{"gene":"MYH7","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2013,"finding":"MYH7 mutations (in the globular head/S1 domain) reduce the maximal force generating capacity of sarcomeres at both maximal and submaximal Ca2+ concentrations, an intrinsic sarcomere defect distinct from cardiomyocyte remodelling. In single myofibril preparations, MYH7mut showed very low Fmax (~73 kN/m²) compared to donor (~113 kN/m²), and this reduction persisted after correction for myofibril density, unlike MYBPC3 mutations.","method":"Force measurements in single membrane-permeabilized cardiomyocytes and single myofibrils from surgical cardiac samples of HCM patients with MYH7 mutations versus controls","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro force measurements in single myofibrils and cardiomyocytes, multiple patient samples, orthogonal preparations, rigorous controls","pmids":["23674513"],"is_preprint":false},{"year":2014,"finding":"The R403Q mutation in MYH7 (located in the S1 actin-binding/motor domain) causes faster cross-bridge detachment kinetics and significantly higher energetic cost of tension generation (tension cost) compared to sarcomere mutation-negative HCM. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher than in HCMsmn myofibrils, and this correlated positively with tension cost in muscle strips.","method":"Single cardiac myofibril force measurements and multicellular cardiac muscle strip tension cost measurements in samples from R403Q HCM patients versus HCMsmn patients; single-cell RT-qPCR confirmed ~41% mutant allele expression","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted myofibril and muscle strip assays with rigorous controls, multiple orthogonal methods (kinetics + energetics), multiple patient samples","pmids":["24928957"],"is_preprint":false},{"year":2004,"finding":"Heterozygous mutations toward the 3' end of MYH7 (encoding the myosin tail/coiled-coil rod region) cause Laing-type early-onset distal myopathy. In silico analysis predicts these mutations locally disrupt the coiled-coil structure of the myosin tail, distinguishing them from head-domain mutations that cause cardiomyopathy.","method":"MYH7 gene sequencing in six families with early-onset distal myopathy; in silico coiled-coil disruption analysis of five novel mutations (Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, Lys1729del)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic identification with segregation in multiple families; in silico structural prediction only (no in vitro reconstitution), but replicated across 6 families","pmids":["15322983"],"is_preprint":false},{"year":2003,"finding":"A missense mutation in the rod region of MYH7 (Arg1845Trp) causes myosin storage myopathy, characterized by accumulation of slow/β-cardiac MyHC in large inclusions in type 1 skeletal muscle fibers, indicating this residue is essential for proper thick filament assembly in skeletal muscle.","method":"Clinical characterization and muscle biopsy immunohistochemistry/histology in patients from two families; genetic sequencing of MYH7","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathological characterization in two independent families with same mutation; mechanism inferred from protein aggregation phenotype on biopsy, no in vitro reconstitution","pmids":["14520662"],"is_preprint":false},{"year":2018,"finding":"The MYH7 E848G mutation (in the motor domain) reduces contractile function in hiPSC-derived cardiomyocytes at single-cell and engineered heart tissue levels. Genome-edited isogenic cells confirmed pathogenicity. Reduced contractility may result from impaired interaction between MYH7 (β-MHC) and cardiac myosin binding protein C (cMyBP-C).","method":"Patient-specific iPSC-derived cardiomyocytes, isogenic CRISPR-edited controls, single-cell contractility measurements, engineered heart tissue assays, co-IP/interaction inference","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic hiPSC-CM model with multiple contractility readouts; cMyBP-C interaction proposed but not directly demonstrated by reconstitution","pmids":["30623132"],"is_preprint":false},{"year":2021,"finding":"The m6A reader YTHDF2 binds Myh7 mRNA in an m6A-dependent manner (interaction increases upon hypertrophic stimulation with ISO or PHE) and promotes its decay, thereby suppressing cardiac hypertrophy. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2.","method":"Immunoprecipitation with mass spectrometry (IP-MS) of YTHDF2-interacting mRNAs, RIP assay, knockdown/overexpression in primary cardiomyocytes and HF mouse model, Western blotting, real-time PCR","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP-MS and functional rescue experiments in primary cells and in vivo; single lab with multiple orthogonal methods","pmids":["34266473"],"is_preprint":false},{"year":2018,"finding":"Burst-like (stochastic on/off) transcription of MYH7 alleles, acting independently for mutant and wildtype alleles, generates large cell-to-cell variation in the fraction of mutant vs. wildtype MYH7 mRNA and protein in HCM cardiomyocytes, resulting in highly heterogeneous Ca²⁺-sensitivity among individual cells. ~27% of nuclei showed no active transcription sites, inconsistent with continuous transcription.","method":"Single-cell RT-qPCR with restriction digest for allele quantification; fluorescence in situ hybridization (FISH) of intronic and exonic MYH7 pre-mRNA to visualize active transcription sites in laser-microdissected cardiomyocytes; single-cell force-Ca²⁺ relationship measurements; mathematical modeling","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (single-cell RT-qPCR, FISH, functional force measurements), modeling validation","pmids":["29686627"],"is_preprint":false},{"year":2019,"finding":"The HCM point mutation R723G in MYH7 alters the secondary structure of the resulting mRNA (detected by SHAPE analysis), which is proposed to prolong mutant mRNA lifetime and thereby cause the observed allelic imbalance (~67% mutant MYH7 mRNA in R723G patients).","method":"Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) on in vitro transcribed wild-type and MYH7-R723G RNA; bioinformatic secondary structure prediction","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical RNA structure assay (SHAPE), but single lab, single method, in vitro RNA only; functional consequence (mRNA lifetime) not directly measured","pmids":["31790337"],"is_preprint":false},{"year":2014,"finding":"Epigenetic reprogramming at the Myh7 promoter during pressure overload-induced heart failure involves opposite histone H3 modifications (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and changes in DNA methylation machinery (DNMT1, DNMT3b, MeCP2) recruitment, mechanistically linking chromatin state changes to Myh7 upregulation in failing myocardium.","method":"Chromatin immunoprecipitation (ChIP) for histone marks at Myh7 promoter in murine TAC hearts; ChIP and promoter occupancy assays for DNA methylation enzymes; RT-PCR for mRNA expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based direct promoter occupancy assays in vivo TAC model, multiple histone marks and DNA methylation factors assessed; single lab","pmids":["25181347"],"is_preprint":false},{"year":2017,"finding":"Allelic imbalance of MYH7 expression (unequal expression of mutant vs. wildtype alleles) occurs both in HCM patients with various MYH7 missense mutations and in non-HCM donors, indicating that intrinsic MYH7 expression regulation independent of the disease-causing mutation contributes to allelic imbalance. This was demonstrated at both the mRNA and protein levels.","method":"Single-cell RT-qPCR with restriction digest allele quantification in laser-microdissected cardiomyocytes; protein-level allelic imbalance assays; comparison across HCM patients and non-HCM donor myocardium","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple patient and donor samples, orthogonal mRNA and protein analyses","pmids":["29101517"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function of vmhcl (the zebrafish MYH7 ortholog) induces cardiomyopathy, and pharmacological/genetic inhibition of either mTOR or MAPK signaling rescues the cardiomyopathy phenotype. mTOR inhibition rescued enlarged cardiomyocyte nuclear size while MAPK inhibition restored prolonged cardiomyocyte cell shape, indicating vmhcl/MYH7 loss activates both mTOR and MAPK pathways.","method":"CRISPR/Cas9 (MMEJ) frameshift mutants in zebrafish; pharmacological screening of 7 signaling pathways; genetic epistasis by CRISPR knockout of 11 candidate genes; cardiac function measurements in embryonic and adult zebrafish","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined phenotypic readouts; epistasis confirmed by both pharmacological and genetic approaches; single lab","pmids":["34935644"],"is_preprint":false},{"year":2024,"finding":"The MYH7 R453C mutation in transgenic piglets activates TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways, causing cardiac fibrosis, cardiomyocyte loss, increased reactive oxygen species, fetal gene re-expression, and inflammatory response—phenotypes not seen with MYH6 R453C—demonstrating isoform-specific pathological signaling.","method":"Transgenic MYH7 R453C and MYH6 R453C pig models; RNA-seq; Western blotting for phospho-Smad2/3, phospho-ERK1/2, phospho-NF-kB p65; Nox4/ROS quantification; H9C2 cardiomyocyte models; drug rescue with epigallocatechin gallate","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large animal transgenic model plus cell model with multiple signaling pathway validations; single lab","pmids":["38862020"],"is_preprint":false},{"year":2024,"finding":"The MYH7 G256E mutation (in the transducer region of the S1 head) reduces the fraction of myosin heads in the folded-back (super-relaxed) state by 33%, resulting in more myosin heads available for contraction, faster and greater tension development in myofibrils, and a hypercontractile phenotype at cell and tissue level. Single-cell transcriptomics and metabolic profiling showed upregulated mitochondrial genes and increased mitochondrial respiration as secondary consequences.","method":"CRISPR gene-edited MYH7WT/G256E hiPSC-CMs; myofibril force measurements; single-cell contractility; engineered heart tissue; biochemical assay of myosin folded-back state fraction; single-cell transcriptomics; metabolic profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — isogenic hiPSC model with reconstituted myofibril assays, direct biochemical measurement of myosin SRX state, multiple orthogonal scales (protein, myofibril, cell, tissue), multiple functional readouts","pmids":["38683993"],"is_preprint":false},{"year":2023,"finding":"The MYH7 E848G/+ mutation increases myofilament Ca²⁺ sensitivity and causes cardiomyocyte hypertrophy, abnormal calcium handling, and diastolic dysfunction in hiPSC-CMs. Increased calcium sensitivity by levosimendan aggravated these phenotypes, while inhibition by mavacamten significantly improved them, establishing enhanced myofilament calcium sensitivity as a primary pathogenic mechanism for MYH7-mutation HCM.","method":"Patient-derived iPSC-CMs with isogenic mutation-corrected controls; morphological, Ca²⁺ handling, diastolic function, and myofilament Ca²⁺ sensitivity assays; pharmacological gain/loss-of-function with levosimendan and mavacamten","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic hiPSC-CM model with pharmacological rescue, multiple functional endpoints; single lab","pmids":["38101154"],"is_preprint":false},{"year":2018,"finding":"Knock-in of the HCM point mutation R723G into the porcine MYH7 gene by TALEN-mediated genome editing produced heterozygous piglets that died within 24 h post-partum with HCM features including myocyte disarray, malformed nuclei, and MYH7 overexpression, demonstrating that this single mutation is sufficient to cause HCM pathology. A shift in α/β-MyHC ratio in the left ventricle was observed.","method":"TALEN-mediated genome editing in porcine fibroblasts followed by somatic cell nuclear transfer cloning; histopathology; MyHC isoform ratio analysis; off-target assessment","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in large animal model with defined pathological phenotype; single mutation confirmed causative; single lab","pmids":["29555974"],"is_preprint":false},{"year":2019,"finding":"Expression of the recessive MYH7 Arg1712Trp mutant protein in COS-7 cells caused abnormal myosin aggregation compared to wild-type, establishing that this mutation disrupts normal myosin self-assembly.","method":"Transient transfection of mutant MYH7 constructs into COS-7 cells; immunofluorescence microscopy to assess myosin aggregation versus wild-type","journal":"Neuromuscular disorders : NMD","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment in non-muscle cells; no in vitro reconstitution or structural validation","pmids":["31130376"],"is_preprint":false},{"year":2016,"finding":"Two proline substitutions in the MYH7 rod domain (p.Ala1437Pro and p.Arg1434Pro) impair myosin self-assembly in non-muscle cells transfected with β-myosin constructs, but do not prevent incorporation of mutant molecules into the sarcomere when expressed in muscle cell context.","method":"Cell culture transfection of mutant MYH7 constructs into non-muscle cells followed by immunofluorescence imaging of myosin assembly; whole exome sequencing for mutation identification","journal":"BMC medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transfection assay in non-muscle cells; single lab, single method for assembly assessment","pmids":["27519903"],"is_preprint":false},{"year":1990,"finding":"The human cardiac β-myosin heavy chain gene (MYH7) was localized to chromosome 14q12 by in situ hybridization.","method":"In situ hybridization of ³H-labeled β-MHC genomic probe to human chromosomes","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct physical mapping by in situ hybridization; foundational chromosomal localization replicated in subsequent studies","pmids":["2249479"],"is_preprint":false},{"year":2023,"finding":"The MYH7 E848G/+ mutation causes increased cardiomyocyte apoptosis associated with elevated p53 activity in hiPSC-CMs. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue contractile force, demonstrating that MYH7 E848G/+-induced cardiomyocyte apoptosis and contractile dysfunction are p53-independent.","method":"Isogenic MYH7E848G/+ and control hiPSC-CMs; TP53 genetic knockout by CRISPR; apoptosis assays; engineered heart tissue twitch force measurements","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic hiPSC model, genetic epistasis (TP53 KO), functional contractility readout; negative epistasis result is mechanistically informative; single lab","pmids":["36902340"],"is_preprint":false},{"year":2024,"finding":"Multiplexed deep mutational scanning of 113 MYH7 codon variants in hiPSC-derived cardiomyocytes showed that β-MHC protein loss occurs in pathogenic MYH7 variant HCM hearts, and that multiplexed assessment of β-MHC variant abundance and cardiomyocyte survival accurately segregated all known pathogenic variants from synonymous variants.","method":"CRISPRa On-Target Editing Retrieval (COTER) to generate hiPSC library with 113 MYH7 codon variants; hiPSC differentiation to cardiomyocytes; massively parallel sequencing for β-MHC abundance; cell survival assays; validation in human HCM heart tissue","journal":"Circulation. Genomic and precision medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large-scale functional screen in disease-relevant human cell type with isogenic comparisons; single lab but multiple orthogonal phenotyping strategies","pmids":["38362799"],"is_preprint":false},{"year":2020,"finding":"Allele-selective knockdown of mutant MYH7 transcripts using shRNA ameliorates contractile defects (reducing disease-associated increases in cardiomyocyte velocity, force, and power) in hiPSC-CMs from HCM patients. ASO-mediated allele-selective knockdown targeting SNPs showed more selective allele targeting but more modest functional improvement.","method":"shRNA and antisense oligonucleotide (ASO) delivery in hiPSC-CMs; traction force microscopy on micropatterning devices; automated video contractility analysis","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments in human iPSC-CMs with direct contractility measurements; two silencing modalities tested; single lab","pmids":["32567507"],"is_preprint":false},{"year":2015,"finding":"miR-143-3p regulates MYH7 expression through the HDAC4-MEF2 pathway. Overexpression of miR-143-3p in porcine skeletal muscle satellite cells increased MYH7 (slow muscle fiber) gene and protein expression, while inhibition reduced it.","method":"Cell transfection with miR-143-3p mimics and inhibitors in porcine skeletal muscle satellite cells; qRT-PCR and Western blot for MYH7; pathway analysis implicating HDAC4-MEF2","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression/inhibition in satellite cells; HDAC4-MEF2 pathway link inferred without direct mechanistic validation in this paper; porcine model","pmids":["25915937"],"is_preprint":false},{"year":2022,"finding":"In female mice fed an obesogenic diet, cardiac hypertrophy is associated with increased miR-143-3p, decreased Sox6 mRNA (a direct repressor of Myh7 transcription), and increased Myh7 expression. Inhibition of miR-143-3p in cardiomyocytes increased Sox6 mRNA and reduced Myh7 expression, and prevented angiotensin II-induced cardiomyocyte hypertrophy, establishing a miR-143-3p → Sox6 ⊣ Myh7 regulatory axis.","method":"Loss-of-function miR-143-3p inhibition in primary cardiomyocytes; RT-PCR for Sox6 and Myh7; in vivo obesogenic diet mouse model; bioinformatic target prediction","journal":"Experimental physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-level loss-of-function with functional readout; indirect pathway inference; Sox6-Myh7 link is a predicted/computational interaction confirmed only at mRNA level","pmids":["35765992"],"is_preprint":false}],"current_model":"MYH7 encodes β-myosin heavy chain (β-MHC), the predominant myosin motor in cardiac ventricles and slow-twitch skeletal muscle; pathogenic mutations in the S1 motor/head domain (e.g., R403Q, G256E) directly impair cross-bridge kinetics and energetics—R403Q increases tension cost via faster cross-bridge detachment, while G256E reduces the fraction of myosin in the super-relaxed folded-back state, increasing available heads and causing hypercontractility—whereas mutations in the rod/tail domain disrupt myosin coiled-coil assembly, causing skeletal myopathies (Laing distal myopathy, myosin storage myopathy); MYH7 mutations also enhance myofilament Ca²⁺ sensitivity leading to abnormal Ca²⁺ handling and diastolic dysfunction (rescued by mavacamten), and activate downstream mTOR, MAPK, TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways; gene expression is regulated by burst-like stochastic transcription (generating cell-to-cell allelic imbalance), epigenetic histone/DNA methylation marks at the promoter, m6A-dependent YTHDF2-mediated mRNA decay, and the miR-143-3p→Sox6 regulatory axis."},"narrative":{"mechanistic_narrative":"MYH7 encodes β-myosin heavy chain (β-MHC), the predominant force-generating motor of cardiac ventricular and slow-twitch skeletal muscle, in which mutations directly perturb sarcomeric mechanics rather than acting solely through secondary remodelling [PMID:23674513]. Mutations in the globular S1 motor/head domain corrupt cross-bridge cycling in distinct ways: R403Q accelerates cross-bridge detachment and elevates the energetic tension cost of contraction [PMID:24928957], whereas G256E in the transducer region reduces the fraction of myosin heads sequestered in the folded-back super-relaxed state, liberating more heads for contraction and producing a hypercontractile phenotype with secondary upregulation of mitochondrial respiration [PMID:38683993]. Head-domain mutations also enhance myofilament Ca²⁺ sensitivity, driving abnormal calcium handling, cardiomyocyte hypertrophy and diastolic dysfunction that is aggravated by the calcium sensitizer levosimendan and reversed by the myosin inhibitor mavacamten [PMID:38101154], and can impair the functional interaction between β-MHC and cardiac myosin binding protein C [PMID:30623132]. In contrast, mutations toward the 3′ rod/coiled-coil tail disrupt thick-filament assembly, causing Laing-type distal myopathy [PMID:15322983] and myosin storage myopathy with aberrant β-MHC aggregation in skeletal fibers [PMID:14520662]. Loss or mutation of MYH7 engages downstream signalling — mTOR and MAPK in zebrafish [PMID:34935644], and TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB in transgenic pig models [PMID:38862020] — linking the primary motor defect to fibrosis, hypertrophy and inflammation. β-MHC abundance is itself tightly controlled: m6A-marked Myh7 mRNA is bound by the reader YTHDF2 and targeted for decay to restrain hypertrophy [PMID:34266473], and the gene shows burst-like stochastic allelic transcription that generates cell-to-cell imbalance in mutant versus wildtype expression and heterogeneous Ca²⁺ sensitivity [PMID:29686627, PMID:29101517]. These properties make allele-selective knockdown of mutant transcripts a tractable strategy for rescuing contractile defects [PMID:32567507], and multiplexed deep mutational scanning resolves pathogenic from benign variants via β-MHC protein loss and cardiomyocyte survival [PMID:38362799].","teleology":[{"year":1990,"claim":"Establishing the chromosomal location of the cardiac β-MHC gene provided the genomic anchor needed to link MYH7 to inherited muscle disease.","evidence":"in situ hybridization of a β-MHC genomic probe to human chromosomes","pmids":["2249479"],"confidence":"Medium","gaps":["Does not address gene function or mutation consequences","No connection to specific disease at this stage"]},{"year":2004,"claim":"Mapping rod/tail mutations to a distinct skeletal myopathy clarified that MYH7 domain location dictates disease phenotype — head mutations cause cardiomyopathy while coiled-coil mutations cause distal myopathy.","evidence":"MYH7 sequencing across six families with early-onset distal myopathy plus in silico coiled-coil disruption analysis (extending myosin storage myopathy findings from 2003)","pmids":["15322983","14520662"],"confidence":"Medium","gaps":["Coiled-coil disruption is predicted in silico, not reconstituted biochemically","How disrupted assembly leads to fiber-type-specific aggregation not resolved"]},{"year":2013,"claim":"Direct force measurements established that MYH7 head-domain mutations cause an intrinsic sarcomeric force deficit, distinguishing a primary motor defect from cardiomyocyte remodelling.","evidence":"force measurements in single membrane-permeabilized cardiomyocytes and myofibrils from HCM patient surgical samples versus controls","pmids":["23674513"],"confidence":"High","gaps":["Does not resolve the molecular step of cross-bridge cycling that is altered","Single force-deficit phenotype does not generalize to all head mutations"]},{"year":2014,"claim":"Resolving the kinetic and energetic signature of R403Q showed that some HCM mutations act by accelerating cross-bridge detachment and raising tension cost, defining a specific mechanochemical lesion.","evidence":"single myofibril kinetics and multicellular muscle strip tension-cost measurements in R403Q patient samples, with single-cell RT-qPCR for allele expression","pmids":["24928957"],"confidence":"High","gaps":["Mechanism may be specific to R403Q and not universal across head mutations","Link between detachment kinetics and clinical hypertrophy not mechanistically traced"]},{"year":2014,"claim":"Demonstrating chromatin-state changes at the Myh7 promoter during heart failure connected upstream epigenetic regulation to pathological β-MHC upregulation.","evidence":"ChIP for histone marks and DNA-methylation machinery occupancy at the Myh7 promoter in murine TAC hearts","pmids":["25181347"],"confidence":"Medium","gaps":["Causality between histone marks and transcription not tested by perturbation","Does not identify the initiating signal for chromatin remodelling"]},{"year":2018,"claim":"Single-cell allele studies revealed that MYH7 is transcribed in stochastic bursts independently per allele, explaining cell-to-cell heterogeneity in mutant fraction and Ca²⁺ sensitivity.","evidence":"single-cell RT-qPCR with allele-specific restriction digest, intronic/exonic pre-mRNA FISH, single-cell force-Ca²⁺ measurements and modeling (with 2017 demonstration that allelic imbalance exists in donors as well as HCM patients)","pmids":["29686627","29101517"],"confidence":"Medium","gaps":["Single lab; mechanism controlling burst frequency unknown","Functional impact of heterogeneity on whole-tissue mechanics not directly measured"]},{"year":2018,"claim":"Isogenic large-animal and hiPSC models established that single point mutations are sufficient to cause HCM pathology and that the E848G motor mutation impairs contractility, possibly via the β-MHC/cMyBP-C interaction.","evidence":"TALEN knock-in R723G porcine model with histopathology; patient and CRISPR-isogenic hiPSC-CMs with single-cell and engineered-heart-tissue contractility and co-IP","pmids":["29555974","30623132"],"confidence":"Medium","gaps":["β-MHC/cMyBP-C interaction inferred, not demonstrated by reconstitution","R723G piglet lethality limits study of chronic disease progression"]},{"year":2019,"claim":"RNA-level studies showed that a coding mutation (R723G) alters mRNA secondary structure and that other rod mutations disrupt myosin self-assembly, broadening MYH7 pathogenesis beyond protein mechanics into transcript stability and filament assembly.","evidence":"SHAPE RNA structure probing of R723G transcript; COS-7 overexpression assembly assays of Arg1712Trp and rod proline mutants","pmids":["31790337","31130376","27519903"],"confidence":"Low","gaps":["mRNA lifetime consequence inferred from structure, not directly measured","Assembly defects shown in non-muscle cells only, without sarcomeric context for some mutants"]},{"year":2021,"claim":"Identifying YTHDF2-mediated m6A decay of Myh7 mRNA and the mTOR/MAPK requirement in vmhcl-deficient zebrafish defined post-transcriptional and signalling control layers governing β-MHC levels and downstream cardiomyopathy.","evidence":"IP-MS, RIP and rescue assays for YTHDF2-Myh7 in cardiomyocytes/HF mice; CRISPR zebrafish vmhcl mutants with pharmacological and genetic mTOR/MAPK epistasis","pmids":["34266473","34935644"],"confidence":"Medium","gaps":["m6A sites on Myh7 not mapped at nucleotide resolution","How loss of motor function activates mTOR/MAPK mechanistically unresolved"]},{"year":2024,"claim":"Direct biochemical measurement of the super-relaxed state for G256E, and Ca²⁺-sensitivity/pharmacology for E848G, pinned hypercontractility and enhanced calcium sensitivity as primary, drug-modifiable HCM mechanisms.","evidence":"CRISPR-isogenic hiPSC-CMs with myofibril force, biochemical folded-back-state assays, single-cell transcriptomics (G256E); Ca²⁺ handling and mavacamten/levosimendan rescue (E848G)","pmids":["38683993","38101154"],"confidence":"High","gaps":["Whether SRX destabilization generalizes across head mutations not established","Long-term and in vivo consequences of altered SRX fraction untested"]},{"year":2024,"claim":"Isoform-specific signalling profiling and multiplexed variant scanning advanced MYH7 toward translation by defining fibrotic/inflammatory pathways and a functional pathogenicity classifier, while p53 epistasis ruled out apoptosis as the driver of contractile failure.","evidence":"transgenic MYH7 vs MYH6 R453C pig and H9C2 models with signalling readouts; deep mutational scanning of 113 codon variants in hiPSC-CMs; TP53-knockout epistasis in E848G hiPSC-CMs; allele-selective shRNA/ASO knockdown","pmids":["38862020","38362799","36902340","32567507"],"confidence":"Medium","gaps":["Signalling cascades shown by association/inhibition, not full causal dissection","Allele-selective knockdown efficacy and selectivity tradeoffs not yet optimized for therapy"]},{"year":null,"claim":"How the diverse primary lesions (cross-bridge kinetics, SRX state, Ca²⁺ sensitivity, mRNA stability, filament assembly) converge on shared hypertrophic and fibrotic signalling, and which node is the optimal therapeutic target, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking distinct biophysical defects to common downstream signalling","Mutation-class-specific therapeutic stratification not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3,16]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,3,16]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5,7]}],"complexes":["sarcomere thick filament"],"partners":["MYBPC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P12883","full_name":"Myosin-7","aliases":["Myosin heavy chain 7","Myosin heavy chain slow isoform","MyHC-slow","Myosin heavy chain, cardiac muscle beta isoform","MyHC-beta"],"length_aa":1935,"mass_kda":223.1,"function":"Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/38862020","citation_count":16,"is_preprint":false},{"pmid":"23153285","id":"PMC_23153285","title":"A de novo germline mutation in MYH7 causes a progressive dominant myopathy in pigs.","date":"2012","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23153285","citation_count":16,"is_preprint":false},{"pmid":"23707328","id":"PMC_23707328","title":"A novel MYH7 mutation with prominent paraspinal and proximal muscle involvement.","date":"2013","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/23707328","citation_count":16,"is_preprint":false},{"pmid":"22765922","id":"PMC_22765922","title":"Resequencing the whole MYH7 gene (including the intronic, promoter, and 3' UTR sequences) in hypertrophic cardiomyopathy.","date":"2012","source":"The Journal of molecular diagnostics : 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genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31790337","citation_count":14,"is_preprint":false},{"pmid":"31130376","id":"PMC_31130376","title":"Recessive MYH7-related myopathy in two families.","date":"2019","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/31130376","citation_count":14,"is_preprint":false},{"pmid":"38819352","id":"PMC_38819352","title":"Atrial Fibrillation Substrate and Catheter Ablation Outcomes in MYBPC3- and MYH7-Mediated Hypertrophic Cardiomyopathy.","date":"2024","source":"JACC. Clinical electrophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/38819352","citation_count":14,"is_preprint":false},{"pmid":"27282841","id":"PMC_27282841","title":"Distal myopathy with coexisting heterozygous TIA1 and MYH7 Variants.","date":"2016","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/27282841","citation_count":14,"is_preprint":false},{"pmid":"38683993","id":"PMC_38683993","title":"Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38683993","citation_count":13,"is_preprint":false},{"pmid":"38362799","id":"PMC_38362799","title":"Multiplexed Functional Assessments of MYH7 Variants in Human Cardiomyocytes.","date":"2024","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38362799","citation_count":13,"is_preprint":false},{"pmid":"33568804","id":"PMC_33568804","title":"Clinical and laboratory reporting impact of ACMG-AMP and modified ClinGen variant classification frameworks in MYH7-related cardiomyopathy.","date":"2021","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33568804","citation_count":13,"is_preprint":false},{"pmid":"33588347","id":"PMC_33588347","title":"Association of variants in MYH7, MYBPC3 and TNNT2 with sudden cardiac death-related risk factors in Brazilian patients with hypertrophic cardiomyopathy.","date":"2021","source":"Forensic science international. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33588347","citation_count":13,"is_preprint":false},{"pmid":"28866666","id":"PMC_28866666","title":"The Cumulative Effects of the MYH7-V878A and CACNA1C-A1594V Mutations in a Chinese Family with Hypertrophic Cardiomyopathy.","date":"2017","source":"Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28866666","citation_count":13,"is_preprint":false},{"pmid":"25576864","id":"PMC_25576864","title":"A rare mutation in MYH7 gene occurs with overlapping phenotype.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25576864","citation_count":13,"is_preprint":false},{"pmid":"27519903","id":"PMC_27519903","title":"Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture.","date":"2016","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27519903","citation_count":13,"is_preprint":false},{"pmid":"25547560","id":"PMC_25547560","title":"A novel MYH7 gene mutation in a fetus with left ventricular noncompaction.","date":"2014","source":"The Canadian journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/25547560","citation_count":13,"is_preprint":false},{"pmid":"29624713","id":"PMC_29624713","title":"Clinical and imaging hallmarks of the MYH7-related myopathy with severe axial involvement.","date":"2018","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/29624713","citation_count":12,"is_preprint":false},{"pmid":"38101154","id":"PMC_38101154","title":"Enhanced myofilament calcium sensitivity aggravates abnormal calcium handling and diastolic dysfunction in patient-specific induced pluripotent stem cell-derived cardiomyocytes with MYH7 mutation.","date":"2023","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/38101154","citation_count":12,"is_preprint":false},{"pmid":"31638223","id":"PMC_31638223","title":"Genetic analysis of monoallelic double MYH7 mutations responsible for familial hypertrophic cardiomyopathy.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31638223","citation_count":12,"is_preprint":false},{"pmid":"33610018","id":"PMC_33610018","title":"Generation of iPSC line from MYH7 R403L mutation carrier with severe hypertrophic cardiomyopathy and isogenic CRISPR/Cas9 corrected control.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33610018","citation_count":12,"is_preprint":false},{"pmid":"25550050","id":"PMC_25550050","title":"Whole-exome sequencing identify a new mutation of MYH7 in a Chinese family with left ventricular noncompaction.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/25550050","citation_count":12,"is_preprint":false},{"pmid":"27737317","id":"PMC_27737317","title":"Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study.","date":"2016","source":"Arquivos brasileiros de cardiologia","url":"https://pubmed.ncbi.nlm.nih.gov/27737317","citation_count":11,"is_preprint":false},{"pmid":"25695922","id":"PMC_25695922","title":"Two families with MYH7 distal myopathy associated with cardiomyopathy and core formations.","date":"2015","source":"Journal of clinical neuromuscular disease","url":"https://pubmed.ncbi.nlm.nih.gov/25695922","citation_count":11,"is_preprint":false},{"pmid":"35765992","id":"PMC_35765992","title":"The miRNA-143-3p-Sox6-Myh7 pathway is altered in obesogenic diet-induced cardiac hypertrophy.","date":"2022","source":"Experimental 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Irish family.","date":"2014","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25447691","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53069,"output_tokens":6521,"usd":0.128511,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15534,"output_tokens":4467,"usd":0.094673,"stage2_stop_reason":"end_turn"},"total_usd":0.223184,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"MYH7 mutations (in the globular head/S1 domain) reduce the maximal force generating capacity of sarcomeres at both maximal and submaximal Ca2+ concentrations, an intrinsic sarcomere defect distinct from cardiomyocyte remodelling. In single myofibril preparations, MYH7mut showed very low Fmax (~73 kN/m²) compared to donor (~113 kN/m²), and this reduction persisted after correction for myofibril density, unlike MYBPC3 mutations.\",\n      \"method\": \"Force measurements in single membrane-permeabilized cardiomyocytes and single myofibrils from surgical cardiac samples of HCM patients with MYH7 mutations versus controls\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro force measurements in single myofibrils and cardiomyocytes, multiple patient samples, orthogonal preparations, rigorous controls\",\n      \"pmids\": [\"23674513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The R403Q mutation in MYH7 (located in the S1 actin-binding/motor domain) causes faster cross-bridge detachment kinetics and significantly higher energetic cost of tension generation (tension cost) compared to sarcomere mutation-negative HCM. Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher than in HCMsmn myofibrils, and this correlated positively with tension cost in muscle strips.\",\n      \"method\": \"Single cardiac myofibril force measurements and multicellular cardiac muscle strip tension cost measurements in samples from R403Q HCM patients versus HCMsmn patients; single-cell RT-qPCR confirmed ~41% mutant allele expression\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted myofibril and muscle strip assays with rigorous controls, multiple orthogonal methods (kinetics + energetics), multiple patient samples\",\n      \"pmids\": [\"24928957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Heterozygous mutations toward the 3' end of MYH7 (encoding the myosin tail/coiled-coil rod region) cause Laing-type early-onset distal myopathy. In silico analysis predicts these mutations locally disrupt the coiled-coil structure of the myosin tail, distinguishing them from head-domain mutations that cause cardiomyopathy.\",\n      \"method\": \"MYH7 gene sequencing in six families with early-onset distal myopathy; in silico coiled-coil disruption analysis of five novel mutations (Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, Lys1729del)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic identification with segregation in multiple families; in silico structural prediction only (no in vitro reconstitution), but replicated across 6 families\",\n      \"pmids\": [\"15322983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A missense mutation in the rod region of MYH7 (Arg1845Trp) causes myosin storage myopathy, characterized by accumulation of slow/β-cardiac MyHC in large inclusions in type 1 skeletal muscle fibers, indicating this residue is essential for proper thick filament assembly in skeletal muscle.\",\n      \"method\": \"Clinical characterization and muscle biopsy immunohistochemistry/histology in patients from two families; genetic sequencing of MYH7\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathological characterization in two independent families with same mutation; mechanism inferred from protein aggregation phenotype on biopsy, no in vitro reconstitution\",\n      \"pmids\": [\"14520662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The MYH7 E848G mutation (in the motor domain) reduces contractile function in hiPSC-derived cardiomyocytes at single-cell and engineered heart tissue levels. Genome-edited isogenic cells confirmed pathogenicity. Reduced contractility may result from impaired interaction between MYH7 (β-MHC) and cardiac myosin binding protein C (cMyBP-C).\",\n      \"method\": \"Patient-specific iPSC-derived cardiomyocytes, isogenic CRISPR-edited controls, single-cell contractility measurements, engineered heart tissue assays, co-IP/interaction inference\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic hiPSC-CM model with multiple contractility readouts; cMyBP-C interaction proposed but not directly demonstrated by reconstitution\",\n      \"pmids\": [\"30623132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The m6A reader YTHDF2 binds Myh7 mRNA in an m6A-dependent manner (interaction increases upon hypertrophic stimulation with ISO or PHE) and promotes its decay, thereby suppressing cardiac hypertrophy. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2.\",\n      \"method\": \"Immunoprecipitation with mass spectrometry (IP-MS) of YTHDF2-interacting mRNAs, RIP assay, knockdown/overexpression in primary cardiomyocytes and HF mouse model, Western blotting, real-time PCR\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP-MS and functional rescue experiments in primary cells and in vivo; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34266473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Burst-like (stochastic on/off) transcription of MYH7 alleles, acting independently for mutant and wildtype alleles, generates large cell-to-cell variation in the fraction of mutant vs. wildtype MYH7 mRNA and protein in HCM cardiomyocytes, resulting in highly heterogeneous Ca²⁺-sensitivity among individual cells. ~27% of nuclei showed no active transcription sites, inconsistent with continuous transcription.\",\n      \"method\": \"Single-cell RT-qPCR with restriction digest for allele quantification; fluorescence in situ hybridization (FISH) of intronic and exonic MYH7 pre-mRNA to visualize active transcription sites in laser-microdissected cardiomyocytes; single-cell force-Ca²⁺ relationship measurements; mathematical modeling\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (single-cell RT-qPCR, FISH, functional force measurements), modeling validation\",\n      \"pmids\": [\"29686627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The HCM point mutation R723G in MYH7 alters the secondary structure of the resulting mRNA (detected by SHAPE analysis), which is proposed to prolong mutant mRNA lifetime and thereby cause the observed allelic imbalance (~67% mutant MYH7 mRNA in R723G patients).\",\n      \"method\": \"Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) on in vitro transcribed wild-type and MYH7-R723G RNA; bioinformatic secondary structure prediction\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical RNA structure assay (SHAPE), but single lab, single method, in vitro RNA only; functional consequence (mRNA lifetime) not directly measured\",\n      \"pmids\": [\"31790337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Epigenetic reprogramming at the Myh7 promoter during pressure overload-induced heart failure involves opposite histone H3 modifications (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and changes in DNA methylation machinery (DNMT1, DNMT3b, MeCP2) recruitment, mechanistically linking chromatin state changes to Myh7 upregulation in failing myocardium.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for histone marks at Myh7 promoter in murine TAC hearts; ChIP and promoter occupancy assays for DNA methylation enzymes; RT-PCR for mRNA expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based direct promoter occupancy assays in vivo TAC model, multiple histone marks and DNA methylation factors assessed; single lab\",\n      \"pmids\": [\"25181347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Allelic imbalance of MYH7 expression (unequal expression of mutant vs. wildtype alleles) occurs both in HCM patients with various MYH7 missense mutations and in non-HCM donors, indicating that intrinsic MYH7 expression regulation independent of the disease-causing mutation contributes to allelic imbalance. This was demonstrated at both the mRNA and protein levels.\",\n      \"method\": \"Single-cell RT-qPCR with restriction digest allele quantification in laser-microdissected cardiomyocytes; protein-level allelic imbalance assays; comparison across HCM patients and non-HCM donor myocardium\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple patient and donor samples, orthogonal mRNA and protein analyses\",\n      \"pmids\": [\"29101517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function of vmhcl (the zebrafish MYH7 ortholog) induces cardiomyopathy, and pharmacological/genetic inhibition of either mTOR or MAPK signaling rescues the cardiomyopathy phenotype. mTOR inhibition rescued enlarged cardiomyocyte nuclear size while MAPK inhibition restored prolonged cardiomyocyte cell shape, indicating vmhcl/MYH7 loss activates both mTOR and MAPK pathways.\",\n      \"method\": \"CRISPR/Cas9 (MMEJ) frameshift mutants in zebrafish; pharmacological screening of 7 signaling pathways; genetic epistasis by CRISPR knockout of 11 candidate genes; cardiac function measurements in embryonic and adult zebrafish\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined phenotypic readouts; epistasis confirmed by both pharmacological and genetic approaches; single lab\",\n      \"pmids\": [\"34935644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The MYH7 R453C mutation in transgenic piglets activates TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways, causing cardiac fibrosis, cardiomyocyte loss, increased reactive oxygen species, fetal gene re-expression, and inflammatory response—phenotypes not seen with MYH6 R453C—demonstrating isoform-specific pathological signaling.\",\n      \"method\": \"Transgenic MYH7 R453C and MYH6 R453C pig models; RNA-seq; Western blotting for phospho-Smad2/3, phospho-ERK1/2, phospho-NF-kB p65; Nox4/ROS quantification; H9C2 cardiomyocyte models; drug rescue with epigallocatechin gallate\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large animal transgenic model plus cell model with multiple signaling pathway validations; single lab\",\n      \"pmids\": [\"38862020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The MYH7 G256E mutation (in the transducer region of the S1 head) reduces the fraction of myosin heads in the folded-back (super-relaxed) state by 33%, resulting in more myosin heads available for contraction, faster and greater tension development in myofibrils, and a hypercontractile phenotype at cell and tissue level. Single-cell transcriptomics and metabolic profiling showed upregulated mitochondrial genes and increased mitochondrial respiration as secondary consequences.\",\n      \"method\": \"CRISPR gene-edited MYH7WT/G256E hiPSC-CMs; myofibril force measurements; single-cell contractility; engineered heart tissue; biochemical assay of myosin folded-back state fraction; single-cell transcriptomics; metabolic profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — isogenic hiPSC model with reconstituted myofibril assays, direct biochemical measurement of myosin SRX state, multiple orthogonal scales (protein, myofibril, cell, tissue), multiple functional readouts\",\n      \"pmids\": [\"38683993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The MYH7 E848G/+ mutation increases myofilament Ca²⁺ sensitivity and causes cardiomyocyte hypertrophy, abnormal calcium handling, and diastolic dysfunction in hiPSC-CMs. Increased calcium sensitivity by levosimendan aggravated these phenotypes, while inhibition by mavacamten significantly improved them, establishing enhanced myofilament calcium sensitivity as a primary pathogenic mechanism for MYH7-mutation HCM.\",\n      \"method\": \"Patient-derived iPSC-CMs with isogenic mutation-corrected controls; morphological, Ca²⁺ handling, diastolic function, and myofilament Ca²⁺ sensitivity assays; pharmacological gain/loss-of-function with levosimendan and mavacamten\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic hiPSC-CM model with pharmacological rescue, multiple functional endpoints; single lab\",\n      \"pmids\": [\"38101154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knock-in of the HCM point mutation R723G into the porcine MYH7 gene by TALEN-mediated genome editing produced heterozygous piglets that died within 24 h post-partum with HCM features including myocyte disarray, malformed nuclei, and MYH7 overexpression, demonstrating that this single mutation is sufficient to cause HCM pathology. A shift in α/β-MyHC ratio in the left ventricle was observed.\",\n      \"method\": \"TALEN-mediated genome editing in porcine fibroblasts followed by somatic cell nuclear transfer cloning; histopathology; MyHC isoform ratio analysis; off-target assessment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in large animal model with defined pathological phenotype; single mutation confirmed causative; single lab\",\n      \"pmids\": [\"29555974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Expression of the recessive MYH7 Arg1712Trp mutant protein in COS-7 cells caused abnormal myosin aggregation compared to wild-type, establishing that this mutation disrupts normal myosin self-assembly.\",\n      \"method\": \"Transient transfection of mutant MYH7 constructs into COS-7 cells; immunofluorescence microscopy to assess myosin aggregation versus wild-type\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment in non-muscle cells; no in vitro reconstitution or structural validation\",\n      \"pmids\": [\"31130376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Two proline substitutions in the MYH7 rod domain (p.Ala1437Pro and p.Arg1434Pro) impair myosin self-assembly in non-muscle cells transfected with β-myosin constructs, but do not prevent incorporation of mutant molecules into the sarcomere when expressed in muscle cell context.\",\n      \"method\": \"Cell culture transfection of mutant MYH7 constructs into non-muscle cells followed by immunofluorescence imaging of myosin assembly; whole exome sequencing for mutation identification\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transfection assay in non-muscle cells; single lab, single method for assembly assessment\",\n      \"pmids\": [\"27519903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The human cardiac β-myosin heavy chain gene (MYH7) was localized to chromosome 14q12 by in situ hybridization.\",\n      \"method\": \"In situ hybridization of ³H-labeled β-MHC genomic probe to human chromosomes\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct physical mapping by in situ hybridization; foundational chromosomal localization replicated in subsequent studies\",\n      \"pmids\": [\"2249479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The MYH7 E848G/+ mutation causes increased cardiomyocyte apoptosis associated with elevated p53 activity in hiPSC-CMs. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue contractile force, demonstrating that MYH7 E848G/+-induced cardiomyocyte apoptosis and contractile dysfunction are p53-independent.\",\n      \"method\": \"Isogenic MYH7E848G/+ and control hiPSC-CMs; TP53 genetic knockout by CRISPR; apoptosis assays; engineered heart tissue twitch force measurements\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic hiPSC model, genetic epistasis (TP53 KO), functional contractility readout; negative epistasis result is mechanistically informative; single lab\",\n      \"pmids\": [\"36902340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Multiplexed deep mutational scanning of 113 MYH7 codon variants in hiPSC-derived cardiomyocytes showed that β-MHC protein loss occurs in pathogenic MYH7 variant HCM hearts, and that multiplexed assessment of β-MHC variant abundance and cardiomyocyte survival accurately segregated all known pathogenic variants from synonymous variants.\",\n      \"method\": \"CRISPRa On-Target Editing Retrieval (COTER) to generate hiPSC library with 113 MYH7 codon variants; hiPSC differentiation to cardiomyocytes; massively parallel sequencing for β-MHC abundance; cell survival assays; validation in human HCM heart tissue\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large-scale functional screen in disease-relevant human cell type with isogenic comparisons; single lab but multiple orthogonal phenotyping strategies\",\n      \"pmids\": [\"38362799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Allele-selective knockdown of mutant MYH7 transcripts using shRNA ameliorates contractile defects (reducing disease-associated increases in cardiomyocyte velocity, force, and power) in hiPSC-CMs from HCM patients. ASO-mediated allele-selective knockdown targeting SNPs showed more selective allele targeting but more modest functional improvement.\",\n      \"method\": \"shRNA and antisense oligonucleotide (ASO) delivery in hiPSC-CMs; traction force microscopy on micropatterning devices; automated video contractility analysis\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments in human iPSC-CMs with direct contractility measurements; two silencing modalities tested; single lab\",\n      \"pmids\": [\"32567507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-143-3p regulates MYH7 expression through the HDAC4-MEF2 pathway. Overexpression of miR-143-3p in porcine skeletal muscle satellite cells increased MYH7 (slow muscle fiber) gene and protein expression, while inhibition reduced it.\",\n      \"method\": \"Cell transfection with miR-143-3p mimics and inhibitors in porcine skeletal muscle satellite cells; qRT-PCR and Western blot for MYH7; pathway analysis implicating HDAC4-MEF2\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression/inhibition in satellite cells; HDAC4-MEF2 pathway link inferred without direct mechanistic validation in this paper; porcine model\",\n      \"pmids\": [\"25915937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In female mice fed an obesogenic diet, cardiac hypertrophy is associated with increased miR-143-3p, decreased Sox6 mRNA (a direct repressor of Myh7 transcription), and increased Myh7 expression. Inhibition of miR-143-3p in cardiomyocytes increased Sox6 mRNA and reduced Myh7 expression, and prevented angiotensin II-induced cardiomyocyte hypertrophy, establishing a miR-143-3p → Sox6 ⊣ Myh7 regulatory axis.\",\n      \"method\": \"Loss-of-function miR-143-3p inhibition in primary cardiomyocytes; RT-PCR for Sox6 and Myh7; in vivo obesogenic diet mouse model; bioinformatic target prediction\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-level loss-of-function with functional readout; indirect pathway inference; Sox6-Myh7 link is a predicted/computational interaction confirmed only at mRNA level\",\n      \"pmids\": [\"35765992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYH7 encodes β-myosin heavy chain (β-MHC), the predominant myosin motor in cardiac ventricles and slow-twitch skeletal muscle; pathogenic mutations in the S1 motor/head domain (e.g., R403Q, G256E) directly impair cross-bridge kinetics and energetics—R403Q increases tension cost via faster cross-bridge detachment, while G256E reduces the fraction of myosin in the super-relaxed folded-back state, increasing available heads and causing hypercontractility—whereas mutations in the rod/tail domain disrupt myosin coiled-coil assembly, causing skeletal myopathies (Laing distal myopathy, myosin storage myopathy); MYH7 mutations also enhance myofilament Ca²⁺ sensitivity leading to abnormal Ca²⁺ handling and diastolic dysfunction (rescued by mavacamten), and activate downstream mTOR, MAPK, TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways; gene expression is regulated by burst-like stochastic transcription (generating cell-to-cell allelic imbalance), epigenetic histone/DNA methylation marks at the promoter, m6A-dependent YTHDF2-mediated mRNA decay, and the miR-143-3p→Sox6 regulatory axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYH7 encodes β-myosin heavy chain (β-MHC), the predominant force-generating motor of cardiac ventricular and slow-twitch skeletal muscle, in which mutations directly perturb sarcomeric mechanics rather than acting solely through secondary remodelling [#0]. Mutations in the globular S1 motor/head domain corrupt cross-bridge cycling in distinct ways: R403Q accelerates cross-bridge detachment and elevates the energetic tension cost of contraction [#1], whereas G256E in the transducer region reduces the fraction of myosin heads sequestered in the folded-back super-relaxed state, liberating more heads for contraction and producing a hypercontractile phenotype with secondary upregulation of mitochondrial respiration [#12]. Head-domain mutations also enhance myofilament Ca²⁺ sensitivity, driving abnormal calcium handling, cardiomyocyte hypertrophy and diastolic dysfunction that is aggravated by the calcium sensitizer levosimendan and reversed by the myosin inhibitor mavacamten [#13], and can impair the functional interaction between β-MHC and cardiac myosin binding protein C [#4]. In contrast, mutations toward the 3′ rod/coiled-coil tail disrupt thick-filament assembly, causing Laing-type distal myopathy [#2] and myosin storage myopathy with aberrant β-MHC aggregation in skeletal fibers [#3]. Loss or mutation of MYH7 engages downstream signalling — mTOR and MAPK in zebrafish [#10], and TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB in transgenic pig models [#11] — linking the primary motor defect to fibrosis, hypertrophy and inflammation. β-MHC abundance is itself tightly controlled: m6A-marked Myh7 mRNA is bound by the reader YTHDF2 and targeted for decay to restrain hypertrophy [#5], and the gene shows burst-like stochastic allelic transcription that generates cell-to-cell imbalance in mutant versus wildtype expression and heterogeneous Ca²⁺ sensitivity [#6, #9]. These properties make allele-selective knockdown of mutant transcripts a tractable strategy for rescuing contractile defects [#20], and multiplexed deep mutational scanning resolves pathogenic from benign variants via β-MHC protein loss and cardiomyocyte survival [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing the chromosomal location of the cardiac β-MHC gene provided the genomic anchor needed to link MYH7 to inherited muscle disease.\",\n      \"evidence\": \"in situ hybridization of a β-MHC genomic probe to human chromosomes\",\n      \"pmids\": [\"2249479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address gene function or mutation consequences\", \"No connection to specific disease at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping rod/tail mutations to a distinct skeletal myopathy clarified that MYH7 domain location dictates disease phenotype — head mutations cause cardiomyopathy while coiled-coil mutations cause distal myopathy.\",\n      \"evidence\": \"MYH7 sequencing across six families with early-onset distal myopathy plus in silico coiled-coil disruption analysis (extending myosin storage myopathy findings from 2003)\",\n      \"pmids\": [\"15322983\", \"14520662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coiled-coil disruption is predicted in silico, not reconstituted biochemically\", \"How disrupted assembly leads to fiber-type-specific aggregation not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Direct force measurements established that MYH7 head-domain mutations cause an intrinsic sarcomeric force deficit, distinguishing a primary motor defect from cardiomyocyte remodelling.\",\n      \"evidence\": \"force measurements in single membrane-permeabilized cardiomyocytes and myofibrils from HCM patient surgical samples versus controls\",\n      \"pmids\": [\"23674513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the molecular step of cross-bridge cycling that is altered\", \"Single force-deficit phenotype does not generalize to all head mutations\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving the kinetic and energetic signature of R403Q showed that some HCM mutations act by accelerating cross-bridge detachment and raising tension cost, defining a specific mechanochemical lesion.\",\n      \"evidence\": \"single myofibril kinetics and multicellular muscle strip tension-cost measurements in R403Q patient samples, with single-cell RT-qPCR for allele expression\",\n      \"pmids\": [\"24928957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism may be specific to R403Q and not universal across head mutations\", \"Link between detachment kinetics and clinical hypertrophy not mechanistically traced\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating chromatin-state changes at the Myh7 promoter during heart failure connected upstream epigenetic regulation to pathological β-MHC upregulation.\",\n      \"evidence\": \"ChIP for histone marks and DNA-methylation machinery occupancy at the Myh7 promoter in murine TAC hearts\",\n      \"pmids\": [\"25181347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between histone marks and transcription not tested by perturbation\", \"Does not identify the initiating signal for chromatin remodelling\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Single-cell allele studies revealed that MYH7 is transcribed in stochastic bursts independently per allele, explaining cell-to-cell heterogeneity in mutant fraction and Ca²⁺ sensitivity.\",\n      \"evidence\": \"single-cell RT-qPCR with allele-specific restriction digest, intronic/exonic pre-mRNA FISH, single-cell force-Ca²⁺ measurements and modeling (with 2017 demonstration that allelic imbalance exists in donors as well as HCM patients)\",\n      \"pmids\": [\"29686627\", \"29101517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism controlling burst frequency unknown\", \"Functional impact of heterogeneity on whole-tissue mechanics not directly measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Isogenic large-animal and hiPSC models established that single point mutations are sufficient to cause HCM pathology and that the E848G motor mutation impairs contractility, possibly via the β-MHC/cMyBP-C interaction.\",\n      \"evidence\": \"TALEN knock-in R723G porcine model with histopathology; patient and CRISPR-isogenic hiPSC-CMs with single-cell and engineered-heart-tissue contractility and co-IP\",\n      \"pmids\": [\"29555974\", \"30623132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"β-MHC/cMyBP-C interaction inferred, not demonstrated by reconstitution\", \"R723G piglet lethality limits study of chronic disease progression\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"RNA-level studies showed that a coding mutation (R723G) alters mRNA secondary structure and that other rod mutations disrupt myosin self-assembly, broadening MYH7 pathogenesis beyond protein mechanics into transcript stability and filament assembly.\",\n      \"evidence\": \"SHAPE RNA structure probing of R723G transcript; COS-7 overexpression assembly assays of Arg1712Trp and rod proline mutants\",\n      \"pmids\": [\"31790337\", \"31130376\", \"27519903\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"mRNA lifetime consequence inferred from structure, not directly measured\", \"Assembly defects shown in non-muscle cells only, without sarcomeric context for some mutants\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying YTHDF2-mediated m6A decay of Myh7 mRNA and the mTOR/MAPK requirement in vmhcl-deficient zebrafish defined post-transcriptional and signalling control layers governing β-MHC levels and downstream cardiomyopathy.\",\n      \"evidence\": \"IP-MS, RIP and rescue assays for YTHDF2-Myh7 in cardiomyocytes/HF mice; CRISPR zebrafish vmhcl mutants with pharmacological and genetic mTOR/MAPK epistasis\",\n      \"pmids\": [\"34266473\", \"34935644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m6A sites on Myh7 not mapped at nucleotide resolution\", \"How loss of motor function activates mTOR/MAPK mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Direct biochemical measurement of the super-relaxed state for G256E, and Ca²⁺-sensitivity/pharmacology for E848G, pinned hypercontractility and enhanced calcium sensitivity as primary, drug-modifiable HCM mechanisms.\",\n      \"evidence\": \"CRISPR-isogenic hiPSC-CMs with myofibril force, biochemical folded-back-state assays, single-cell transcriptomics (G256E); Ca²⁺ handling and mavacamten/levosimendan rescue (E848G)\",\n      \"pmids\": [\"38683993\", \"38101154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SRX destabilization generalizes across head mutations not established\", \"Long-term and in vivo consequences of altered SRX fraction untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Isoform-specific signalling profiling and multiplexed variant scanning advanced MYH7 toward translation by defining fibrotic/inflammatory pathways and a functional pathogenicity classifier, while p53 epistasis ruled out apoptosis as the driver of contractile failure.\",\n      \"evidence\": \"transgenic MYH7 vs MYH6 R453C pig and H9C2 models with signalling readouts; deep mutational scanning of 113 codon variants in hiPSC-CMs; TP53-knockout epistasis in E848G hiPSC-CMs; allele-selective shRNA/ASO knockdown\",\n      \"pmids\": [\"38862020\", \"38362799\", \"36902340\", \"32567507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signalling cascades shown by association/inhibition, not full causal dissection\", \"Allele-selective knockdown efficacy and selectivity tradeoffs not yet optimized for therapy\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse primary lesions (cross-bridge kinetics, SRX state, Ca²⁺ sensitivity, mRNA stability, filament assembly) converge on shared hypertrophic and fibrotic signalling, and which node is the optimal therapeutic target, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking distinct biophysical defects to common downstream signalling\", \"Mutation-class-specific therapeutic stratification not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3, 16]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 16]},\n      {\"term_id\": \"GO:0005863\", \"supporting_discovery_ids\": []}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"complexes\": [\"sarcomere thick filament\"],\n    \"partners\": [\"MYBPC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}