{"gene":"MYH6","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2016,"finding":"Under pathological stress in mice, BRG1 (nucleosome-remodeling factor) recruits G9a/GLP (histone methyltransferase) and then DNMT3 (DNA methyltransferase) to assemble repressive chromatin on the Myh6 promoter, marked by H3K9 and CpG methylation, thereby silencing Myh6 and impairing cardiac contraction. Disruption of any component (Brg1, G9a, or Dnmt3) de-represses Myh6 and reduces stress-induced cardiac dysfunction.","method":"Chromatin immunoprecipitation, co-immunoprecipitation of BRG1-G9a/GLP-DNMT3 complex, genetic disruption of each component in mice, histone/DNA methylation assays, cardiac function readouts","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP of complex components, genetic disruption of multiple components each showing de-repression, functional cardiac readout; replicated finding in human hypertrophic hearts","pmids":["26952936"],"is_preprint":false},{"year":2013,"finding":"The HCM-causing Myh6 R403Q mutant allele can be selectively silenced by allele-specific RNAi delivered via AAV; a 25% reduction in mutant transcript levels was sufficient to prevent hypertrophy and myocardial fibrosis in MHC403/+ mice for at least 6 months, establishing that partial allele-specific silencing of mutant Myh6 suppresses the dominant pathological mechanism.","method":"AAV-delivered RNAi in transgenic MHC403/+ mice; histological and echocardiographic assessment of hypertrophy and fibrosis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with specific phenotypic readout (hypertrophy and fibrosis prevention) over 6-month follow-up; rigorous allele-specific design","pmids":["24092743"],"is_preprint":false},{"year":2009,"finding":"A nonsense mutation in the X. tropicalis cardiac myosin heavy chain gene myh6 (muzak mutation) causes a premature stop codon that deletes the coiled-coil domain responsible for polymerization into thick filaments, leading to non-contractile hearts with severely disrupted cardiomyocyte cytoskeleton. Despite loss of contractile activity and thick filament assembly, early cardiac morphogenesis (looping, chamber formation) proceeds normally; later, dilated chambers form with compressed endocardium and failure to form valves and trabeculae.","method":"Positional cloning, sequencing, phenotypic characterization of homozygous mutant embryos by imaging and histology","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — first positional cloning of an X. tropicalis mutation; direct causative link between nonsense mutation, loss of thick filament assembly, and non-contractile heart phenotype established by ortholog genetics","pmids":["19769958"],"is_preprint":false},{"year":2010,"finding":"Specific MYH6 missense mutations (A230P and A1366D) significantly disrupt myofibril formation in mouse myoblasts transfected with GFP-MYH6 fusion proteins, whereas the H252Q mutation significantly enhances myofibril assembly, establishing that MYH6 variants associated with congenital heart defects functionally alter sarcomere/myofibril assembly.","method":"Transfection of GFP-MYH6 fusion constructs (wild-type and mutant) in mouse myoblasts; fluorescence microscopy assessment of myofibril formation","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based functional assay in heterologous myoblast system with multiple mutants tested; single lab but two distinct phenotypic outcomes (disruption vs. enhancement) provide internal controls","pmids":["20656787"],"is_preprint":false},{"year":1993,"finding":"The human MYH6 gene consists of 39 exons (37 coding), with the 5'-UTR split into 3 exons and the AUG initiation codon in the third exon. All exon/intron boundaries are conserved with beta-MyHC (MYH7) except one intron. The gene spans 26,159 bp and the intergenic 5'-flanking region is 4484 bp.","method":"Complete nucleotide sequencing of the gene and 5'-flanking region; exon/intron boundary mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete gene sequencing with full structural characterization; foundational structural paper for the gene","pmids":["8307559"],"is_preprint":false},{"year":2019,"finding":"Adult zebrafish homozygous for myh6 loss-of-function mutations (weak atrium line) develop atrial hypoplasia with elastin deposition and ventricular enlargement occurring predominantly through hyperplasia (increased cardiomyocyte proliferation) rather than hypertrophy, despite activation of transcriptional profiles similar to mammalian hypertrophic response; ER-stress pathway activation was also detected.","method":"Immunohistochemistry and confocal microscopy for cardiomyocyte size, density, and proliferation markers; RT-PCR for hypertrophy markers; western blot for ER-stress pathway","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function zebrafish model with multiple orthogonal assays (proliferation, histology, gene expression, protein) in single lab","pmids":["31129720"],"is_preprint":false},{"year":2020,"finding":"iPSC-derived cardiomyocytes carrying the MYH6-R443P head domain variant (from HLHS patients) exhibit dysmorphic sarcomere structure, exclusive beta-myosin heavy chain (MYH7) expression (no alpha-MHC) after differentiation day 15, slower contraction rate, reduced shortening, and slower shortening and relaxation velocities. CRISPR/Cas9 introduction of R443P into unaffected parent iPSCs recapitulated the phenotype; correction of R443P in proband iPSCs rescued sarcomere organization and contractile defects.","method":"iPSC-derived cardiomyocyte differentiation; CRISPR/Cas9 isogenic editing (introduction and correction of R443P); sarcomere imaging; contractility measurement; protein expression analysis","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional isogenic CRISPR editing (knock-in and rescue) with multiple functional readouts; strong causal link established","pmids":["32656206"],"is_preprint":false},{"year":2021,"finding":"Variants in the promoter region of MYH6 (g.4085G>C and g.4716G>A) found only in ventricular septal defect patients significantly reduced transcriptional activity of the MYH6 promoter and altered transcription factor binding sites as detected by EMSA, providing a loss-of-expression mechanism for VSD.","method":"Dual luciferase reporter assay; electrophoretic mobility shift assay (EMSA); bioinformatics (JASPAR) for transcription factor binding prediction","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional assays (luciferase + EMSA) in cell lines; single lab","pmids":["36209093"],"is_preprint":false},{"year":2023,"finding":"Variants in the MYH6 gene promoter found in tetralogy of Fallot patients (including two novel variants g.3384G>T and g.4518T>C) reduce transcriptional activity and alter transcription factor binding, as demonstrated by dual luciferase reporter assays and EMSA in three different cell lines (HEK-293, HL-1, H9C2).","method":"Dual luciferase reporter assay; EMSA in three cell lines; bioinformatics JASPAR analysis","journal":"Pediatric research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional assays replicated across three cell lines; single lab","pmids":["38135727"],"is_preprint":false},{"year":2024,"finding":"Variants in the MYH6 gene promoter found only in patent ductus arteriosus patients reduce transcriptional activity and alter transcription factor binding, as demonstrated by dual luciferase reporter and EMSA in three cell lines (HEK-293, HL-1, H9C2).","method":"Dual luciferase reporter assay; EMSA in three cell lines; sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal functional assays across three cell lines; single lab","pmids":["38340456"],"is_preprint":false},{"year":2022,"finding":"An insertion mutation (Arg1822_Glu1823dup) in the MYH6 coiled-coil domain impairs myofibril formation and increases apoptosis in transfected myoblast C2C12 cells; molecular simulation reveals the variant disrupts the myosin α-helix and increases coiled-coil dimer stability, suggesting aberrant self-aggregation.","method":"Transfection of mutant MYH6 in C2C12 myoblasts; myofibril formation assay; apoptosis assay; molecular dynamics simulation","journal":"European journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based functional assay plus molecular modeling; single lab with two complementary approaches","pmids":["34481090"],"is_preprint":false},{"year":2011,"finding":"Three novel MYH6 missense mutations (R17H, C539R, K543R) causing familial atrial septal defects are located in the highly conserved motor domain region involved in myosin-actin interaction, co-segregate with disease, and are absent in controls, placing the pathological mechanism at the level of myosin-actin interaction in the motor domain.","method":"Array-based resequencing of sarcomeric genes; family co-segregation analysis; structural/homology analysis of motor domain","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genetic and structural/homology analysis only; no direct biochemical or functional assay of myosin-actin interaction","pmids":["22194935"],"is_preprint":false},{"year":2024,"finding":"MYH6 overexpression in prostate cancer cells suppresses proliferation and migration, and RNA-seq identified KIT proto-oncogene as a downstream target of MYH6; rescue assays confirmed KIT mediates the tumor suppressive effects of MYH6.","method":"Overexpression in prostate cancer cell lines; in vitro proliferation and migration assays; RNA-seq; rescue assays with KIT; in vivo xenograft","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, non-cardiac context, mechanism supported by rescue assays but no direct biochemical interaction established between MYH6 and KIT","pmids":["39181964"],"is_preprint":false},{"year":2026,"finding":"CRISPR/Cas9-generated myh6 knockout zebrafish show impaired atrial and ventricular function, disordered sarcomere organization, and transcriptomic changes enriched in muscle development, calcium ion homeostasis, and sarcomere pathways (1318 differentially expressed genes), establishing that myh6 is required for maintaining atrial function and sarcomere integrity in vivo.","method":"CRISPR/Cas9 zebrafish knockout; echocardiographic/structural assessment; transcriptomic sequencing; sarcomere imaging","journal":"NPJ genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple orthogonal readouts (structural, functional, transcriptomic); single lab","pmids":["42236494"],"is_preprint":false},{"year":2025,"finding":"A gene regulatory enhancer element directly interacts with the MYH6 locus (confirmed by chromatin conformation assays) and controls MYH6 expression in hiPSC-derived cardiomyocytes; epigenome editing to activate this enhancer alters cardiomyocyte response to endothelin-1 stress, preventing polyploidization and changing calcium dynamics.","method":"Chromatin conformation assays (Hi-C/3C type); epigenome editing to activate enhancer; endothelin-1 stress assay; calcium imaging; polyploidy assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin conformation plus epigenome editing with functional phenotypic readouts; preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"hiPSC-CMs carrying MYH6 R725C (equivalent to MYH7 R723C) mutation show sarcomere disorganization, reduced cortical F-actin, increased central F-actin, cellular hypertrophy, and TGF-β1 overexpression; mutant cardiomyocytes activate fibroblasts via TGF-β1, and blocking TGF-β1 receptor signaling reduces fibroblast activation and contractile force to control levels.","method":"Base editing to introduce R725C in hiPSCs; 3D engineered heart tissue with cardiomyocytes and fibroblasts; immunostaining; RNA-seq; calcium imaging; force measurement; TGF-β1 receptor blockade rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic hiPSC model with multiple orthogonal assays and pharmacological rescue; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"hiPSC-CMs with MYH6 R725C mutation (alongside MYH7 R723C) display upregulation of cytoskeletal and sarcomere transcripts, cellular hypertrophy, increased aspect ratio, sarcomere disorganization with lower sarcomeric order, reduced cortical F-actin and increased central F-actin compared to isogenic controls, with pathological changes accumulating progressively over time.","method":"Base editing to generate isogenic mutant hiPSC-CMs; bulk RNA-seq with KEGG and GO analysis; immunostaining; morphological analysis","journal":"Journal of cardiovascular development and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic base-edited hiPSC model with transcriptomic and phenotypic analyses; single lab, peer-reviewed","pmids":["41440879"],"is_preprint":false},{"year":2024,"finding":"MYH6 variant carriers (HLHS patients) show decreased right atrial active strain (impaired atrial contractility) measured by 2D speckle-tracking echocardiography compared to controls, with no significant difference in right ventricular function, establishing that α-MHC dysfunction specifically impairs atrial (not ventricular) contractile function consistent with predominant atrial MYH6 expression.","method":"2D speckle-tracking echocardiography (2D-STE) with blinded assessment; case-control matching","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct functional measurement of atrial strain in genotyped patients; blinded design; multiple strain parameters assessed; single center","pmids":["39596649"],"is_preprint":false},{"year":2024,"finding":"Mice carrying both heterozygous Myh6-R453C and Tnnt2-R92W mutations develop significantly greater HCM phenotypes (hypertrophy) at 4 weeks compared to single heterozygous mutants, establishing a synergistic aggravation of HCM by double sarcomere mutations involving MYH6.","method":"Generation of single and double heterozygous knock-in mice; echocardiography; histology for hypertrophy assessment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in isogenic mouse models with functional cardiac readouts; single lab","pmids":["39191188"],"is_preprint":false}],"current_model":"MYH6 encodes the α-myosin heavy chain, the predominant sarcomeric motor protein in adult atria and fetal heart, where it assembles into thick filaments via its coiled-coil tail domain and drives actin-dependent cardiac contraction; pathological stress triggers a BRG1-G9a/GLP-DNMT3 repressive chromatin complex on the Myh6 promoter to silence its expression, while mutations in its motor or tail domains disrupt myofibril formation and sarcomere organization, reduce contractile velocity and force, and can activate compensatory MYH7 upregulation and TGF-β1-mediated fibrosis, collectively causing a spectrum of cardiac defects from congenital heart disease to cardiomyopathy and arrhythmia."},"narrative":{"mechanistic_narrative":"MYH6 encodes the α-cardiac myosin heavy chain, the sarcomeric motor whose coiled-coil tail polymerizes into thick filaments and whose motor domain drives actin-dependent cardiac contraction; loss of this activity yields non-contractile hearts and disrupted cardiomyocyte cytoskeleton, while early cardiac morphogenesis can still proceed [PMID:19769958]. In vivo loss of α-MHC compromises sarcomere integrity and pump function with predominantly atrial impact, producing atrial hypoplasia, disordered sarcomeres, and transcriptomic shifts in muscle development, calcium homeostasis, and sarcomere pathways [PMID:31129720, PMID:42236494]; consistent with α-MHC's predominant atrial expression, human variant carriers show selectively impaired atrial contractile strain [PMID:39596649]. Pathogenic missense and insertion variants act through the motor and tail domains to alter myofibril assembly and sarcomere organization—some disrupting and one even enhancing assembly—and tail-domain insertions destabilize the α-helix to promote aberrant self-aggregation [PMID:20656787, PMID:34481090]. Isogenic CRISPR/base-edited hiPSC-cardiomyocyte models causally tie head-domain variants (R443P, R725C) to dysmorphic sarcomeres, a switch to exclusive MYH7 (β-MHC) expression, reduced contraction and shortening velocity, F-actin redistribution, cellular hypertrophy, and TGF-β1–driven fibroblast activation that is reversible by TGF-β1 receptor blockade [PMID:32656206, PMID:41440879]. The locus is regulated at multiple levels: a stress-activated BRG1–G9a/GLP–DNMT3 repressive chromatin complex assembles on the Myh6 promoter to silence it during pathological stress, and disease-associated promoter and enhancer variants reduce MYH6 transcription and alter its stress response [PMID:26952936, PMID:36209093, PMID:38135727, PMID:38340456]. These mechanisms link MYH6 dysfunction to a spectrum of congenital heart disease, hypertrophic cardiomyopathy, and arrhythmia, and partial allele-specific silencing of a dominant HCM allele prevents hypertrophy and fibrosis in vivo [PMID:24092743, PMID:39191188].","teleology":[{"year":1993,"claim":"Established the complete genomic architecture of human MYH6, defining its 39-exon structure and its close structural relationship to the β-MyHC gene, providing the foundation for variant interpretation.","evidence":"Complete gene and 5'-flanking sequencing with exon/intron boundary mapping","pmids":["8307559"],"confidence":"High","gaps":["Structural genomics alone; does not address protein function or regulation","No expression or tissue-specificity data"]},{"year":2009,"claim":"Defined the core motor function of α-MHC by showing that loss of the coiled-coil/thick-filament assembly domain produces a non-contractile heart, while distinguishing contraction from early morphogenesis which proceeds independently.","evidence":"Positional cloning of the X. tropicalis myh6 muzak nonsense mutation with imaging/histology of homozygous embryos","pmids":["19769958"],"confidence":"High","gaps":["Ortholog model; mammalian biochemistry of filament assembly not addressed","Mechanism of valve/trabecula failure secondary to contractile loss unresolved"]},{"year":2010,"claim":"Connected specific congenital heart defect variants to altered sarcomere assembly, showing variants can either disrupt or enhance myofibril formation rather than acting uniformly.","evidence":"GFP-MYH6 wild-type/mutant transfection in mouse myoblasts with fluorescence assessment of myofibril formation","pmids":["20656787"],"confidence":"Medium","gaps":["Heterologous myoblast system, not cardiomyocytes","No measurement of motor activity or force","Single lab"]},{"year":2013,"claim":"Demonstrated that the dominant pathogenic mechanism of an HCM allele can be neutralized therapeutically, establishing that partial allele-specific silencing suffices to prevent disease.","evidence":"AAV-delivered allele-specific RNAi against R403Q in MHC403/+ mice with histological/echocardiographic follow-up","pmids":["24092743"],"confidence":"High","gaps":["Single allele tested; generalizability to other variants unknown","Long-term durability beyond 6 months not assessed"]},{"year":2016,"claim":"Revealed an epigenetic silencing mechanism whereby pathological stress represses Myh6 through an assembled chromatin-modifying complex, linking gene regulation to contractile dysfunction.","evidence":"ChIP, reciprocal co-IP of BRG1–G9a/GLP–DNMT3, genetic disruption of each component in mice with methylation and cardiac function readouts","pmids":["26952936"],"confidence":"High","gaps":["Upstream signal triggering complex assembly not defined","Relative contribution of MYH6 silencing vs other targets to dysfunction unclear"]},{"year":2019,"claim":"Showed that adult loss of α-MHC drives atrial hypoplasia and compensatory ventricular growth via hyperplasia, alongside ER-stress activation, characterizing the in vivo consequences of chronic deficiency.","evidence":"Zebrafish weak atrium loss-of-function line with histology, proliferation markers, hypertrophy-marker RT-PCR, and ER-stress western blot","pmids":["31129720"],"confidence":"Medium","gaps":["Ortholog model; mammalian relevance of hyperplasia response uncertain","Mechanism linking α-MHC loss to ER stress unresolved"]},{"year":2020,"claim":"Provided rigorous causal evidence that a head-domain variant produces sarcomere and contractile defects and a switch to β-MHC, using bidirectional isogenic editing to both recapitulate and rescue the phenotype.","evidence":"hiPSC-CM differentiation with CRISPR knock-in and correction of R443P, sarcomere imaging, contractility and protein-expression analysis","pmids":["32656206"],"confidence":"High","gaps":["Mechanism driving MYH7 isoform switch not defined","Single variant; in vivo confirmation absent"]},{"year":2024,"claim":"Linked head-domain dysfunction to a fibrotic disease mechanism, showing mutant cardiomyocytes activate fibroblasts via TGF-β1 in a reversible manner.","evidence":"Base-edited R725C hiPSC-CMs in 3D engineered heart tissue with fibroblasts, RNA-seq, force measurement, and TGF-β1 receptor blockade rescue (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; awaits peer review","Single lab; in vivo fibrosis link not established here"]},{"year":2024,"claim":"Distinguished chamber-specific consequences of α-MHC dysfunction in humans, showing selective impairment of atrial contractility consistent with predominant atrial MYH6 expression.","evidence":"2D speckle-tracking echocardiography in genotyped HLHS variant carriers with blinded case-control design","pmids":["39596649"],"confidence":"Medium","gaps":["Single center; correlation not mechanistic","Does not establish causal molecular pathway in vivo"]},{"year":2024,"claim":"Demonstrated genetic synergy between MYH6 and another sarcomere gene, showing double mutations aggravate hypertrophy beyond single mutants.","evidence":"Single and double heterozygous Myh6-R453C/Tnnt2-R92W knock-in mice with echocardiography and histology","pmids":["39191188"],"confidence":"Medium","gaps":["Molecular basis of synergy not defined","Single lab"]},{"year":2024,"claim":"Extended a tumor-suppressive role for MYH6 outside the heart, identifying KIT as a downstream effector in prostate cancer cells.","evidence":"MYH6 overexpression in prostate cancer lines with proliferation/migration assays, RNA-seq, KIT rescue, and xenograft","pmids":["39181964"],"confidence":"Low","gaps":["Non-cardiac context; relevance to sarcomeric function unclear","No direct MYH6–KIT biochemical interaction shown","Single lab"]},{"year":2024,"claim":"Localized congenital-defect pathology to transcriptional dysregulation, showing disease-associated promoter variants reduce MYH6 transcription and alter transcription-factor binding across multiple defect types.","evidence":"Dual luciferase reporter and EMSA assays for VSD, TOF, and PDA promoter variants in multiple cell lines","pmids":["36209093","38135727","38340456"],"confidence":"Medium","gaps":["Specific transcription factors not definitively identified","In vivo expression effects not measured","Single lab"]},{"year":2025,"claim":"Identified distal enhancer control of MYH6 that shapes the cardiomyocyte stress response, linking 3D genome architecture to calcium dynamics and polyploidization.","evidence":"Chromatin conformation assays plus epigenome editing in hiPSC-CMs with endothelin-1 stress, calcium imaging, and polyploidy readouts (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; awaits peer review","Endogenous role of enhancer in vivo not established"]},{"year":2026,"claim":"Provided clean loss-of-function evidence that MYH6 maintains atrial/ventricular function and sarcomere integrity, with broad transcriptomic dependencies in muscle, calcium, and sarcomere pathways.","evidence":"CRISPR/Cas9 zebrafish knockout with structural/functional assessment, sarcomere imaging, and transcriptomics","pmids":["42236494"],"confidence":"Medium","gaps":["Ortholog model; mammalian transcriptomic conservation untested","Direct vs secondary transcriptomic effects not separated"]},{"year":null,"claim":"The biochemical mechanism by which specific motor-domain variants alter myosin-actin interaction, force, and the trigger that converts these defects into the MYH7 isoform switch and fibrotic program remain to be defined at the molecular level.","evidence":"No direct biochemical reconstitution of mutant α-MHC motor activity present in the corpus","pmids":[],"confidence":"Low","gaps":["No in vitro motility/ATPase assay of mutant α-MHC in the corpus","Signal coupling MYH6 dysfunction to MYH7 upregulation undefined","Upstream activator of the stress-induced repressive chromatin complex unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11,15]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3,13]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[2,6,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,18]}],"complexes":["sarcomere thick filament"],"partners":["MYH7","TNNT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P13533","full_name":"Myosin-6","aliases":["Myosin heavy chain 6","Myosin heavy chain, cardiac muscle alpha isoform","MyHC-alpha"],"length_aa":1939,"mass_kda":223.7,"function":"Muscle contraction","subcellular_location":"Cytoplasm, myofibril","url":"https://www.uniprot.org/uniprotkb/P13533/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYH6","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYH6","total_profiled":1310},"omim":[{"mim_id":"616096","title":"MYOSIN HEAVY CHAIN-ASSOCIATED RNA TRANSCRIPT, NONCODING; MHRT","url":"https://www.omim.org/entry/616096"},{"mim_id":"615396","title":"LEFT VENTRICULAR NONCOMPACTION 10; LVNC10","url":"https://www.omim.org/entry/615396"},{"mim_id":"614090","title":"SICK SINUS SYNDROME 3, SUSCEPTIBILITY TO; SSS3","url":"https://www.omim.org/entry/614090"},{"mim_id":"614089","title":"ATRIAL SEPTAL DEFECT 3; ASD3","url":"https://www.omim.org/entry/614089"},{"mim_id":"613613","title":"MICRO RNA 208B; MIR208B","url":"https://www.omim.org/entry/613613"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Focal adhesion sites","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":4840.4}],"url":"https://www.proteinatlas.org/search/MYH6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P13533","domains":[{"cath_id":"1.20.5","chopping":"843-970","consensus_level":"medium","plddt":79.0079,"start":843,"end":970}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13533","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13533-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13533-F1-predicted_aligned_error_v6.png","plddt_mean":74.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYH6","jax_strain_url":"https://www.jax.org/strain/search?query=MYH6"},"sequence":{"accession":"P13533","fasta_url":"https://rest.uniprot.org/uniprotkb/P13533.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13533/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13533"}},"corpus_meta":[{"pmid":"21378987","id":"PMC_21378987","title":"A rare variant in MYH6 is associated with high risk of sick sinus syndrome.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21378987","citation_count":247,"is_preprint":false},{"pmid":"20215591","id":"PMC_20215591","title":"Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.","date":"2010","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20215591","citation_count":199,"is_preprint":false},{"pmid":"24092743","id":"PMC_24092743","title":"Allele-specific silencing of mutant Myh6 transcripts in mice suppresses hypertrophic cardiomyopathy.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24092743","citation_count":184,"is_preprint":false},{"pmid":"20656787","id":"PMC_20656787","title":"Alpha-cardiac myosin heavy chain (MYH6) mutations affecting myofibril formation are associated with congenital heart defects.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20656787","citation_count":122,"is_preprint":false},{"pmid":"27789736","id":"PMC_27789736","title":"Impact of MYH6 variants in hypoplastic left heart syndrome.","date":"2016","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27789736","citation_count":75,"is_preprint":false},{"pmid":"22194935","id":"PMC_22194935","title":"Cardiac alpha-myosin (MYH6) is the predominant sarcomeric disease gene for familial atrial septal defects.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22194935","citation_count":74,"is_preprint":false},{"pmid":"26085007","id":"PMC_26085007","title":"Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction.","date":"2015","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26085007","citation_count":70,"is_preprint":false},{"pmid":"29590334","id":"PMC_29590334","title":"A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta.","date":"2018","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/29590334","citation_count":60,"is_preprint":false},{"pmid":"26952936","id":"PMC_26952936","title":"Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26952936","citation_count":57,"is_preprint":false},{"pmid":"19769958","id":"PMC_19769958","title":"Absence of heartbeat in the Xenopus tropicalis mutation muzak is caused by a nonsense mutation in cardiac myosin myh6.","date":"2009","source":"Developmental 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Disruption of any component (Brg1, G9a, or Dnmt3) de-represses Myh6 and reduces stress-induced cardiac dysfunction.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation of BRG1-G9a/GLP-DNMT3 complex, genetic disruption of each component in mice, histone/DNA methylation assays, cardiac function readouts\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP of complex components, genetic disruption of multiple components each showing de-repression, functional cardiac readout; replicated finding in human hypertrophic hearts\",\n      \"pmids\": [\"26952936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HCM-causing Myh6 R403Q mutant allele can be selectively silenced by allele-specific RNAi delivered via AAV; a 25% reduction in mutant transcript levels was sufficient to prevent hypertrophy and myocardial fibrosis in MHC403/+ mice for at least 6 months, establishing that partial allele-specific silencing of mutant Myh6 suppresses the dominant pathological mechanism.\",\n      \"method\": \"AAV-delivered RNAi in transgenic MHC403/+ mice; histological and echocardiographic assessment of hypertrophy and fibrosis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with specific phenotypic readout (hypertrophy and fibrosis prevention) over 6-month follow-up; rigorous allele-specific design\",\n      \"pmids\": [\"24092743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A nonsense mutation in the X. tropicalis cardiac myosin heavy chain gene myh6 (muzak mutation) causes a premature stop codon that deletes the coiled-coil domain responsible for polymerization into thick filaments, leading to non-contractile hearts with severely disrupted cardiomyocyte cytoskeleton. Despite loss of contractile activity and thick filament assembly, early cardiac morphogenesis (looping, chamber formation) proceeds normally; later, dilated chambers form with compressed endocardium and failure to form valves and trabeculae.\",\n      \"method\": \"Positional cloning, sequencing, phenotypic characterization of homozygous mutant embryos by imaging and histology\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — first positional cloning of an X. tropicalis mutation; direct causative link between nonsense mutation, loss of thick filament assembly, and non-contractile heart phenotype established by ortholog genetics\",\n      \"pmids\": [\"19769958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Specific MYH6 missense mutations (A230P and A1366D) significantly disrupt myofibril formation in mouse myoblasts transfected with GFP-MYH6 fusion proteins, whereas the H252Q mutation significantly enhances myofibril assembly, establishing that MYH6 variants associated with congenital heart defects functionally alter sarcomere/myofibril assembly.\",\n      \"method\": \"Transfection of GFP-MYH6 fusion constructs (wild-type and mutant) in mouse myoblasts; fluorescence microscopy assessment of myofibril formation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based functional assay in heterologous myoblast system with multiple mutants tested; single lab but two distinct phenotypic outcomes (disruption vs. enhancement) provide internal controls\",\n      \"pmids\": [\"20656787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human MYH6 gene consists of 39 exons (37 coding), with the 5'-UTR split into 3 exons and the AUG initiation codon in the third exon. All exon/intron boundaries are conserved with beta-MyHC (MYH7) except one intron. The gene spans 26,159 bp and the intergenic 5'-flanking region is 4484 bp.\",\n      \"method\": \"Complete nucleotide sequencing of the gene and 5'-flanking region; exon/intron boundary mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complete gene sequencing with full structural characterization; foundational structural paper for the gene\",\n      \"pmids\": [\"8307559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Adult zebrafish homozygous for myh6 loss-of-function mutations (weak atrium line) develop atrial hypoplasia with elastin deposition and ventricular enlargement occurring predominantly through hyperplasia (increased cardiomyocyte proliferation) rather than hypertrophy, despite activation of transcriptional profiles similar to mammalian hypertrophic response; ER-stress pathway activation was also detected.\",\n      \"method\": \"Immunohistochemistry and confocal microscopy for cardiomyocyte size, density, and proliferation markers; RT-PCR for hypertrophy markers; western blot for ER-stress pathway\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function zebrafish model with multiple orthogonal assays (proliferation, histology, gene expression, protein) in single lab\",\n      \"pmids\": [\"31129720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"iPSC-derived cardiomyocytes carrying the MYH6-R443P head domain variant (from HLHS patients) exhibit dysmorphic sarcomere structure, exclusive beta-myosin heavy chain (MYH7) expression (no alpha-MHC) after differentiation day 15, slower contraction rate, reduced shortening, and slower shortening and relaxation velocities. CRISPR/Cas9 introduction of R443P into unaffected parent iPSCs recapitulated the phenotype; correction of R443P in proband iPSCs rescued sarcomere organization and contractile defects.\",\n      \"method\": \"iPSC-derived cardiomyocyte differentiation; CRISPR/Cas9 isogenic editing (introduction and correction of R443P); sarcomere imaging; contractility measurement; protein expression analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional isogenic CRISPR editing (knock-in and rescue) with multiple functional readouts; strong causal link established\",\n      \"pmids\": [\"32656206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Variants in the promoter region of MYH6 (g.4085G>C and g.4716G>A) found only in ventricular septal defect patients significantly reduced transcriptional activity of the MYH6 promoter and altered transcription factor binding sites as detected by EMSA, providing a loss-of-expression mechanism for VSD.\",\n      \"method\": \"Dual luciferase reporter assay; electrophoretic mobility shift assay (EMSA); bioinformatics (JASPAR) for transcription factor binding prediction\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional assays (luciferase + EMSA) in cell lines; single lab\",\n      \"pmids\": [\"36209093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Variants in the MYH6 gene promoter found in tetralogy of Fallot patients (including two novel variants g.3384G>T and g.4518T>C) reduce transcriptional activity and alter transcription factor binding, as demonstrated by dual luciferase reporter assays and EMSA in three different cell lines (HEK-293, HL-1, H9C2).\",\n      \"method\": \"Dual luciferase reporter assay; EMSA in three cell lines; bioinformatics JASPAR analysis\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional assays replicated across three cell lines; single lab\",\n      \"pmids\": [\"38135727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Variants in the MYH6 gene promoter found only in patent ductus arteriosus patients reduce transcriptional activity and alter transcription factor binding, as demonstrated by dual luciferase reporter and EMSA in three cell lines (HEK-293, HL-1, H9C2).\",\n      \"method\": \"Dual luciferase reporter assay; EMSA in three cell lines; sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal functional assays across three cell lines; single lab\",\n      \"pmids\": [\"38340456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"An insertion mutation (Arg1822_Glu1823dup) in the MYH6 coiled-coil domain impairs myofibril formation and increases apoptosis in transfected myoblast C2C12 cells; molecular simulation reveals the variant disrupts the myosin α-helix and increases coiled-coil dimer stability, suggesting aberrant self-aggregation.\",\n      \"method\": \"Transfection of mutant MYH6 in C2C12 myoblasts; myofibril formation assay; apoptosis assay; molecular dynamics simulation\",\n      \"journal\": \"European journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based functional assay plus molecular modeling; single lab with two complementary approaches\",\n      \"pmids\": [\"34481090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Three novel MYH6 missense mutations (R17H, C539R, K543R) causing familial atrial septal defects are located in the highly conserved motor domain region involved in myosin-actin interaction, co-segregate with disease, and are absent in controls, placing the pathological mechanism at the level of myosin-actin interaction in the motor domain.\",\n      \"method\": \"Array-based resequencing of sarcomeric genes; family co-segregation analysis; structural/homology analysis of motor domain\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genetic and structural/homology analysis only; no direct biochemical or functional assay of myosin-actin interaction\",\n      \"pmids\": [\"22194935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYH6 overexpression in prostate cancer cells suppresses proliferation and migration, and RNA-seq identified KIT proto-oncogene as a downstream target of MYH6; rescue assays confirmed KIT mediates the tumor suppressive effects of MYH6.\",\n      \"method\": \"Overexpression in prostate cancer cell lines; in vitro proliferation and migration assays; RNA-seq; rescue assays with KIT; in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, non-cardiac context, mechanism supported by rescue assays but no direct biochemical interaction established between MYH6 and KIT\",\n      \"pmids\": [\"39181964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CRISPR/Cas9-generated myh6 knockout zebrafish show impaired atrial and ventricular function, disordered sarcomere organization, and transcriptomic changes enriched in muscle development, calcium ion homeostasis, and sarcomere pathways (1318 differentially expressed genes), establishing that myh6 is required for maintaining atrial function and sarcomere integrity in vivo.\",\n      \"method\": \"CRISPR/Cas9 zebrafish knockout; echocardiographic/structural assessment; transcriptomic sequencing; sarcomere imaging\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple orthogonal readouts (structural, functional, transcriptomic); single lab\",\n      \"pmids\": [\"42236494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A gene regulatory enhancer element directly interacts with the MYH6 locus (confirmed by chromatin conformation assays) and controls MYH6 expression in hiPSC-derived cardiomyocytes; epigenome editing to activate this enhancer alters cardiomyocyte response to endothelin-1 stress, preventing polyploidization and changing calcium dynamics.\",\n      \"method\": \"Chromatin conformation assays (Hi-C/3C type); epigenome editing to activate enhancer; endothelin-1 stress assay; calcium imaging; polyploidy assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin conformation plus epigenome editing with functional phenotypic readouts; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hiPSC-CMs carrying MYH6 R725C (equivalent to MYH7 R723C) mutation show sarcomere disorganization, reduced cortical F-actin, increased central F-actin, cellular hypertrophy, and TGF-β1 overexpression; mutant cardiomyocytes activate fibroblasts via TGF-β1, and blocking TGF-β1 receptor signaling reduces fibroblast activation and contractile force to control levels.\",\n      \"method\": \"Base editing to introduce R725C in hiPSCs; 3D engineered heart tissue with cardiomyocytes and fibroblasts; immunostaining; RNA-seq; calcium imaging; force measurement; TGF-β1 receptor blockade rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic hiPSC model with multiple orthogonal assays and pharmacological rescue; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hiPSC-CMs with MYH6 R725C mutation (alongside MYH7 R723C) display upregulation of cytoskeletal and sarcomere transcripts, cellular hypertrophy, increased aspect ratio, sarcomere disorganization with lower sarcomeric order, reduced cortical F-actin and increased central F-actin compared to isogenic controls, with pathological changes accumulating progressively over time.\",\n      \"method\": \"Base editing to generate isogenic mutant hiPSC-CMs; bulk RNA-seq with KEGG and GO analysis; immunostaining; morphological analysis\",\n      \"journal\": \"Journal of cardiovascular development and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic base-edited hiPSC model with transcriptomic and phenotypic analyses; single lab, peer-reviewed\",\n      \"pmids\": [\"41440879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYH6 variant carriers (HLHS patients) show decreased right atrial active strain (impaired atrial contractility) measured by 2D speckle-tracking echocardiography compared to controls, with no significant difference in right ventricular function, establishing that α-MHC dysfunction specifically impairs atrial (not ventricular) contractile function consistent with predominant atrial MYH6 expression.\",\n      \"method\": \"2D speckle-tracking echocardiography (2D-STE) with blinded assessment; case-control matching\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct functional measurement of atrial strain in genotyped patients; blinded design; multiple strain parameters assessed; single center\",\n      \"pmids\": [\"39596649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mice carrying both heterozygous Myh6-R453C and Tnnt2-R92W mutations develop significantly greater HCM phenotypes (hypertrophy) at 4 weeks compared to single heterozygous mutants, establishing a synergistic aggravation of HCM by double sarcomere mutations involving MYH6.\",\n      \"method\": \"Generation of single and double heterozygous knock-in mice; echocardiography; histology for hypertrophy assessment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in isogenic mouse models with functional cardiac readouts; single lab\",\n      \"pmids\": [\"39191188\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYH6 encodes the α-myosin heavy chain, the predominant sarcomeric motor protein in adult atria and fetal heart, where it assembles into thick filaments via its coiled-coil tail domain and drives actin-dependent cardiac contraction; pathological stress triggers a BRG1-G9a/GLP-DNMT3 repressive chromatin complex on the Myh6 promoter to silence its expression, while mutations in its motor or tail domains disrupt myofibril formation and sarcomere organization, reduce contractile velocity and force, and can activate compensatory MYH7 upregulation and TGF-β1-mediated fibrosis, collectively causing a spectrum of cardiac defects from congenital heart disease to cardiomyopathy and arrhythmia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYH6 encodes the α-cardiac myosin heavy chain, the sarcomeric motor whose coiled-coil tail polymerizes into thick filaments and whose motor domain drives actin-dependent cardiac contraction; loss of this activity yields non-contractile hearts and disrupted cardiomyocyte cytoskeleton, while early cardiac morphogenesis can still proceed [#2]. In vivo loss of α-MHC compromises sarcomere integrity and pump function with predominantly atrial impact, producing atrial hypoplasia, disordered sarcomeres, and transcriptomic shifts in muscle development, calcium homeostasis, and sarcomere pathways [#5, #13]; consistent with α-MHC's predominant atrial expression, human variant carriers show selectively impaired atrial contractile strain [#17]. Pathogenic missense and insertion variants act through the motor and tail domains to alter myofibril assembly and sarcomere organization—some disrupting and one even enhancing assembly—and tail-domain insertions destabilize the α-helix to promote aberrant self-aggregation [#3, #10]. Isogenic CRISPR/base-edited hiPSC-cardiomyocyte models causally tie head-domain variants (R443P, R725C) to dysmorphic sarcomeres, a switch to exclusive MYH7 (β-MHC) expression, reduced contraction and shortening velocity, F-actin redistribution, cellular hypertrophy, and TGF-β1–driven fibroblast activation that is reversible by TGF-β1 receptor blockade [#6, #15, #16]. The locus is regulated at multiple levels: a stress-activated BRG1–G9a/GLP–DNMT3 repressive chromatin complex assembles on the Myh6 promoter to silence it during pathological stress, and disease-associated promoter and enhancer variants reduce MYH6 transcription and alter its stress response [#0, #7, #8, #9, #14]. These mechanisms link MYH6 dysfunction to a spectrum of congenital heart disease, hypertrophic cardiomyopathy, and arrhythmia, and partial allele-specific silencing of a dominant HCM allele prevents hypertrophy and fibrosis in vivo [#1, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the complete genomic architecture of human MYH6, defining its 39-exon structure and its close structural relationship to the β-MyHC gene, providing the foundation for variant interpretation.\",\n      \"evidence\": \"Complete gene and 5'-flanking sequencing with exon/intron boundary mapping\",\n      \"pmids\": [\"8307559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural genomics alone; does not address protein function or regulation\", \"No expression or tissue-specificity data\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the core motor function of α-MHC by showing that loss of the coiled-coil/thick-filament assembly domain produces a non-contractile heart, while distinguishing contraction from early morphogenesis which proceeds independently.\",\n      \"evidence\": \"Positional cloning of the X. tropicalis myh6 muzak nonsense mutation with imaging/histology of homozygous embryos\",\n      \"pmids\": [\"19769958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ortholog model; mammalian biochemistry of filament assembly not addressed\", \"Mechanism of valve/trabecula failure secondary to contractile loss unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected specific congenital heart defect variants to altered sarcomere assembly, showing variants can either disrupt or enhance myofibril formation rather than acting uniformly.\",\n      \"evidence\": \"GFP-MYH6 wild-type/mutant transfection in mouse myoblasts with fluorescence assessment of myofibril formation\",\n      \"pmids\": [\"20656787\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous myoblast system, not cardiomyocytes\", \"No measurement of motor activity or force\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that the dominant pathogenic mechanism of an HCM allele can be neutralized therapeutically, establishing that partial allele-specific silencing suffices to prevent disease.\",\n      \"evidence\": \"AAV-delivered allele-specific RNAi against R403Q in MHC403/+ mice with histological/echocardiographic follow-up\",\n      \"pmids\": [\"24092743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single allele tested; generalizability to other variants unknown\", \"Long-term durability beyond 6 months not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an epigenetic silencing mechanism whereby pathological stress represses Myh6 through an assembled chromatin-modifying complex, linking gene regulation to contractile dysfunction.\",\n      \"evidence\": \"ChIP, reciprocal co-IP of BRG1–G9a/GLP–DNMT3, genetic disruption of each component in mice with methylation and cardiac function readouts\",\n      \"pmids\": [\"26952936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal triggering complex assembly not defined\", \"Relative contribution of MYH6 silencing vs other targets to dysfunction unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed that adult loss of α-MHC drives atrial hypoplasia and compensatory ventricular growth via hyperplasia, alongside ER-stress activation, characterizing the in vivo consequences of chronic deficiency.\",\n      \"evidence\": \"Zebrafish weak atrium loss-of-function line with histology, proliferation markers, hypertrophy-marker RT-PCR, and ER-stress western blot\",\n      \"pmids\": [\"31129720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog model; mammalian relevance of hyperplasia response uncertain\", \"Mechanism linking α-MHC loss to ER stress unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided rigorous causal evidence that a head-domain variant produces sarcomere and contractile defects and a switch to β-MHC, using bidirectional isogenic editing to both recapitulate and rescue the phenotype.\",\n      \"evidence\": \"hiPSC-CM differentiation with CRISPR knock-in and correction of R443P, sarcomere imaging, contractility and protein-expression analysis\",\n      \"pmids\": [\"32656206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism driving MYH7 isoform switch not defined\", \"Single variant; in vivo confirmation absent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked head-domain dysfunction to a fibrotic disease mechanism, showing mutant cardiomyocytes activate fibroblasts via TGF-β1 in a reversible manner.\",\n      \"evidence\": \"Base-edited R725C hiPSC-CMs in 3D engineered heart tissue with fibroblasts, RNA-seq, force measurement, and TGF-β1 receptor blockade rescue (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; awaits peer review\", \"Single lab; in vivo fibrosis link not established here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Distinguished chamber-specific consequences of α-MHC dysfunction in humans, showing selective impairment of atrial contractility consistent with predominant atrial MYH6 expression.\",\n      \"evidence\": \"2D speckle-tracking echocardiography in genotyped HLHS variant carriers with blinded case-control design\",\n      \"pmids\": [\"39596649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single center; correlation not mechanistic\", \"Does not establish causal molecular pathway in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated genetic synergy between MYH6 and another sarcomere gene, showing double mutations aggravate hypertrophy beyond single mutants.\",\n      \"evidence\": \"Single and double heterozygous Myh6-R453C/Tnnt2-R92W knock-in mice with echocardiography and histology\",\n      \"pmids\": [\"39191188\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of synergy not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended a tumor-suppressive role for MYH6 outside the heart, identifying KIT as a downstream effector in prostate cancer cells.\",\n      \"evidence\": \"MYH6 overexpression in prostate cancer lines with proliferation/migration assays, RNA-seq, KIT rescue, and xenograft\",\n      \"pmids\": [\"39181964\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Non-cardiac context; relevance to sarcomeric function unclear\", \"No direct MYH6–KIT biochemical interaction shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Localized congenital-defect pathology to transcriptional dysregulation, showing disease-associated promoter variants reduce MYH6 transcription and alter transcription-factor binding across multiple defect types.\",\n      \"evidence\": \"Dual luciferase reporter and EMSA assays for VSD, TOF, and PDA promoter variants in multiple cell lines\",\n      \"pmids\": [\"36209093\", \"38135727\", \"38340456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific transcription factors not definitively identified\", \"In vivo expression effects not measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified distal enhancer control of MYH6 that shapes the cardiomyocyte stress response, linking 3D genome architecture to calcium dynamics and polyploidization.\",\n      \"evidence\": \"Chromatin conformation assays plus epigenome editing in hiPSC-CMs with endothelin-1 stress, calcium imaging, and polyploidy readouts (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; awaits peer review\", \"Endogenous role of enhancer in vivo not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided clean loss-of-function evidence that MYH6 maintains atrial/ventricular function and sarcomere integrity, with broad transcriptomic dependencies in muscle, calcium, and sarcomere pathways.\",\n      \"evidence\": \"CRISPR/Cas9 zebrafish knockout with structural/functional assessment, sarcomere imaging, and transcriptomics\",\n      \"pmids\": [\"42236494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog model; mammalian transcriptomic conservation untested\", \"Direct vs secondary transcriptomic effects not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which specific motor-domain variants alter myosin-actin interaction, force, and the trigger that converts these defects into the MYH7 isoform switch and fibrotic program remain to be defined at the molecular level.\",\n      \"evidence\": \"No direct biochemical reconstitution of mutant α-MHC motor activity present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro motility/ATPase assay of mutant α-MHC in the corpus\", \"Signal coupling MYH6 dysfunction to MYH7 upregulation undefined\", \"Upstream activator of the stress-induced repressive chromatin complex unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [2, 6, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 18]}\n    ],\n    \"complexes\": [\"sarcomere thick filament\"],\n    \"partners\": [\"MYH7\", \"TNNT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}