemistry in rat fetal myocardium), GATA4 stable overexpression in hiPSC, Western blot, qRT-PCR","journal":"Wei sheng yan jiu = Journal of hygiene research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GATA4 overexpression rescue of MYOM2 expression is a direct functional test, supported by in vivo and in vitro evidence, single lab","pmids":["40355336"],"is_preprint":false},{"year":2025,"finding":"The non-coding SNP rs2280906 regulates MYOM2 expression in an allele-specific, methylation-dependent manner relevant to schizophrenia. In healthy individuals, hypomethylation of the reference C allele permits MYOM2 expression; in affected individuals, hypermethylation leads to biallelic methylation, increased recruitment of repressive transcription factors, and MYOM2 downregulation.","method":"Mendelian randomization, dual-luciferase reporter assays, gene editing, methylation editing, electrophoretic mobility shift assay (EMSA), gene expression quantification","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (EMSA, luciferase, methylation editing) establishing mechanism at a specific regulatory locus, single lab","pmids":["41324836"],"is_preprint":false},{"year":2026,"finding":"Postnatal upregulation of MYOM2 suppresses cardiomyocyte proliferation and promotes binucleation. Adenoviral overexpression of Myom2 in neonatal rat cardiomyocytes significantly reduced the proportion of proliferating cardiomyocytes and promoted binucleation.","method":"Single-cell RNA-seq pseudotime trajectory analysis, adenoviral overexpression, immunofluorescence microscopy for proliferation markers and binucleation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression with quantitative proliferation and binucleation readout, supported by scRNA-seq trajectory, single lab","pmids":["42241973"],"is_preprint":false},{"year":2025,"finding":"MYOM2 (myomesin 2) and MYLK2 (myosin light chain kinase 2) are elevated in aging vocal fold lamina propria and are associated with myofibroblast differentiation. Inhibition of MYOM2 reduces cellular contraction and stiffness in fibroblasts, establishing a functional role in regulation of vocal fold stiffness.","method":"Next-generation sequencing of rat vocal fold lamina propria, gene ontology/network analysis, validation in human vocal fold tissue, functional inhibition assays for contraction and stiffness","journal":"Biogerontology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional inhibition result supports role in contraction/stiffness, but detailed mechanism not fully resolved; single lab, abstract lacks full method detail","pmids":["41251884"],"is_preprint":false},{"year":2017,"finding":"siRNA silencing of MYOM2 in mouse podocytes leads to significant downregulation of CD2AP and synaptopodin, indicating a role in maintaining podocyte cytoskeletal integrity.","method":"siRNA silencing in mouse podocytes, gene expression readout for CD2AP and synaptopodin","journal":"Kidney international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment with downstream marker readout, no direct mechanistic pathway established, single lab","pmids":["28709640"],"is_preprint":false}],"current_model":"MYOM2 encodes myomesin-2 (M-protein), a structural component of the sarcomere M-band that provides mechanical elasticity and force buffering in cardiomyocytes and skeletal muscle; it is transcriptionally regulated by SIM2/ARNT1 via a non-canonical E-box element, by MEF2C with nTRIP6/HDAC5 co-repressor recruitment, by GATA4, and by allele-specific methylation at rs2280906; it directly interacts with dysferlin in skeletal muscle and colocalizes with ALPK3 at the M-band and nuclear envelope; its postnatal upregulation suppresses cardiomyocyte proliferation and promotes binucleation; loss of function in Drosophila causes cardiac dilation, arrhythmias, and oxidative stress; and CaMKII regulates its expression in the context of myocardial contractility."},"narrative":{"mechanistic_narrative":"MYOM2 encodes myomesin-2 (M-protein), a major structural component of the sarcomere M-band that confers mechanical elasticity and force buffering in striated muscle; patient-derived cardiomyocytes carrying MYOM2 mutations show myofibrillar disarray and reduced passive force at increasing sarcomere lengths, and loss of the Drosophila ortholog produces cardiac dilation and synergistic genetic interactions with the thick-filament gene Mhc (MYH6/7) [PMID:33033063]. Proper M-band incorporation of MYOM2 depends on ALPK3, with which it colocalizes at both the M-band and the nuclear envelope; ALPK3 loss mislocalizes MYOM2 and disrupts M-band architecture [PMID:36321451]. In skeletal muscle, MYOM2 is a direct binding partner within the dysferlin protein complex [PMID:23792176]. Beyond its structural role, MYOM2 is a developmentally controlled node in cardiomyocyte maturation: its postnatal upregulation marks and drives a mature phenotype while suppressing cardiomyocyte proliferation and promoting binucleation [PMID:32144297, PMID:42241973]. MYOM2 transcription is tightly regulated by muscle transcription factors, including activation by SIM2/ARNT1 through a non-canonical E-box [PMID:18480125], repression via MEF2C through nTRIP6-mediated recruitment of HDAC5 [PMID:27292777], and control by GATA4 [PMID:40355336]. Tissue-specific functional output is reflected in layer-specific expression across muscle types that tunes thick-filament lattice order and elasticity [PMID:17325154].","teleology":[{"year":2007,"claim":"Established that MYOM2 content varies between muscle types and layers in a way that tunes M-band composition and mechanical properties, framing it as a determinant of muscle-specific elasticity rather than a uniform structural filler.","evidence":"qPCR, immunohistochemistry, and electron microscopy with inter-thick-filament distance quantification in extraocular versus tibialis anterior muscle","pmids":["17325154"],"confidence":"Medium","gaps":["Functional elasticity/force consequences were modeled, not directly measured","Does not address molecular determinants of layer-specific expression"]},{"year":2008,"claim":"Identified the first direct transcriptional regulator of MYOM2, showing SIM2/ARNT1 binds a non-canonical E-box in its promoter and exerts context-dependent activation versus repression.","evidence":"ChIP, promoter truncation/mutagenesis, luciferase reporter assays, and siRNA knockdown in HEK293 and human myoblasts","pmids":["18480125"],"confidence":"High","gaps":["Mechanism behind the activator-versus-repressor switch in myoblasts not resolved","In vivo relevance to muscle development not tested"]},{"year":2013,"claim":"Placed MYOM2 within the dysferlin protein complex by demonstrating a direct physical interaction, linking the M-band protein to membrane-repair/complex biology in skeletal muscle.","evidence":"Co-IP, blue native gel electrophoresis, and FLIM-FRET in human skeletal muscle and myotubes","pmids":["23792176"],"confidence":"High","gaps":["Functional consequence of the dysferlin-MYOM2 interaction not defined","Interaction interface and stoichiometry unknown"]},{"year":2016,"claim":"Defined a repressive transcriptional circuit controlling MYOM2 in proliferating myoblasts, showing nTRIP6 co-represses MEF2C and recruits HDAC5 to the MYOM2 promoter.","evidence":"Reciprocal Co-IP, ChIP at the MYOM2 promoter, and siRNA knockdown with expression readout in myoblasts","pmids":["27292777"],"confidence":"High","gaps":["Does not address de-repression timing during differentiation","Direct chromatin state changes at MYOM2 not measured"]},{"year":2020,"claim":"Demonstrated that MYOM2 marks mature cardiomyocytes and established it as a useful reporter for maturation, defining a developmental expression program rather than only a static structural role.","evidence":"Myom2-locus knock-in fluorescent reporter in mouse ESC-derived cardiomyocytes with flow cytometry, sarcomere shortening, and transcriptional profiling","pmids":["32144297"],"confidence":"Medium","gaps":["Whether MYOM2 drives maturation or simply reports it not separated here","Laminin effect upstream of MYOM2 not mechanistically connected"]},{"year":2020,"claim":"Established MYOM2 as a functionally required M-band component whose loss reduces passive sarcomere force and produces cardiomyopathy-like phenotypes across human and Drosophila systems.","evidence":"Patient-derived cardiomyocyte force measurements, Drosophila cardiac knockdown, and genetic epistasis with Mhc/MYH6/7","pmids":["33033063"],"confidence":"High","gaps":["No structural model of how MYOM2 cross-links thick filaments","Human disease causality from defined MYOM2 variants not formally established as Mendelian"]},{"year":2022,"claim":"Identified ALPK3 as a determinant of MYOM2 localization, showing M-band integrity and dual M-band/nuclear-envelope positioning of MYOM2 depend on ALPK3.","evidence":"Immunofluorescence colocalization plus ALPK3 loss-of-function in isogenic hiPSC-cardiomyocytes, mice, and patient tissue","pmids":["36321451"],"confidence":"High","gaps":["Whether ALPK3 directly binds MYOM2 or acts indirectly not resolved","Significance of nuclear-envelope MYOM2 pool unknown"]},{"year":2022,"claim":"Linked MYOM2 loss to diastolic dysfunction, arrhythmia, and oxidative stress in vivo, and showed exercise upregulates it, extending its role from structure to functional cardiac homeostasis.","evidence":"Drosophila tissue-specific RNAi with cardiac functional assays, oxidative stress markers, climbing, and lifespan analysis","pmids":["36554435"],"confidence":"Medium","gaps":["Mechanistic link between M-band loss and oxidative stress not defined","Findings in fly may not transfer quantitatively to mammalian heart"]},{"year":2023,"claim":"Connected MYOM2 protein levels to upstream contractility signaling by showing CaMKII activity regulates its expression and that CaMKII inhibition rescues drug-induced MYOM2 and rhythm changes.","evidence":"TMT proteomics, CaMKII Thr287 autophosphorylation analysis, KN-93 rescue, and rat ECG recording","pmids":["37037889"],"confidence":"Medium","gaps":["Whether CaMKII acts transcriptionally or post-translationally on MYOM2 not distinguished","Direct CaMKII-MYOM2 relationship versus indirect not established"]},{"year":2025,"claim":"Added GATA4 as a transcriptional regulator of MYOM2 during cardiomyocyte differentiation and showed GATA4 can rescue toxicant-induced MYOM2 loss.","evidence":"GATA4 overexpression rescue in hiPSC, with in vivo immunohistochemistry, Western blot, and qRT-PCR","pmids":["40355336"],"confidence":"Medium","gaps":["Direct GATA4 binding to the MYOM2 locus not demonstrated","Relationship to other MYOM2 transcription factors not integrated"]},{"year":2025,"claim":"Defined an allele- and methylation-specific cis-regulatory mechanism at rs2280906 controlling MYOM2 expression, linking it to schizophrenia risk.","evidence":"Mendelian randomization, dual-luciferase assays, gene and methylation editing, and EMSA","pmids":["41324836"],"confidence":"Medium","gaps":["Tissue context for the neuropsychiatric link not clarified","Identity of the recruited repressive factors not fully defined"]},{"year":2026,"claim":"Showed MYOM2 is not merely a maturation marker but actively enforces cell-cycle exit, with overexpression suppressing cardiomyocyte proliferation and driving binucleation.","evidence":"scRNA-seq pseudotime analysis plus adenoviral Myom2 overexpression with proliferation and binucleation readouts in neonatal rat cardiomyocytes","pmids":["42241973"],"confidence":"Medium","gaps":["Molecular pathway linking M-band protein to cell-cycle machinery unknown","Whether structural assembly is required for the anti-proliferative effect not tested"]},{"year":null,"claim":"How MYOM2's structural M-band role mechanistically couples to its signaling outputs (proliferation suppression, oxidative stress protection, nuclear-envelope localization) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MYOM2 cross-bridging within the M-band","No molecular mechanism linking MYOM2 to cell-cycle exit","Functional meaning of nuclear-envelope MYOM2 pool undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,11]}],"complexes":["sarcomere M-band","dysferlin protein complex"],"partners":["ALPK3","DYSF","MYH6","MYH7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P54296","full_name":"Myomesin-2","aliases":["165 kDa connectin-associated protein","165 kDa titin-associated protein","M-protein","Myomesin family member 2"],"length_aa":1465,"mass_kda":164.9,"function":"Major component of the vertebrate myofibrillar M band. Binds myosin, titin, and light meromyosin. This binding is dose dependent","subcellular_location":"Cytoplasm, myofibril, sarcomere, M line","url":"https://www.uniprot.org/uniprotkb/P54296/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYOM2","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/MYOM2","total_profiled":1310},"omim":[{"mim_id":"616832","title":"MYOMESIN 3; MYOM3","url":"https://www.omim.org/entry/616832"},{"mim_id":"603509","title":"MYOMESIN 2; MYOM2","url":"https://www.omim.org/entry/603509"},{"mim_id":"603508","title":"MYOMESIN 1; MYOM1","url":"https://www.omim.org/entry/603508"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":324.6},{"tissue":"skeletal muscle","ntpm":372.0}],"url":"https://www.proteinatlas.org/search/MYOM2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P54296","domains":[{"cath_id":"2.60.40.10","chopping":"154-248_275-363","consensus_level":"medium","plddt":79.6484,"start":154,"end":363},{"cath_id":"2.60.40.10","chopping":"376-494","consensus_level":"medium","plddt":76.3992,"start":376,"end":494},{"cath_id":"2.60.40.10","chopping":"510-609","consensus_level":"medium","plddt":83.3069,"start":510,"end":609},{"cath_id":"2.60.40.10","chopping":"618-705","consensus_level":"high","plddt":80.9677,"start":618,"end":705},{"cath_id":"2.60.40.10","chopping":"716-806","consensus_level":"high","plddt":87.1564,"start":716,"end":806},{"cath_id":"2.60.40.10","chopping":"818-908","consensus_level":"high","plddt":84.9973,"start":818,"end":908},{"cath_id":"2.60.40.10","chopping":"918-1012","consensus_level":"high","plddt":83.2706,"start":918,"end":1012},{"cath_id":"2.60.40.10","chopping":"1019-1123","consensus_level":"medium","plddt":90.1623,"start":1019,"end":1123},{"cath_id":"2.60.40.10","chopping":"1130-1216","consensus_level":"medium","plddt":88.8541,"start":1130,"end":1216},{"cath_id":"2.60.40.10","chopping":"1344-1437","consensus_level":"medium","plddt":86.5323,"start":1344,"end":1437}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54296","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54296-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54296-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYOM2","jax_strain_url":"https://www.jax.org/strain/search?query=MYOM2"},"sequence":{"accession":"P54296","fasta_url":"https://rest.uniprot.org/uniprotkb/P54296.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54296/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54296"}},"corpus_meta":[{"pmid":"31230720","id":"PMC_31230720","title":"The 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Patient-derived cardiomyocytes with MYOM2 mutations exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. In Drosophila, the putative ortholog CG14964 (dMnM) partial loss-of-function or cardiac knockdown results in cardiac dilation, while more severely reduced function causes a constricted phenotype and increased sarcomere myosin protein. Compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions.\",\n      \"method\": \"Patient-derived cardiomyocyte force measurements, Drosophila cardiac knockdown genetics, genetic epistasis with Mhc/MYH6/7\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (human patient cardiomyocyte functional assays, Drosophila loss-of-function, genetic epistasis), single focused study on MYOM2\",\n      \"pmids\": [\"33033063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALPK3 (alpha-kinase 3) colocalizes with MYOM2 (myomesin-2) at both the nuclear envelope and the sarcomere M-band. Loss of ALPK3 causes MYOM2 to mislocalize, disrupting M-band architecture and impairing cardiomyocyte structure and function.\",\n      \"method\": \"Immunofluorescence colocalization in iPSC-derived cardiomyocytes and patient tissues, ALPK3 loss-of-function experiments in isogenic hiPSC-CMs and mice\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal colocalization, loss-of-function with defined phenotype, multiple model systems (iPSC-CMs, mice, human tissue)\",\n      \"pmids\": [\"36321451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dysferlin directly interacts with myomesin-2 (MYOM2) in human skeletal muscle, as demonstrated by fluorescence lifetime imaging-FRET (FLIM-FRET) analysis in healthy myotubes. MYOM2 is a component of the dysferlin protein complex.\",\n      \"method\": \"Immunoprecipitation, blue native gel electrophoresis, FLIM-FRET in human skeletal muscle and myotubes\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — FLIM-FRET establishes direct interaction (not just complex membership), combined with Co-IP and blue native electrophoresis, single lab\",\n      \"pmids\": [\"23792176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The bHLH/PAS transcription factor SIM2, when heterodimerized with ARNT1, directly binds a non-canonical E-box sequence (5'-AACGTG-3') in the MYOM2 promoter and activates MYOM2 transcription in HEK293 cells. In immortalized human myoblasts, SIM2 knockdown increases MYOM2 RNA levels, indicating context-dependent repressor activity.\",\n      \"method\": \"Microarray, promoter truncation/mutation assays, chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ChIP, promoter mutagenesis, reporter assay, siRNA), direct binding site identified\",\n      \"pmids\": [\"18480125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The LIM domain protein nTRIP6 acts as a co-repressor for MEF2C by interacting with MEF2C and being co-recruited to MEF2-binding regions of the MYOM2 promoter (among other MEF2C target gene promoters) in proliferating myoblasts. nTRIP6 mediates recruitment of class IIa histone deacetylase HDAC5 to these promoters. Silencing nTRIP6 or preventing its interaction with MEF2C increases MYOM2 expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression analysis in myoblasts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP at MYOM2 promoter, functional knockdown with gene expression readout, multiple orthogonal methods\",\n      \"pmids\": [\"27292777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MYOM2 (M-protein) and MYOM1 show layer-specific differential expression in extraocular muscle (EOM): MYOM2 is expressed at higher levels in the global layer than the orbital layer. This differential M-band composition is associated with differences in thick filament lattice order and predicted to confer increased elasticity but reduced force in EOMs compared to tibialis anterior muscle.\",\n      \"method\": \"Semi-quantitative PCR, qPCR, immunohistochemistry, confocal microscopy, electron microscopy with inter-thick-filament distance quantification\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EM, qPCR, IHC) in single lab; functional inference is modeled rather than directly tested\",\n      \"pmids\": [\"17325154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myom2 expression is upregulated postnatally in cardiomyocytes, and Myom2-RFP+ PSC-derived cardiomyocytes exhibit more mature phenotypes (morphology, function, transcriptomics) than RFP- cells. Laminin-511/521 were identified as potent enhancers of cardiomyocyte maturation using this Myom2 reporter system.\",\n      \"method\": \"Myom2 locus knock-in fluorescent reporter in mouse ESCs, flow cytometry, sarcomere shortening assay, transcriptional profiling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous locus tagging with functional validation via multiple assays, single lab\",\n      \"pmids\": [\"32144297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of dMnM (MYOM2 Drosophila homolog) in cardiomyocytes results in diastolic cardiac defects (diastolic dysfunction and arrhythmias) and increased cardiac oxidative stress. Knockdown in indirect flight muscle reduces climbing ability and shortens lifespan. Regular exercise ameliorates these defects and upregulates cardiomyocyte dMnM expression.\",\n      \"method\": \"Drosophila cardiac-specific and muscle-specific RNAi knockdown, cardiac functional assays (diastolic diameter, arrhythmia index), oxidative stress markers, climbing assay, lifespan analysis\",\n      \"journal\": \"International journal of environmental research and public health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific loss-of-function with multiple phenotypic readouts in Drosophila model, single lab\",\n      \"pmids\": [\"36554435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CaMKII regulates MYOM2 protein expression in cardiomyocytes. Diacetylmorphine increases autophosphorylation of CaMKII at Thr287, which is accompanied by altered MYOM2 and TPM1 expression and myocardial rhythm abnormalities. CaMKII inhibitor KN-93 rescues the toxic effects on MYOM2 expression and normalizes ECG changes.\",\n      \"method\": \"In vitro cardiomyocyte treatment, TMT relative quantitative proteomics, CaMKII inhibitor (KN-93) rescue experiment, rat ECG recording\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics with pharmacological rescue, single lab, mechanistic link between CaMKII phosphorylation and MYOM2 regulation demonstrated\",\n      \"pmids\": [\"37037889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GATA4 regulates MYOM2 expression during cardiomyocyte differentiation. Overexpression of GATA4 reverses the low expression of MYOM2 caused by sodium arsenite exposure. Sodium arsenite reduces both GATA4 and MYOM2 protein/mRNA levels, and folic acid treatment restores their expression in hiPSC cells.\",\n      \"method\": \"Bioinformatics of hiPSC differentiation dataset (GSE85623), animal experiments (immunohistochemistry in rat fetal myocardium), GATA4 stable overexpression in hiPSC, Western blot, qRT-PCR\",\n      \"journal\": \"Wei sheng yan jiu = Journal of hygiene research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GATA4 overexpression rescue of MYOM2 expression is a direct functional test, supported by in vivo and in vitro evidence, single lab\",\n      \"pmids\": [\"40355336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The non-coding SNP rs2280906 regulates MYOM2 expression in an allele-specific, methylation-dependent manner relevant to schizophrenia. In healthy individuals, hypomethylation of the reference C allele permits MYOM2 expression; in affected individuals, hypermethylation leads to biallelic methylation, increased recruitment of repressive transcription factors, and MYOM2 downregulation.\",\n      \"method\": \"Mendelian randomization, dual-luciferase reporter assays, gene editing, methylation editing, electrophoretic mobility shift assay (EMSA), gene expression quantification\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (EMSA, luciferase, methylation editing) establishing mechanism at a specific regulatory locus, single lab\",\n      \"pmids\": [\"41324836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Postnatal upregulation of MYOM2 suppresses cardiomyocyte proliferation and promotes binucleation. Adenoviral overexpression of Myom2 in neonatal rat cardiomyocytes significantly reduced the proportion of proliferating cardiomyocytes and promoted binucleation.\",\n      \"method\": \"Single-cell RNA-seq pseudotime trajectory analysis, adenoviral overexpression, immunofluorescence microscopy for proliferation markers and binucleation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression with quantitative proliferation and binucleation readout, supported by scRNA-seq trajectory, single lab\",\n      \"pmids\": [\"42241973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYOM2 (myomesin 2) and MYLK2 (myosin light chain kinase 2) are elevated in aging vocal fold lamina propria and are associated with myofibroblast differentiation. Inhibition of MYOM2 reduces cellular contraction and stiffness in fibroblasts, establishing a functional role in regulation of vocal fold stiffness.\",\n      \"method\": \"Next-generation sequencing of rat vocal fold lamina propria, gene ontology/network analysis, validation in human vocal fold tissue, functional inhibition assays for contraction and stiffness\",\n      \"journal\": \"Biogerontology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional inhibition result supports role in contraction/stiffness, but detailed mechanism not fully resolved; single lab, abstract lacks full method detail\",\n      \"pmids\": [\"41251884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA silencing of MYOM2 in mouse podocytes leads to significant downregulation of CD2AP and synaptopodin, indicating a role in maintaining podocyte cytoskeletal integrity.\",\n      \"method\": \"siRNA silencing in mouse podocytes, gene expression readout for CD2AP and synaptopodin\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment with downstream marker readout, no direct mechanistic pathway established, single lab\",\n      \"pmids\": [\"28709640\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYOM2 encodes myomesin-2 (M-protein), a structural component of the sarcomere M-band that provides mechanical elasticity and force buffering in cardiomyocytes and skeletal muscle; it is transcriptionally regulated by SIM2/ARNT1 via a non-canonical E-box element, by MEF2C with nTRIP6/HDAC5 co-repressor recruitment, by GATA4, and by allele-specific methylation at rs2280906; it directly interacts with dysferlin in skeletal muscle and colocalizes with ALPK3 at the M-band and nuclear envelope; its postnatal upregulation suppresses cardiomyocyte proliferation and promotes binucleation; loss of function in Drosophila causes cardiac dilation, arrhythmias, and oxidative stress; and CaMKII regulates its expression in the context of myocardial contractility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYOM2 encodes myomesin-2 (M-protein), a major structural component of the sarcomere M-band that confers mechanical elasticity and force buffering in striated muscle; patient-derived cardiomyocytes carrying MYOM2 mutations show myofibrillar disarray and reduced passive force at increasing sarcomere lengths, and loss of the Drosophila ortholog produces cardiac dilation and synergistic genetic interactions with the thick-filament gene Mhc (MYH6/7) [#0]. Proper M-band incorporation of MYOM2 depends on ALPK3, with which it colocalizes at both the M-band and the nuclear envelope; ALPK3 loss mislocalizes MYOM2 and disrupts M-band architecture [#1]. In skeletal muscle, MYOM2 is a direct binding partner within the dysferlin protein complex [#2]. Beyond its structural role, MYOM2 is a developmentally controlled node in cardiomyocyte maturation: its postnatal upregulation marks and drives a mature phenotype while suppressing cardiomyocyte proliferation and promoting binucleation [#6, #11]. MYOM2 transcription is tightly regulated by muscle transcription factors, including activation by SIM2/ARNT1 through a non-canonical E-box [#3], repression via MEF2C through nTRIP6-mediated recruitment of HDAC5 [#4], and control by GATA4 [#9]. Tissue-specific functional output is reflected in layer-specific expression across muscle types that tunes thick-filament lattice order and elasticity [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that MYOM2 content varies between muscle types and layers in a way that tunes M-band composition and mechanical properties, framing it as a determinant of muscle-specific elasticity rather than a uniform structural filler.\",\n      \"evidence\": \"qPCR, immunohistochemistry, and electron microscopy with inter-thick-filament distance quantification in extraocular versus tibialis anterior muscle\",\n      \"pmids\": [\"17325154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional elasticity/force consequences were modeled, not directly measured\", \"Does not address molecular determinants of layer-specific expression\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first direct transcriptional regulator of MYOM2, showing SIM2/ARNT1 binds a non-canonical E-box in its promoter and exerts context-dependent activation versus repression.\",\n      \"evidence\": \"ChIP, promoter truncation/mutagenesis, luciferase reporter assays, and siRNA knockdown in HEK293 and human myoblasts\",\n      \"pmids\": [\"18480125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism behind the activator-versus-repressor switch in myoblasts not resolved\", \"In vivo relevance to muscle development not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed MYOM2 within the dysferlin protein complex by demonstrating a direct physical interaction, linking the M-band protein to membrane-repair/complex biology in skeletal muscle.\",\n      \"evidence\": \"Co-IP, blue native gel electrophoresis, and FLIM-FRET in human skeletal muscle and myotubes\",\n      \"pmids\": [\"23792176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the dysferlin-MYOM2 interaction not defined\", \"Interaction interface and stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a repressive transcriptional circuit controlling MYOM2 in proliferating myoblasts, showing nTRIP6 co-represses MEF2C and recruits HDAC5 to the MYOM2 promoter.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at the MYOM2 promoter, and siRNA knockdown with expression readout in myoblasts\",\n      \"pmids\": [\"27292777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address de-repression timing during differentiation\", \"Direct chromatin state changes at MYOM2 not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that MYOM2 marks mature cardiomyocytes and established it as a useful reporter for maturation, defining a developmental expression program rather than only a static structural role.\",\n      \"evidence\": \"Myom2-locus knock-in fluorescent reporter in mouse ESC-derived cardiomyocytes with flow cytometry, sarcomere shortening, and transcriptional profiling\",\n      \"pmids\": [\"32144297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MYOM2 drives maturation or simply reports it not separated here\", \"Laminin effect upstream of MYOM2 not mechanistically connected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established MYOM2 as a functionally required M-band component whose loss reduces passive sarcomere force and produces cardiomyopathy-like phenotypes across human and Drosophila systems.\",\n      \"evidence\": \"Patient-derived cardiomyocyte force measurements, Drosophila cardiac knockdown, and genetic epistasis with Mhc/MYH6/7\",\n      \"pmids\": [\"33033063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of how MYOM2 cross-links thick filaments\", \"Human disease causality from defined MYOM2 variants not formally established as Mendelian\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ALPK3 as a determinant of MYOM2 localization, showing M-band integrity and dual M-band/nuclear-envelope positioning of MYOM2 depend on ALPK3.\",\n      \"evidence\": \"Immunofluorescence colocalization plus ALPK3 loss-of-function in isogenic hiPSC-cardiomyocytes, mice, and patient tissue\",\n      \"pmids\": [\"36321451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ALPK3 directly binds MYOM2 or acts indirectly not resolved\", \"Significance of nuclear-envelope MYOM2 pool unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked MYOM2 loss to diastolic dysfunction, arrhythmia, and oxidative stress in vivo, and showed exercise upregulates it, extending its role from structure to functional cardiac homeostasis.\",\n      \"evidence\": \"Drosophila tissue-specific RNAi with cardiac functional assays, oxidative stress markers, climbing, and lifespan analysis\",\n      \"pmids\": [\"36554435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between M-band loss and oxidative stress not defined\", \"Findings in fly may not transfer quantitatively to mammalian heart\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected MYOM2 protein levels to upstream contractility signaling by showing CaMKII activity regulates its expression and that CaMKII inhibition rescues drug-induced MYOM2 and rhythm changes.\",\n      \"evidence\": \"TMT proteomics, CaMKII Thr287 autophosphorylation analysis, KN-93 rescue, and rat ECG recording\",\n      \"pmids\": [\"37037889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CaMKII acts transcriptionally or post-translationally on MYOM2 not distinguished\", \"Direct CaMKII-MYOM2 relationship versus indirect not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added GATA4 as a transcriptional regulator of MYOM2 during cardiomyocyte differentiation and showed GATA4 can rescue toxicant-induced MYOM2 loss.\",\n      \"evidence\": \"GATA4 overexpression rescue in hiPSC, with in vivo immunohistochemistry, Western blot, and qRT-PCR\",\n      \"pmids\": [\"40355336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GATA4 binding to the MYOM2 locus not demonstrated\", \"Relationship to other MYOM2 transcription factors not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an allele- and methylation-specific cis-regulatory mechanism at rs2280906 controlling MYOM2 expression, linking it to schizophrenia risk.\",\n      \"evidence\": \"Mendelian randomization, dual-luciferase assays, gene and methylation editing, and EMSA\",\n      \"pmids\": [\"41324836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue context for the neuropsychiatric link not clarified\", \"Identity of the recruited repressive factors not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed MYOM2 is not merely a maturation marker but actively enforces cell-cycle exit, with overexpression suppressing cardiomyocyte proliferation and driving binucleation.\",\n      \"evidence\": \"scRNA-seq pseudotime analysis plus adenoviral Myom2 overexpression with proliferation and binucleation readouts in neonatal rat cardiomyocytes\",\n      \"pmids\": [\"42241973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking M-band protein to cell-cycle machinery unknown\", \"Whether structural assembly is required for the anti-proliferative effect not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYOM2's structural M-band role mechanistically couples to its signaling outputs (proliferation suppression, oxidative stress protection, nuclear-envelope localization) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MYOM2 cross-bridging within the M-band\", \"No molecular mechanism linking MYOM2 to cell-cycle exit\", \"Functional meaning of nuclear-envelope MYOM2 pool undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 11]}\n    ],\n    \"complexes\": [\"sarcomere M-band\", \"dysferlin protein complex\"],\n    \"partners\": [\"ALPK3\", \"DYSF\", \"MYH6\", \"MYH7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}