{"gene":"MYH7","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2013,"finding":"MYH7 mutations (in the globular head/S1 domain) reduce the intrinsic force-generating capacity of sarcomeres at both maximal and submaximal Ca²⁺ concentrations, as demonstrated in single membrane-permeabilized cardiomyocytes and single myofibrils from HCM patients carrying MYH7 mutations, even after correction for myofibril density.","method":"Force measurements in single membrane-permeabilized cardiomyocytes and single myofibrils from human cardiac tissue","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 — direct mechanical assay on human patient tissue with multiple orthogonal preparations (cardiomyocytes and myofibrils), replicated across multiple MYH7 mutation carriers","pmids":["23674513"],"is_preprint":false},{"year":2014,"finding":"The R403Q mutation in MYH7 (located in the S1 actin-binding globular head) increases cross-bridge detachment kinetics (faster slow relaxation) and significantly raises the energetic cost of tension generation (tension cost) in human HCM myofibrils and muscle strips, establishing a direct link between cross-bridge kinetics and energetic inefficiency.","method":"Single cardiac myofibril mechanics and ATPase-based tension cost measurements in multicellular cardiac muscle strips from R403Q HCM patients vs. sarcomere mutation-negative HCM","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — in vitro myofibril reconstitution assay plus ATPase energetics, orthogonal methods, human tissue","pmids":["24928957"],"is_preprint":false},{"year":2024,"finding":"The MYH7 G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back (super-relaxed) state by ~33%, resulting in more myosin heads available for actin interaction and a hypercontractile phenotype with faster and greater tension development across protein, myofibril, cell, and tissue scales; this is accompanied by upregulated mitochondrial gene expression and increased mitochondrial respiration.","method":"Biochemical assay of myosin folded-back state, myofibril mechanics in gene-edited hiPSC-CMs, traction force microscopy in single cells, engineered heart tissues, 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 — multi-scale reconstitution from purified protein through engineered tissue with mutagenesis-confirmed mechanism in a single rigorous study","pmids":["38683993"],"is_preprint":false},{"year":2018,"finding":"The MYH7 E848G mutation causes reduced contractile function in hiPSC-derived cardiomyocytes and engineered heart tissues; genome-edited isogenic controls confirmed pathogenicity, and reduced contractility may result from impaired interaction between MYH7 protein and cardiac myosin binding protein C (cMyBP-C).","method":"hiPSC-derived cardiomyocytes, engineered heart tissues, genome editing (isogenic controls), contractile force measurements","journal":"JACC. Basic to translational science","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic hiPSC-CM model with functional readout; MYH7–cMyBP-C interaction inferred but not directly demonstrated by co-IP/pulldown","pmids":["30623132"],"is_preprint":false},{"year":2003,"finding":"A missense mutation Arg1845Trp in the rod region of MYH7 (slow/β-cardiac myosin heavy chain) causes myosin storage myopathy characterized by large subsarcolemmal inclusions of slow/β-cardiac myosin in type I skeletal muscle fibers, indicating that this residue is essential for proper thick filament assembly.","method":"Muscle biopsy with immunohistochemistry and electron microscopy confirming myosin-containing inclusions; genetic sequencing identifying Arg1845Trp in rod domain","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2–3 — mutation identified with histopathological confirmation of myosin aggregation phenotype; assembly defect inferred from pathology","pmids":["14520662"],"is_preprint":false},{"year":2004,"finding":"Heterozygous mutations toward the 3′ end of MYH7 (exons 32–36, encoding the coiled-coil rod/tail region) cause Laing early-onset distal myopathy; in silico analysis predicts these mutations locally disrupt the coiled-coil structure of the myosin tail, preventing normal thick filament assembly.","method":"Genetic sequencing of MYH7 in six affected families; in silico coiled-coil disruption prediction","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic identification with computational structural prediction; no direct biochemical validation of coiled-coil disruption in this paper","pmids":["15322983"],"is_preprint":false},{"year":2019,"finding":"Expression of mutant MYH7 (Arg1712Trp) protein in COS-7 cells results in abnormal myosin aggregation compared to wild-type MYH7, directly demonstrating that this rod-domain mutation impairs myosin self-assembly.","method":"Heterologous expression of mutant vs. wild-type MYH7 in COS-7 cells with imaging of protein aggregation","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based reconstitution experiment with direct imaging of assembly defect","pmids":["31130376"],"is_preprint":false},{"year":2016,"finding":"Two novel proline substitutions in the rod domain of MYH7 (Ala1437Pro and 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, dissociating filament assembly from sarcomere incorporation.","method":"Transfection of mutant β-myosin constructs in non-muscle cells with fluorescence imaging of assembly","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based functional reconstitution with two distinct mutations tested","pmids":["27519903"],"is_preprint":false},{"year":2021,"finding":"The m6A reader YTHDF2 suppresses cardiac hypertrophy by binding Myh7 mRNA in an m6A-dependent manner (confirmed by immunoprecipitation and mass spectrometry), promoting its decay; knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effect, placing Myh7 mRNA as a direct target of YTHDF2-mediated post-transcriptional regulation.","method":"Immunoprecipitation with mass spectrometry (RIP), Western blotting, real-time PCR, siRNA knockdown, domain-deletion experiments in primary cardiomyocytes and TAC mouse model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — RIP-MS identification of MYH7 mRNA as YTHDF2 target with functional rescue by domain deletion and Myh7 KD","pmids":["34266473"],"is_preprint":false},{"year":2021,"finding":"Loss of vmhcl (zebrafish MYH7 ortholog) function is sufficient to induce cardiomyopathy; pharmacological and genetic epistasis screens identified mTOR and MAPK signaling as downstream pathways mediating vmhcl/MYH7 cardiomyopathy, with mTOR inhibition rescuing enlarged cardiomyocyte nuclear size and MAPK inhibition restoring prolonged cardiomyocyte cell shape.","method":"CRISPR/Cas9 frameshift mutants in zebrafish, pharmacological pathway inhibition, MMEJ-based genetic epistasis with 11 candidate genes","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis plus orthogonal pharmacological rescue in zebrafish ortholog model","pmids":["34935644"],"is_preprint":false},{"year":2018,"finding":"Knock-in of the HCM point mutation R723G into porcine MYH7 via TALEN-mediated genome editing produces neonatal pigs with hallmarks of HCM including myocyte disarray, malformed nuclei, and MYH7 overexpression, with a shift in α/β-MyHC ratio in the left ventricle contributing to heart failure.","method":"TALEN-mediated knock-in in porcine fibroblasts, somatic cell nuclear transfer cloning, histopathology, qPCR for MyHC isoform ratio","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — germline knock-in large animal model with defined HCM pathology confirmed by histology and molecular profiling","pmids":["29555974"],"is_preprint":false},{"year":2019,"finding":"The R723G MYH7 mutation alters mRNA secondary structure as detected by SHAPE analysis, providing experimental evidence that the point mutation changes mRNA folding which may contribute to allelic imbalance (elevated mutant allele mRNA) observed in HCM patients.","method":"SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) analysis of wild-type vs. R723G MYH7 RNA","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 1 in vitro RNA structure probing, single lab, single method","pmids":["31790337"],"is_preprint":false},{"year":2017,"finding":"MYH7 allelic imbalance (unequal expression of mutant vs. wild-type allele) occurs both in HCM patients and in non-HCM donors, indicating that intrinsic MYH7 expression regulation—independent of mutation—contributes to allelic imbalance; this is detected at both mRNA and protein levels.","method":"Allele-specific qPCR and protein quantification in cardiac tissue from HCM patients and non-HCM donors","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 2 — mRNA and protein quantification across patient and donor tissue showing intrinsic allelic regulation","pmids":["29101517"],"is_preprint":false},{"year":2024,"finding":"MYH7 R453C mutation activates TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways in transgenic pigs, causing cardiac hypertrophy with fibrosis and cardiomyocyte loss distinct from MYH6 R453C, establishing pathway-specific cardiac remodeling mechanisms downstream of the MYH7 mutation.","method":"Transgenic pig model (MYH7 R453C vs. MYH6 R453C), RNA-seq, Western blotting for pathway proteins, ROS measurement, H9C2 cell model with mutation","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic large animal model with RNA-seq and pathway-level protein analysis; comparative MYH6 vs MYH7 design adds specificity","pmids":["38862020"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9-mediated MYH7 knockout in zebrafish causes impaired cardiovascular development, and a novel missense variant (Leu655Met) in the actin-binding domain of MYH7 is predicted to reduce actin-myosin binding energy, supporting a role for MYH7 in ventricular wall morphogenesis through actin interaction.","method":"CRISPR/Cas9 knockout in zebrafish; in silico molecular docking for actin-binding energy; whole-exome sequencing in human LVNC family","journal":"Frontiers in cardiovascular medicine","confidence":"Low","confidence_rationale":"Tier 3 — zebrafish KO phenotype without rescue; actin-binding mechanism is computational prediction only","pmids":["35463789"],"is_preprint":false},{"year":1990,"finding":"The human cardiac β-myosin heavy chain gene (MYH7) was localized to chromosome 14q12 by in situ hybridization, and is tightly linked to the α-MHC gene (MYH6) on this chromosome.","method":"In situ hybridization with ³H-labeled probe derived from β-MHC genomic clone","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 — direct cytogenetic localization by in situ hybridization","pmids":["2249479"],"is_preprint":false},{"year":2022,"finding":"The miR-143-3p–Sox6–Myh7 pathway regulates Myh7 expression in obesity-induced cardiac hypertrophy: miR-143-3p targets Sox6 (a transcriptional repressor of Myh7), and inhibition of miR-143-3p in cardiomyocytes increases Sox6 mRNA and reduces Myh7 expression, preventing angiotensin II-induced cardiomyocyte hypertrophy.","method":"Loss-of-function experiments with miR-143-3p inhibitor in cardiomyocytes; qPCR for Sox6 and Myh7; obese mouse model with cardiac hypertrophy","journal":"Experimental physiology","confidence":"Medium","confidence_rationale":"Tier 2 — functional inhibitor experiment in cardiomyocytes with defined upstream regulator of Myh7 transcription","pmids":["35765992"],"is_preprint":false},{"year":2014,"finding":"Epigenetic modifications at the Myh7 promoter underlie pressure overload-induced upregulation: TAC-induced heart failure is accompanied by distinct histone H3 methylation marks (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and changes in DNA methylation machinery (DNMT1, DNMT3b, MeCP2) at the Myh7 promoter, opposite to those at the Atp2a2 (SERCA-2A) promoter.","method":"ChIP assay for histone modifications at Myh7 and Atp2a2 promoters in TAC mouse hearts; qPCR for mRNA levels; assessment of KDM2A and DNMT recruitment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — chromatin immunoprecipitation with multiple histone marks and methylation machinery components at defined promoter regions","pmids":["25181347"],"is_preprint":false},{"year":2023,"finding":"MYH7 E848G mutation in hiPSC-CMs increases cardiomyocyte size, reduces maximum engineered heart tissue twitch forces, and increases apoptosis associated with elevated p53 activity; however, genetic ablation of TP53 did not rescue contractile dysfunction or survival, indicating the apoptosis and contractile defect are p53-independent downstream consequences of the mutation.","method":"Isogenic hiPSC-CM model (MYH7 E848G/+), engineered heart tissue force measurements, single-cell size quantification, apoptosis assays, TP53 genetic knockout","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — isogenic genome-edited human cell model with orthogonal functional readouts and pathway interrogation by genetic ablation","pmids":["36902340"],"is_preprint":false},{"year":2024,"finding":"Deep mutational scanning of 113 MYH7 codon variants in hiPSC-CMs showed that pathogenic MYH7 missense variants cause reduced β-MHC protein abundance (confirmed in human HCM heart tissue) and decreased cardiomyocyte survival, providing multiplexed functional evidence that protein instability/loss is a shared mechanism for pathogenic MYH7 variants.","method":"CRISPRa-based hiPSC library generation, hiPSC-CM differentiation, massively parallel sequencing for β-MHC variant abundance, cell survival assay; validation in human HCM heart tissue","journal":"Circulation. Genomic and precision medicine","confidence":"High","confidence_rationale":"Tier 1–2 — genome-scale functional assay in disease-relevant human cells with orthogonal validation in patient tissue; multiple variants tested systematically","pmids":["38362799"],"is_preprint":false}],"current_model":"MYH7 encodes the β-myosin heavy chain (β-MHC), the primary motor protein of cardiac ventricles and slow-twitch skeletal muscle; pathogenic mutations in the globular S1 head domain cause hypercontractility (e.g., G256E reduces super-relaxed state) or hypocontractility/force loss (e.g., R403Q increases cross-bridge detachment and energy cost; other head mutations reduce sarcomere force generation), while rod/tail domain mutations disrupt coiled-coil assembly and cause myosin aggregation in skeletal muscle; the fraction of mutant protein and allelic imbalance (regulated in part by mRNA secondary structure and intrinsic transcriptional mechanisms) modulates disease severity; downstream signaling through mTOR, MAPK, TGF-β/Smad2/3, and Nox4/ROS/NF-κB pathways mediates cardiac remodeling, and Myh7 expression is post-transcriptionally controlled by YTHDF2-m6A-dependent mRNA decay and transcriptionally regulated via the miR-143-3p–Sox6 axis and epigenetic histone modifications at its promoter."},"narrative":{"teleology":[{"year":1990,"claim":"Establishing the chromosomal location of MYH7 at 14q12 linked to MYH6 resolved where the β-MHC gene resides and enabled subsequent mutation mapping.","evidence":"In situ hybridization with ³H-labeled β-MHC genomic probe on human chromosomes","pmids":["2249479"],"confidence":"High","gaps":["Physical linkage distance and regulatory relationship between MYH7 and MYH6 loci not defined","No functional consequence of locus organization addressed"]},{"year":2003,"claim":"Identification that a rod-domain mutation (R1845W) causes myosin storage myopathy with subsarcolemmal myosin inclusions established that the MYH7 rod region is essential for thick-filament assembly in slow-twitch skeletal muscle.","evidence":"Muscle biopsy with immunohistochemistry, electron microscopy, and genetic sequencing in affected patients","pmids":["14520662"],"confidence":"Medium","gaps":["Assembly defect inferred from pathology rather than biochemically reconstituted","No in vitro filament assembly assay performed"]},{"year":2004,"claim":"Mapping of Laing distal myopathy mutations to the coiled-coil rod/tail domain (exons 32–36) demonstrated that disruption of coiled-coil structure underlies a distinct skeletal myopathy mechanism separable from head-domain cardiomyopathy mutations.","evidence":"Genetic sequencing in six families with in silico coiled-coil disruption prediction","pmids":["15322983"],"confidence":"Medium","gaps":["Coiled-coil disruption was computationally predicted, not biochemically validated","Mechanism of selective distal muscle vulnerability not explained"]},{"year":2013,"claim":"Direct force measurements on patient cardiomyocytes and myofibrils showed that MYH7 head-domain mutations reduce intrinsic sarcomere force generation, answering whether the primary defect is mechanical rather than purely signaling-based.","evidence":"Single membrane-permeabilized cardiomyocyte and single myofibril force measurements from human HCM cardiac tissue","pmids":["23674513"],"confidence":"High","gaps":["Multiple different head-domain mutations were grouped; variant-specific mechanisms not deconvolved","Whether force deficit is dominant-negative or haploinsufficient not resolved"]},{"year":2014,"claim":"The R403Q mutation was shown to increase cross-bridge detachment kinetics and energetic cost of tension, establishing that specific head mutations produce energetic inefficiency—not just force loss—linking MYH7 dysfunction to metabolic stress in HCM.","evidence":"Single myofibril mechanics and ATPase-based tension cost measurements in human R403Q cardiac tissue versus mutation-negative HCM","pmids":["24928957"],"confidence":"High","gaps":["Whether energetic inefficiency is a universal feature of all head-domain mutations or specific to R403Q not tested","In vivo metabolic consequences not measured"]},{"year":2014,"claim":"Epigenetic characterization of the Myh7 promoter revealed that specific histone marks (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and DNA methylation machinery changes accompany pathological Myh7 upregulation, establishing a chromatin-level regulatory mechanism for the α-to-β MHC isoform switch in heart failure.","evidence":"ChIP for histone modifications and methylation machinery at Myh7 promoter in TAC mouse hearts","pmids":["25181347"],"confidence":"Medium","gaps":["Causal role of individual histone marks not tested by perturbation","Whether these marks are MYH7-specific or part of a broader hypertrophic gene program not resolved"]},{"year":2016,"claim":"Cell-based reconstitution of rod-domain proline substitutions (A1437P, R1434P) demonstrated that myosin self-assembly and sarcomere incorporation are dissociable, refining the understanding of how rod mutations cause disease without preventing all filament integration.","evidence":"Fluorescent β-myosin constructs expressed in non-muscle cells with imaging of assembly versus sarcomeric incorporation","pmids":["27519903"],"confidence":"Medium","gaps":["Non-muscle cell system may not recapitulate sarcomere-level assembly fidelity","No force or contractile consequence measured"]},{"year":2017,"claim":"Detection of MYH7 allelic imbalance in both HCM patients and non-HCM donors revealed that intrinsic regulatory mechanisms—independent of mutation identity—govern unequal allelic expression, establishing allelic dosage as a disease-modifying variable.","evidence":"Allele-specific qPCR and protein quantification in human cardiac tissue from patients and donors","pmids":["29101517"],"confidence":"Medium","gaps":["Molecular basis of intrinsic allelic imbalance not identified","Whether allelic imbalance is heritable or stochastic not resolved"]},{"year":2018,"claim":"A porcine R723G knock-in model and an isogenic hiPSC-CM E848G model independently confirmed that specific MYH7 point mutations are sufficient to produce HCM hallmarks (disarray, hypertrophy, altered MHC isoform ratio, reduced contractility), validating genotype-phenotype causality in large-animal and human-cell systems.","evidence":"TALEN-mediated porcine knock-in with histopathology; genome-edited hiPSC-CM engineered heart tissue force measurements","pmids":["29555974","30623132"],"confidence":"Medium","gaps":["E848G–cMyBP-C interaction mechanism inferred but not directly biochemically validated","Long-term progression in porcine model limited by neonatal lethality of clones"]},{"year":2019,"claim":"SHAPE analysis of R723G mRNA demonstrated that a single missense mutation alters MYH7 mRNA secondary structure, providing a molecular basis for mutation-specific allelic imbalance through post-transcriptional RNA-structural effects.","evidence":"SHAPE RNA structure probing of wild-type versus R723G MYH7 mRNA in vitro","pmids":["31790337"],"confidence":"Medium","gaps":["Functional link between altered mRNA structure and differential mRNA stability/translation not experimentally demonstrated","Single mutation tested; generalizability unknown"]},{"year":2021,"claim":"Identification of YTHDF2 as a direct m6A-dependent regulator of Myh7 mRNA decay established the first post-transcriptional pathway controlling β-MHC levels and linked epitranscriptomic regulation to cardiac hypertrophy.","evidence":"RIP-MS, domain-deletion, and siRNA knockdown experiments in primary cardiomyocytes and TAC mouse model","pmids":["34266473"],"confidence":"Medium","gaps":["Specific m6A sites on Myh7 mRNA not mapped","Whether YTHDF2-mediated decay is sufficient to modulate allelic imbalance not tested"]},{"year":2021,"claim":"Genetic epistasis in zebrafish showed that loss of MYH7 ortholog function activates mTOR and MAPK signaling as downstream mediators of cardiomyopathy, with pathway-specific rescue of distinct cellular phenotypes (nuclear size vs. cell shape), deconvolving signaling consequences of MYH7 loss.","evidence":"CRISPR/Cas9 zebrafish mutants with pharmacological and MMEJ-based genetic epistasis screens","pmids":["34935644"],"confidence":"Medium","gaps":["Zebrafish-to-mammalian translatability of pathway hierarchy not confirmed","Upstream sensor linking sarcomere dysfunction to mTOR/MAPK activation unknown"]},{"year":2022,"claim":"The miR-143-3p–Sox6 axis was identified as a transcriptional regulatory circuit controlling Myh7 expression in cardiomyocytes, connecting obesity-associated microRNA dysregulation to pathological MHC isoform switching.","evidence":"miR-143-3p inhibitor in cardiomyocytes with qPCR for Sox6 and Myh7; obese mouse cardiac hypertrophy model","pmids":["35765992"],"confidence":"Medium","gaps":["Direct Sox6 binding to Myh7 promoter not demonstrated by ChIP in this study","Whether miR-143-3p regulation is cardiac-specific or also operates in skeletal muscle not tested"]},{"year":2023,"claim":"Genetic ablation of TP53 failed to rescue contractile dysfunction or survival in MYH7 E848G hiPSC-CMs despite elevated p53 activity, establishing that the apoptotic and contractile phenotypes are p53-independent consequences of the mutation.","evidence":"Isogenic hiPSC-CM MYH7 E848G model with TP53 knockout, engineered heart tissue force and apoptosis assays","pmids":["36902340"],"confidence":"Medium","gaps":["Alternative cell-death pathways mediating apoptosis not identified","Whether p53-independent mechanism generalizes to other MYH7 variants unknown"]},{"year":2024,"claim":"Multi-scale analysis of G256E established the super-relaxed state as a quantitative regulator of contractile output, showing that disruption of the myosin folded-back conformation increases available cross-bridges and causes hypercontractility with compensatory mitochondrial upregulation—a gain-of-function mechanism distinct from the force-loss seen with other head mutations.","evidence":"Biochemical super-relaxed state assay, myofibril mechanics, traction force microscopy, engineered heart tissues, and single-cell transcriptomics in gene-edited hiPSC-CMs","pmids":["38683993"],"confidence":"High","gaps":["Whether mavacamten or other myosin inhibitors fully restore super-relaxed fraction in G256E not tested in this study","Long-term in vivo consequences of hypercontractile mechanism not assessed"]},{"year":2024,"claim":"Deep mutational scanning across 113 codon positions revealed that reduced β-MHC protein abundance and impaired cell survival are shared features of pathogenic MYH7 missense variants, suggesting protein instability as a convergent pathomechanism beyond allele-specific kinetic changes.","evidence":"CRISPRa-based hiPSC-CM library with massively parallel variant abundance sequencing; validation in human HCM tissue","pmids":["38362799"],"confidence":"High","gaps":["Whether protein instability reflects folding defects versus enhanced degradation not mechanistically resolved","Functional consequences (force, kinetics) not measured for most variants in this screen"]},{"year":2024,"claim":"Transgenic pig MYH7 R453C model identified TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB as mutation-specific downstream remodeling pathways, distinguishing MYH7 signaling from MYH6 and providing therapeutic targets.","evidence":"Transgenic pig (MYH7 vs. MYH6 R453C), RNA-seq, Western blotting, ROS measurement, H9C2 cell model","pmids":["38862020"],"confidence":"Medium","gaps":["Pathway activation causality versus correlation not fully disentangled","Whether pathway specificity is mutation-position or isoform-dependent not resolved"]},{"year":null,"claim":"Key unresolved questions include: how sarcomere mechanical dysfunction is sensed and transduced to activate mTOR/MAPK/TGF-β pathways; whether protein instability versus altered kinetics is the dominant pathomechanism across the full MYH7 variant spectrum; and what determines the tissue-specific vulnerability (cardiac versus skeletal) of different domain mutations.","evidence":"","pmids":[],"confidence":"High","gaps":["No mechanosensor linking sarcomere dysfunction to signaling cascades has been identified","Structural basis for domain-specific disease presentation (head = cardiac, rod/tail = skeletal) remains unexplained","Therapeutic thresholds for allelic balance correction are unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5,6,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,4,7]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2,5,19]}],"complexes":["thick filament (sarcomere)"],"partners":["MYBPC3","MYH6","YTHDF2","SOX6"],"other_free_text":[]},"mechanistic_narrative":"MYH7 encodes the β-myosin heavy chain (β-MHC), the principal sarcomeric motor protein of cardiac ventricles and slow-twitch skeletal muscle, whose mutations are a major cause of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, Laing distal myopathy, and myosin storage myopathy [PMID:23674513, PMID:15322983, PMID:14520662]. Pathogenic mutations in the globular S1 head domain alter cross-bridge kinetics and force generation—either reducing intrinsic sarcomere force or destabilizing the super-relaxed (folded-back) state to produce hypercontractility with increased energy cost—while rod/tail-domain mutations disrupt coiled-coil structure and myosin thick-filament assembly, leading to protein aggregation in skeletal muscle fibers [PMID:24928957, PMID:38683993, PMID:31130376, PMID:27519903]. Deep mutational scanning reveals that pathogenic missense variants broadly reduce β-MHC protein abundance and cardiomyocyte survival, and downstream remodeling is mediated through TGF-β/Smad2/3, ERK1/2, mTOR, MAPK, and Nox4/ROS/NF-κB signaling pathways [PMID:38362799, PMID:38862020, PMID:34935644]. MYH7 expression is regulated transcriptionally by epigenetic histone modifications at its promoter and by the miR-143-3p–Sox6 axis, and post-transcriptionally by YTHDF2-mediated m6A-dependent mRNA decay, with allelic imbalance modulated in part by mutation-induced changes in mRNA secondary structure [PMID:25181347, PMID:35765992, PMID:34266473, PMID:31790337, PMID:29101517]."},"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. Forms regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle","subcellular_location":"Cytoplasm, myofibril; Cytoplasm, myofibril, sarcomere","url":"https://www.uniprot.org/uniprotkb/P12883/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYH7","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYH7","total_profiled":1310},"omim":[{"mim_id":"621503","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 39; LRRC39","url":"https://www.omim.org/entry/621503"},{"mim_id":"620247","title":"CARDIOMYOPATHY, DILATED, 1OO; CMD1OO","url":"https://www.omim.org/entry/620247"},{"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":"613874","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 18; CMH18","url":"https://www.omim.org/entry/613874"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Focal adhesion sites","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":7145.3},{"tissue":"skeletal muscle","ntpm":13633.1},{"tissue":"tongue","ntpm":5024.6}],"url":"https://www.proteinatlas.org/search/MYH7"},"hgnc":{"alias_symbol":["CMD1S"],"prev_symbol":["CMH1","MPD1"]},"alphafold":{"accession":"P12883","domains":[{"cath_id":"2.30.30.360","chopping":"34-79","consensus_level":"medium","plddt":84.6152,"start":34,"end":79},{"cath_id":"3.30.70.1590","chopping":"710-768","consensus_level":"medium","plddt":81.5232,"start":710,"end":768},{"cath_id":"1.20.5","chopping":"1560-1658","consensus_level":"medium","plddt":77.1247,"start":1560,"end":1658}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P12883","model_url":"https://alphafold.ebi.ac.uk/files/AF-P12883-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P12883-F1-predicted_aligned_error_v6.png","plddt_mean":74.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYH7","jax_strain_url":"https://www.jax.org/strain/search?query=MYH7"},"sequence":{"accession":"P12883","fasta_url":"https://rest.uniprot.org/uniprotkb/P12883.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P12883/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P12883"}},"corpus_meta":[{"pmid":"29300372","id":"PMC_29300372","title":"Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.","date":"2018","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29300372","citation_count":272,"is_preprint":false},{"pmid":"15322983","id":"PMC_15322983","title":"Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).","date":"2004","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15322983","citation_count":167,"is_preprint":false},{"pmid":"19412328","id":"PMC_19412328","title":"Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.","date":"2008","source":"Clinical and translational science","url":"https://pubmed.ncbi.nlm.nih.gov/19412328","citation_count":158,"is_preprint":false},{"pmid":"21127202","id":"PMC_21127202","title":"Mutations in the sarcomere gene MYH7 in Ebstein anomaly.","date":"2010","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21127202","citation_count":128,"is_preprint":false},{"pmid":"14520662","id":"PMC_14520662","title":"Myosin storage myopathy associated with a heterozygous missense mutation in MYH7.","date":"2003","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/14520662","citation_count":122,"is_preprint":false},{"pmid":"23674513","id":"PMC_23674513","title":"Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy.","date":"2013","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/23674513","citation_count":90,"is_preprint":false},{"pmid":"20733148","id":"PMC_20733148","title":"MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy.","date":"2010","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20733148","citation_count":79,"is_preprint":false},{"pmid":"24664454","id":"PMC_24664454","title":"Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy.","date":"2014","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/24664454","citation_count":76,"is_preprint":false},{"pmid":"24928957","id":"PMC_24928957","title":"Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation.","date":"2014","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24928957","citation_count":70,"is_preprint":false},{"pmid":"30623132","id":"PMC_30623132","title":"Novel Adult-Onset Systolic Cardiomyopathy Due to MYH7 E848G Mutation in Patient-Derived Induced Pluripotent Stem Cells.","date":"2018","source":"JACC. Basic to translational science","url":"https://pubmed.ncbi.nlm.nih.gov/30623132","citation_count":70,"is_preprint":false},{"pmid":"30354366","id":"PMC_30354366","title":"Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy.","date":"2018","source":"Circulation. Heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/30354366","citation_count":69,"is_preprint":false},{"pmid":"36007715","id":"PMC_36007715","title":"Natural History of MYH7-Related Dilated Cardiomyopathy.","date":"2022","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/36007715","citation_count":66,"is_preprint":false},{"pmid":"27387980","id":"PMC_27387980","title":"MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.","date":"2016","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27387980","citation_count":66,"is_preprint":false},{"pmid":"34266473","id":"PMC_34266473","title":"YTHDF2 alleviates cardiac hypertrophy via regulating Myh7 mRNA decoy.","date":"2021","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/34266473","citation_count":61,"is_preprint":false},{"pmid":"22784669","id":"PMC_22784669","title":"Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement.","date":"2012","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/22784669","citation_count":61,"is_preprint":false},{"pmid":"19150014","id":"PMC_19150014","title":"[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy].","date":"2009","source":"Revista espanola de cardiologia","url":"https://pubmed.ncbi.nlm.nih.gov/19150014","citation_count":58,"is_preprint":false},{"pmid":"12788380","id":"PMC_12788380","title":"Novel deletions in MYH7 and MYBPC3 identified in Indian families with familial hypertrophic cardiomyopathy.","date":"2003","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/12788380","citation_count":57,"is_preprint":false},{"pmid":"12881443","id":"PMC_12881443","title":"Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients.","date":"2003","source":"Clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12881443","citation_count":57,"is_preprint":false},{"pmid":"7649260","id":"PMC_7649260","title":"Isolation and characterization of a yeast gene, MPD1, the overexpression of which suppresses inviability caused by protein disulfide isomerase depletion.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7649260","citation_count":50,"is_preprint":false},{"pmid":"24093860","id":"PMC_24093860","title":"Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy.","date":"2013","source":"American heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/24093860","citation_count":45,"is_preprint":false},{"pmid":"17336526","id":"PMC_17336526","title":"MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy.","date":"2007","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/17336526","citation_count":45,"is_preprint":false},{"pmid":"23794396","id":"PMC_23794396","title":"Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7.","date":"2013","source":"American journal of medical genetics. Part C, Seminars in medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23794396","citation_count":44,"is_preprint":false},{"pmid":"28193612","id":"PMC_28193612","title":"Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.","date":"2017","source":"Circulation. Cardiovascular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/28193612","citation_count":44,"is_preprint":false},{"pmid":"32567507","id":"PMC_32567507","title":"Silencing of MYH7 ameliorates disease phenotypes in human iPSC-cardiomyocytes.","date":"2020","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32567507","citation_count":43,"is_preprint":false},{"pmid":"15699387","id":"PMC_15699387","title":"Myosin storage myopathy: slow skeletal myosin (MYH7) mutation in two isolated cases.","date":"2005","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15699387","citation_count":42,"is_preprint":false},{"pmid":"37079208","id":"PMC_37079208","title":"MYH7 in cardiomyopathy and skeletal muscle myopathy.","date":"2023","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37079208","citation_count":40,"is_preprint":false},{"pmid":"21288719","id":"PMC_21288719","title":"A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy.","date":"2011","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/21288719","citation_count":40,"is_preprint":false},{"pmid":"22521714","id":"PMC_22521714","title":"New phenotype and pathology features in MYH7-related distal myopathy.","date":"2012","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/22521714","citation_count":38,"is_preprint":false},{"pmid":"15483641","id":"PMC_15483641","title":"One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations [corrected] in MYH7 rod region.","date":"2005","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/15483641","citation_count":38,"is_preprint":false},{"pmid":"34935644","id":"PMC_34935644","title":"Inhibition of mTOR or MAPK ameliorates vmhcl/myh7 cardiomyopathy in zebrafish.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34935644","citation_count":37,"is_preprint":false},{"pmid":"16684601","id":"PMC_16684601","title":"Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred.","date":"2006","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/16684601","citation_count":37,"is_preprint":false},{"pmid":"32525266","id":"PMC_32525266","title":"Radiomic Analysis of Native T1 Mapping Images Discriminates Between MYH7 and MYBPC3-Related Hypertrophic Cardiomyopathy.","date":"2020","source":"Journal of magnetic resonance imaging : JMRI","url":"https://pubmed.ncbi.nlm.nih.gov/32525266","citation_count":35,"is_preprint":false},{"pmid":"25181347","id":"PMC_25181347","title":"Epigenetic switch at atp2a2 and myh7 gene promoters in pressure overload-induced heart failure.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25181347","citation_count":34,"is_preprint":false},{"pmid":"23478172","id":"PMC_23478172","title":"A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies.","date":"2013","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/23478172","citation_count":34,"is_preprint":false},{"pmid":"7848420","id":"PMC_7848420","title":"The electrocardiogram is a more sensitive indicator than echocardiography of hypertrophic cardiomyopathy in families with a mutation in the MYH7 gene.","date":"1994","source":"British heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/7848420","citation_count":33,"is_preprint":false},{"pmid":"29555974","id":"PMC_29555974","title":"Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29555974","citation_count":32,"is_preprint":false},{"pmid":"17383184","id":"PMC_17383184","title":"Symptomatic distal myopathy with cardiomyopathy due to a MYH7 mutation.","date":"2007","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/17383184","citation_count":31,"is_preprint":false},{"pmid":"30924982","id":"PMC_30924982","title":"Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype.","date":"2019","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30924982","citation_count":30,"is_preprint":false},{"pmid":"21604106","id":"PMC_21604106","title":"Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7.","date":"2013","source":"Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/21604106","citation_count":30,"is_preprint":false},{"pmid":"19138847","id":"PMC_19138847","title":"Striking phenotypic variability in two familial cases of myosin storage myopathy with a MYH7 Leu1793pro mutation.","date":"2009","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/19138847","citation_count":29,"is_preprint":false},{"pmid":"23956225","id":"PMC_23956225","title":"Familial ebstein anomaly, left ventricular hypertrabeculation, and ventricular septal defect associated with a MYH7 mutation.","date":"2013","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/23956225","citation_count":27,"is_preprint":false},{"pmid":"28642161","id":"PMC_28642161","title":"Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy.","date":"2017","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28642161","citation_count":27,"is_preprint":false},{"pmid":"29101517","id":"PMC_29101517","title":"Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy.","date":"2017","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/29101517","citation_count":25,"is_preprint":false},{"pmid":"21959974","id":"PMC_21959974","title":"A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India.","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21959974","citation_count":25,"is_preprint":false},{"pmid":"31164718","id":"PMC_31164718","title":"A feline orthologue of the human MYH7 c.5647G>A (p.(Glu1883Lys)) variant causes hypertrophic cardiomyopathy in a Domestic Shorthair cat.","date":"2019","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/31164718","citation_count":25,"is_preprint":false},{"pmid":"25607779","id":"PMC_25607779","title":"Coexistence of Digenic Mutations in Both Thin (TPM1) and Thick (MYH7) Filaments of Sarcomeric Genes Leads to Severe Hypertrophic Cardiomyopathy in a South Indian FHCM.","date":"2015","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25607779","citation_count":25,"is_preprint":false},{"pmid":"25666907","id":"PMC_25666907","title":"Homozygous MYH7 R1820W mutation results in recessive myosin storage myopathy: scapuloperoneal and respiratory weakness with dilated cardiomyopathy.","date":"2015","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25666907","citation_count":24,"is_preprint":false},{"pmid":"30577544","id":"PMC_30577544","title":"Detection of Plasmid-Mediated β-Lactamase Genes and Emergence of a Novel AmpC (CMH-1) in Enterobacter cloacae at a Medical Center in Southern Taiwan.","date":"2018","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30577544","citation_count":23,"is_preprint":false},{"pmid":"28927343","id":"PMC_28927343","title":"A triple stranded G-quadruplex formation in the promoter region of human myosin β(Myh7) gene.","date":"2017","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/28927343","citation_count":22,"is_preprint":false},{"pmid":"22859017","id":"PMC_22859017","title":"Prenatal ultrasound diagnosis of MYH7 non-compaction cardiomyopathy.","date":"2013","source":"Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/22859017","citation_count":21,"is_preprint":false},{"pmid":"32092825","id":"PMC_32092825","title":"Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32092825","citation_count":20,"is_preprint":false},{"pmid":"23782526","id":"PMC_23782526","title":"Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.","date":"2013","source":"Circulation journal : official journal of the Japanese Circulation Society","url":"https://pubmed.ncbi.nlm.nih.gov/23782526","citation_count":20,"is_preprint":false},{"pmid":"30650640","id":"PMC_30650640","title":"Digenic Inheritance of LAMA4 and MYH7 Mutations in Patient with Infantile Dilated Cardiomyopathy.","date":"2019","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/30650640","citation_count":20,"is_preprint":false},{"pmid":"29343710","id":"PMC_29343710","title":"Phenotypic diversity identified by cardiac magnetic resonance in a large hypertrophic cardiomyopathy family with a single MYH7 mutation.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29343710","citation_count":19,"is_preprint":false},{"pmid":"34542152","id":"PMC_34542152","title":"A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34542152","citation_count":18,"is_preprint":false},{"pmid":"28864942","id":"PMC_28864942","title":"A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects.","date":"2017","source":"Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/28864942","citation_count":18,"is_preprint":false},{"pmid":"25825456","id":"PMC_25825456","title":"Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family.","date":"2015","source":"Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/25825456","citation_count":18,"is_preprint":false},{"pmid":"37409452","id":"PMC_37409452","title":"Long-Term Prevalence of Systolic Dysfunction in MYBPC3 Versus MYH7-Related Hypertrophic Cardiomyopathy.","date":"2023","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37409452","citation_count":17,"is_preprint":false},{"pmid":"35409153","id":"PMC_35409153","title":"Circulating miR-499a-5p Is a Potential Biomarker of MYH7-Associated Hypertrophic Cardiomyopathy.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35409153","citation_count":17,"is_preprint":false},{"pmid":"24828896","id":"PMC_24828896","title":"Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene.","date":"2014","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24828896","citation_count":17,"is_preprint":false},{"pmid":"21031054","id":"PMC_21031054","title":"Genetic variations of β-MYH7 in hypertrophic cardiomyopathy and dilated cardiomyopathy.","date":"2010","source":"Indian journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21031054","citation_count":17,"is_preprint":false},{"pmid":"35463789","id":"PMC_35463789","title":"A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction.","date":"2022","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35463789","citation_count":17,"is_preprint":false},{"pmid":"2249479","id":"PMC_2249479","title":"Localization of human cardiac beta-myosin heavy chain gene (MYH7) to chromosome 14q12 by in situ hybridization.","date":"1990","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2249479","citation_count":17,"is_preprint":false},{"pmid":"34680864","id":"PMC_34680864","title":"Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy-The Graz Hypertrophic Cardiomyopathy Registry.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34680864","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":"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":"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 : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/22765922","citation_count":16,"is_preprint":false},{"pmid":"32612965","id":"PMC_32612965","title":"Left Bundle Pacing for Left Bundle Branch Block and Intermittent Third-Degree Atrioventricular Block in a MYH7 Mutation-Related Hypertrophic Cardiomyopathy With Restrictive Phenotype in a Child.","date":"2020","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/32612965","citation_count":16,"is_preprint":false},{"pmid":"21395566","id":"PMC_21395566","title":"Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients.","date":"2011","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21395566","citation_count":15,"is_preprint":false},{"pmid":"24300783","id":"PMC_24300783","title":"Exome sequencing identifies Laing distal myopathy MYH7 mutation in a Roma family previously diagnosed with distal neuronopathy.","date":"2013","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/24300783","citation_count":15,"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":"36902340","id":"PMC_36902340","title":"Cardiomyocyte Apoptosis Is Associated with Contractile Dysfunction in Stem Cell Model of MYH7 E848G Hypertrophic Cardiomyopathy.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36902340","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":"30745532","id":"PMC_30745532","title":"Different Clinical Presentation and Tissue Characterization in a Monozygotic Twin Pair with MYH7 Mutation-Related Hypertrophic Cardiomyopathy.","date":"2019","source":"International heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/30745532","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":"31790337","id":"PMC_31790337","title":"Hypertrophic cardiomyopathy MYH7 mutation R723G alters mRNA secondary structure.","date":"2019","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31790337","citation_count":13,"is_preprint":false},{"pmid":"28395747","id":"PMC_28395747","title":"Generation of induced pluripotent stem cells (iPSCs) from a hypertrophic cardiomyopathy patient with the pathogenic variant p.Val698Ala in beta-myosin heavy chain (MYH7) gene.","date":"2017","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28395747","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":"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":"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":"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":"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":"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":"26567828","id":"PMC_26567828","title":"Electrochemical primer extension for the detection of single nucleotide polymorphisms in the cardiomyopathy associated MYH7 gene.","date":"2016","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/26567828","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":"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":"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":"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":11,"is_preprint":false},{"pmid":"38862020","id":"PMC_38862020","title":"MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways.","date":"2024","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/38862020","citation_count":10,"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 physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35765992","citation_count":10,"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":10,"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":10,"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":10,"is_preprint":false},{"pmid":"17495353","id":"PMC_17495353","title":"Mutation of the MYH7 gene in a child with hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome.","date":"2007","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17495353","citation_count":10,"is_preprint":false},{"pmid":"29170849","id":"PMC_29170849","title":"MYH7 mutation associated with two phenotypes of myopathy.","date":"2017","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/29170849","citation_count":10,"is_preprint":false},{"pmid":"30166250","id":"PMC_30166250","title":"A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain.","date":"2018","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/30166250","citation_count":9,"is_preprint":false},{"pmid":"25447691","id":"PMC_25447691","title":"A novel MYH7 Leu1453pro mutation resulting in Laing distal myopathy in an Irish family.","date":"2014","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25447691","citation_count":9,"is_preprint":false},{"pmid":"32309617","id":"PMC_32309617","title":"A rare case of familial restrictive cardiomyopathy, with mutations in MYH7 and ABCC9 genes.","date":"2019","source":"Discoveries (Craiova, Romania)","url":"https://pubmed.ncbi.nlm.nih.gov/32309617","citation_count":9,"is_preprint":false},{"pmid":"28002430","id":"PMC_28002430","title":"A Novel HRAS Mutation Independently Contributes to Left Ventricular Hypertrophy in a Family with a Known MYH7 Mutation.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28002430","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50193,"output_tokens":5048,"usd":0.11315},"stage2":{"model":"claude-opus-4-6","input_tokens":8631,"output_tokens":4153,"usd":0.22047},"total_usd":0.33362,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","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 intrinsic force-generating capacity of sarcomeres at both maximal and submaximal Ca²⁺ concentrations, as demonstrated in single membrane-permeabilized cardiomyocytes and single myofibrils from HCM patients carrying MYH7 mutations, even after correction for myofibril density.\",\n      \"method\": \"Force measurements in single membrane-permeabilized cardiomyocytes and single myofibrils from human cardiac tissue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct mechanical assay on human patient tissue with multiple orthogonal preparations (cardiomyocytes and myofibrils), replicated across multiple MYH7 mutation carriers\",\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 globular head) increases cross-bridge detachment kinetics (faster slow relaxation) and significantly raises the energetic cost of tension generation (tension cost) in human HCM myofibrils and muscle strips, establishing a direct link between cross-bridge kinetics and energetic inefficiency.\",\n      \"method\": \"Single cardiac myofibril mechanics and ATPase-based tension cost measurements in multicellular cardiac muscle strips from R403Q HCM patients vs. sarcomere mutation-negative HCM\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro myofibril reconstitution assay plus ATPase energetics, orthogonal methods, human tissue\",\n      \"pmids\": [\"24928957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The MYH7 G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back (super-relaxed) state by ~33%, resulting in more myosin heads available for actin interaction and a hypercontractile phenotype with faster and greater tension development across protein, myofibril, cell, and tissue scales; this is accompanied by upregulated mitochondrial gene expression and increased mitochondrial respiration.\",\n      \"method\": \"Biochemical assay of myosin folded-back state, myofibril mechanics in gene-edited hiPSC-CMs, traction force microscopy in single cells, engineered heart tissues, 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 — multi-scale reconstitution from purified protein through engineered tissue with mutagenesis-confirmed mechanism in a single rigorous study\",\n      \"pmids\": [\"38683993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The MYH7 E848G mutation causes reduced contractile function in hiPSC-derived cardiomyocytes and engineered heart tissues; genome-edited isogenic controls confirmed pathogenicity, and reduced contractility may result from impaired interaction between MYH7 protein and cardiac myosin binding protein C (cMyBP-C).\",\n      \"method\": \"hiPSC-derived cardiomyocytes, engineered heart tissues, genome editing (isogenic controls), contractile force measurements\",\n      \"journal\": \"JACC. Basic to translational science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic hiPSC-CM model with functional readout; MYH7–cMyBP-C interaction inferred but not directly demonstrated by co-IP/pulldown\",\n      \"pmids\": [\"30623132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A missense mutation Arg1845Trp in the rod region of MYH7 (slow/β-cardiac myosin heavy chain) causes myosin storage myopathy characterized by large subsarcolemmal inclusions of slow/β-cardiac myosin in type I skeletal muscle fibers, indicating that this residue is essential for proper thick filament assembly.\",\n      \"method\": \"Muscle biopsy with immunohistochemistry and electron microscopy confirming myosin-containing inclusions; genetic sequencing identifying Arg1845Trp in rod domain\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mutation identified with histopathological confirmation of myosin aggregation phenotype; assembly defect inferred from pathology\",\n      \"pmids\": [\"14520662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Heterozygous mutations toward the 3′ end of MYH7 (exons 32–36, encoding the coiled-coil rod/tail region) cause Laing early-onset distal myopathy; in silico analysis predicts these mutations locally disrupt the coiled-coil structure of the myosin tail, preventing normal thick filament assembly.\",\n      \"method\": \"Genetic sequencing of MYH7 in six affected families; in silico coiled-coil disruption prediction\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic identification with computational structural prediction; no direct biochemical validation of coiled-coil disruption in this paper\",\n      \"pmids\": [\"15322983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Expression of mutant MYH7 (Arg1712Trp) protein in COS-7 cells results in abnormal myosin aggregation compared to wild-type MYH7, directly demonstrating that this rod-domain mutation impairs myosin self-assembly.\",\n      \"method\": \"Heterologous expression of mutant vs. wild-type MYH7 in COS-7 cells with imaging of protein aggregation\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based reconstitution experiment with direct imaging of assembly defect\",\n      \"pmids\": [\"31130376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Two novel proline substitutions in the rod domain of MYH7 (Ala1437Pro and 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, dissociating filament assembly from sarcomere incorporation.\",\n      \"method\": \"Transfection of mutant β-myosin constructs in non-muscle cells with fluorescence imaging of assembly\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based functional reconstitution with two distinct mutations tested\",\n      \"pmids\": [\"27519903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The m6A reader YTHDF2 suppresses cardiac hypertrophy by binding Myh7 mRNA in an m6A-dependent manner (confirmed by immunoprecipitation and mass spectrometry), promoting its decay; knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effect, placing Myh7 mRNA as a direct target of YTHDF2-mediated post-transcriptional regulation.\",\n      \"method\": \"Immunoprecipitation with mass spectrometry (RIP), Western blotting, real-time PCR, siRNA knockdown, domain-deletion experiments in primary cardiomyocytes and TAC mouse model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP-MS identification of MYH7 mRNA as YTHDF2 target with functional rescue by domain deletion and Myh7 KD\",\n      \"pmids\": [\"34266473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of vmhcl (zebrafish MYH7 ortholog) function is sufficient to induce cardiomyopathy; pharmacological and genetic epistasis screens identified mTOR and MAPK signaling as downstream pathways mediating vmhcl/MYH7 cardiomyopathy, with mTOR inhibition rescuing enlarged cardiomyocyte nuclear size and MAPK inhibition restoring prolonged cardiomyocyte cell shape.\",\n      \"method\": \"CRISPR/Cas9 frameshift mutants in zebrafish, pharmacological pathway inhibition, MMEJ-based genetic epistasis with 11 candidate genes\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus orthogonal pharmacological rescue in zebrafish ortholog model\",\n      \"pmids\": [\"34935644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knock-in of the HCM point mutation R723G into porcine MYH7 via TALEN-mediated genome editing produces neonatal pigs with hallmarks of HCM including myocyte disarray, malformed nuclei, and MYH7 overexpression, with a shift in α/β-MyHC ratio in the left ventricle contributing to heart failure.\",\n      \"method\": \"TALEN-mediated knock-in in porcine fibroblasts, somatic cell nuclear transfer cloning, histopathology, qPCR for MyHC isoform ratio\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — germline knock-in large animal model with defined HCM pathology confirmed by histology and molecular profiling\",\n      \"pmids\": [\"29555974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The R723G MYH7 mutation alters mRNA secondary structure as detected by SHAPE analysis, providing experimental evidence that the point mutation changes mRNA folding which may contribute to allelic imbalance (elevated mutant allele mRNA) observed in HCM patients.\",\n      \"method\": \"SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) analysis of wild-type vs. R723G MYH7 RNA\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 in vitro RNA structure probing, single lab, single method\",\n      \"pmids\": [\"31790337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYH7 allelic imbalance (unequal expression of mutant vs. wild-type allele) occurs both in HCM patients and in non-HCM donors, indicating that intrinsic MYH7 expression regulation—independent of mutation—contributes to allelic imbalance; this is detected at both mRNA and protein levels.\",\n      \"method\": \"Allele-specific qPCR and protein quantification in cardiac tissue from HCM patients and non-HCM donors\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mRNA and protein quantification across patient and donor tissue showing intrinsic allelic regulation\",\n      \"pmids\": [\"29101517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYH7 R453C mutation activates TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB signaling pathways in transgenic pigs, causing cardiac hypertrophy with fibrosis and cardiomyocyte loss distinct from MYH6 R453C, establishing pathway-specific cardiac remodeling mechanisms downstream of the MYH7 mutation.\",\n      \"method\": \"Transgenic pig model (MYH7 R453C vs. MYH6 R453C), RNA-seq, Western blotting for pathway proteins, ROS measurement, H9C2 cell model with mutation\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic large animal model with RNA-seq and pathway-level protein analysis; comparative MYH6 vs MYH7 design adds specificity\",\n      \"pmids\": [\"38862020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9-mediated MYH7 knockout in zebrafish causes impaired cardiovascular development, and a novel missense variant (Leu655Met) in the actin-binding domain of MYH7 is predicted to reduce actin-myosin binding energy, supporting a role for MYH7 in ventricular wall morphogenesis through actin interaction.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish; in silico molecular docking for actin-binding energy; whole-exome sequencing in human LVNC family\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — zebrafish KO phenotype without rescue; actin-binding mechanism is computational prediction only\",\n      \"pmids\": [\"35463789\"],\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, and is tightly linked to the α-MHC gene (MYH6) on this chromosome.\",\n      \"method\": \"In situ hybridization with ³H-labeled probe derived from β-MHC genomic clone\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cytogenetic localization by in situ hybridization\",\n      \"pmids\": [\"2249479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The miR-143-3p–Sox6–Myh7 pathway regulates Myh7 expression in obesity-induced cardiac hypertrophy: miR-143-3p targets Sox6 (a transcriptional repressor of Myh7), and inhibition of miR-143-3p in cardiomyocytes increases Sox6 mRNA and reduces Myh7 expression, preventing angiotensin II-induced cardiomyocyte hypertrophy.\",\n      \"method\": \"Loss-of-function experiments with miR-143-3p inhibitor in cardiomyocytes; qPCR for Sox6 and Myh7; obese mouse model with cardiac hypertrophy\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional inhibitor experiment in cardiomyocytes with defined upstream regulator of Myh7 transcription\",\n      \"pmids\": [\"35765992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Epigenetic modifications at the Myh7 promoter underlie pressure overload-induced upregulation: TAC-induced heart failure is accompanied by distinct histone H3 methylation marks (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and changes in DNA methylation machinery (DNMT1, DNMT3b, MeCP2) at the Myh7 promoter, opposite to those at the Atp2a2 (SERCA-2A) promoter.\",\n      \"method\": \"ChIP assay for histone modifications at Myh7 and Atp2a2 promoters in TAC mouse hearts; qPCR for mRNA levels; assessment of KDM2A and DNMT recruitment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chromatin immunoprecipitation with multiple histone marks and methylation machinery components at defined promoter regions\",\n      \"pmids\": [\"25181347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYH7 E848G mutation in hiPSC-CMs increases cardiomyocyte size, reduces maximum engineered heart tissue twitch forces, and increases apoptosis associated with elevated p53 activity; however, genetic ablation of TP53 did not rescue contractile dysfunction or survival, indicating the apoptosis and contractile defect are p53-independent downstream consequences of the mutation.\",\n      \"method\": \"Isogenic hiPSC-CM model (MYH7 E848G/+), engineered heart tissue force measurements, single-cell size quantification, apoptosis assays, TP53 genetic knockout\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isogenic genome-edited human cell model with orthogonal functional readouts and pathway interrogation by genetic ablation\",\n      \"pmids\": [\"36902340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Deep mutational scanning of 113 MYH7 codon variants in hiPSC-CMs showed that pathogenic MYH7 missense variants cause reduced β-MHC protein abundance (confirmed in human HCM heart tissue) and decreased cardiomyocyte survival, providing multiplexed functional evidence that protein instability/loss is a shared mechanism for pathogenic MYH7 variants.\",\n      \"method\": \"CRISPRa-based hiPSC library generation, hiPSC-CM differentiation, massively parallel sequencing for β-MHC variant abundance, cell survival assay; validation in human HCM heart tissue\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genome-scale functional assay in disease-relevant human cells with orthogonal validation in patient tissue; multiple variants tested systematically\",\n      \"pmids\": [\"38362799\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYH7 encodes the β-myosin heavy chain (β-MHC), the primary motor protein of cardiac ventricles and slow-twitch skeletal muscle; pathogenic mutations in the globular S1 head domain cause hypercontractility (e.g., G256E reduces super-relaxed state) or hypocontractility/force loss (e.g., R403Q increases cross-bridge detachment and energy cost; other head mutations reduce sarcomere force generation), while rod/tail domain mutations disrupt coiled-coil assembly and cause myosin aggregation in skeletal muscle; the fraction of mutant protein and allelic imbalance (regulated in part by mRNA secondary structure and intrinsic transcriptional mechanisms) modulates disease severity; downstream signaling through mTOR, MAPK, TGF-β/Smad2/3, and Nox4/ROS/NF-κB pathways mediates cardiac remodeling, and Myh7 expression is post-transcriptionally controlled by YTHDF2-m6A-dependent mRNA decay and transcriptionally regulated via the miR-143-3p–Sox6 axis and epigenetic histone modifications at its promoter.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYH7 encodes the β-myosin heavy chain (β-MHC), the principal sarcomeric motor protein of cardiac ventricles and slow-twitch skeletal muscle, whose mutations are a major cause of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, Laing distal myopathy, and myosin storage myopathy [PMID:23674513, PMID:15322983, PMID:14520662]. Pathogenic mutations in the globular S1 head domain alter cross-bridge kinetics and force generation—either reducing intrinsic sarcomere force or destabilizing the super-relaxed (folded-back) state to produce hypercontractility with increased energy cost—while rod/tail-domain mutations disrupt coiled-coil structure and myosin thick-filament assembly, leading to protein aggregation in skeletal muscle fibers [PMID:24928957, PMID:38683993, PMID:31130376, PMID:27519903]. Deep mutational scanning reveals that pathogenic missense variants broadly reduce β-MHC protein abundance and cardiomyocyte survival, and downstream remodeling is mediated through TGF-β/Smad2/3, ERK1/2, mTOR, MAPK, and Nox4/ROS/NF-κB signaling pathways [PMID:38362799, PMID:38862020, PMID:34935644]. MYH7 expression is regulated transcriptionally by epigenetic histone modifications at its promoter and by the miR-143-3p–Sox6 axis, and post-transcriptionally by YTHDF2-mediated m6A-dependent mRNA decay, with allelic imbalance modulated in part by mutation-induced changes in mRNA secondary structure [PMID:25181347, PMID:35765992, PMID:34266473, PMID:31790337, PMID:29101517].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing the chromosomal location of MYH7 at 14q12 linked to MYH6 resolved where the β-MHC gene resides and enabled subsequent mutation mapping.\",\n      \"evidence\": \"In situ hybridization with ³H-labeled β-MHC genomic probe on human chromosomes\",\n      \"pmids\": [\"2249479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical linkage distance and regulatory relationship between MYH7 and MYH6 loci not defined\", \"No functional consequence of locus organization addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification that a rod-domain mutation (R1845W) causes myosin storage myopathy with subsarcolemmal myosin inclusions established that the MYH7 rod region is essential for thick-filament assembly in slow-twitch skeletal muscle.\",\n      \"evidence\": \"Muscle biopsy with immunohistochemistry, electron microscopy, and genetic sequencing in affected patients\",\n      \"pmids\": [\"14520662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Assembly defect inferred from pathology rather than biochemically reconstituted\", \"No in vitro filament assembly assay performed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping of Laing distal myopathy mutations to the coiled-coil rod/tail domain (exons 32–36) demonstrated that disruption of coiled-coil structure underlies a distinct skeletal myopathy mechanism separable from head-domain cardiomyopathy mutations.\",\n      \"evidence\": \"Genetic sequencing in six families with in silico coiled-coil disruption prediction\",\n      \"pmids\": [\"15322983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Coiled-coil disruption was computationally predicted, not biochemically validated\", \"Mechanism of selective distal muscle vulnerability not explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Direct force measurements on patient cardiomyocytes and myofibrils showed that MYH7 head-domain mutations reduce intrinsic sarcomere force generation, answering whether the primary defect is mechanical rather than purely signaling-based.\",\n      \"evidence\": \"Single membrane-permeabilized cardiomyocyte and single myofibril force measurements from human HCM cardiac tissue\",\n      \"pmids\": [\"23674513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Multiple different head-domain mutations were grouped; variant-specific mechanisms not deconvolved\", \"Whether force deficit is dominant-negative or haploinsufficient not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The R403Q mutation was shown to increase cross-bridge detachment kinetics and energetic cost of tension, establishing that specific head mutations produce energetic inefficiency—not just force loss—linking MYH7 dysfunction to metabolic stress in HCM.\",\n      \"evidence\": \"Single myofibril mechanics and ATPase-based tension cost measurements in human R403Q cardiac tissue versus mutation-negative HCM\",\n      \"pmids\": [\"24928957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether energetic inefficiency is a universal feature of all head-domain mutations or specific to R403Q not tested\", \"In vivo metabolic consequences not measured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Epigenetic characterization of the Myh7 promoter revealed that specific histone marks (H3K4me2, H3K9me2, H3K27me3, H3K36me2) and DNA methylation machinery changes accompany pathological Myh7 upregulation, establishing a chromatin-level regulatory mechanism for the α-to-β MHC isoform switch in heart failure.\",\n      \"evidence\": \"ChIP for histone modifications and methylation machinery at Myh7 promoter in TAC mouse hearts\",\n      \"pmids\": [\"25181347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of individual histone marks not tested by perturbation\", \"Whether these marks are MYH7-specific or part of a broader hypertrophic gene program not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Cell-based reconstitution of rod-domain proline substitutions (A1437P, R1434P) demonstrated that myosin self-assembly and sarcomere incorporation are dissociable, refining the understanding of how rod mutations cause disease without preventing all filament integration.\",\n      \"evidence\": \"Fluorescent β-myosin constructs expressed in non-muscle cells with imaging of assembly versus sarcomeric incorporation\",\n      \"pmids\": [\"27519903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-muscle cell system may not recapitulate sarcomere-level assembly fidelity\", \"No force or contractile consequence measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Detection of MYH7 allelic imbalance in both HCM patients and non-HCM donors revealed that intrinsic regulatory mechanisms—independent of mutation identity—govern unequal allelic expression, establishing allelic dosage as a disease-modifying variable.\",\n      \"evidence\": \"Allele-specific qPCR and protein quantification in human cardiac tissue from patients and donors\",\n      \"pmids\": [\"29101517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of intrinsic allelic imbalance not identified\", \"Whether allelic imbalance is heritable or stochastic not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A porcine R723G knock-in model and an isogenic hiPSC-CM E848G model independently confirmed that specific MYH7 point mutations are sufficient to produce HCM hallmarks (disarray, hypertrophy, altered MHC isoform ratio, reduced contractility), validating genotype-phenotype causality in large-animal and human-cell systems.\",\n      \"evidence\": \"TALEN-mediated porcine knock-in with histopathology; genome-edited hiPSC-CM engineered heart tissue force measurements\",\n      \"pmids\": [\"29555974\", \"30623132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E848G–cMyBP-C interaction mechanism inferred but not directly biochemically validated\", \"Long-term progression in porcine model limited by neonatal lethality of clones\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SHAPE analysis of R723G mRNA demonstrated that a single missense mutation alters MYH7 mRNA secondary structure, providing a molecular basis for mutation-specific allelic imbalance through post-transcriptional RNA-structural effects.\",\n      \"evidence\": \"SHAPE RNA structure probing of wild-type versus R723G MYH7 mRNA in vitro\",\n      \"pmids\": [\"31790337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional link between altered mRNA structure and differential mRNA stability/translation not experimentally demonstrated\", \"Single mutation tested; generalizability unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of YTHDF2 as a direct m6A-dependent regulator of Myh7 mRNA decay established the first post-transcriptional pathway controlling β-MHC levels and linked epitranscriptomic regulation to cardiac hypertrophy.\",\n      \"evidence\": \"RIP-MS, domain-deletion, and siRNA knockdown experiments in primary cardiomyocytes and TAC mouse model\",\n      \"pmids\": [\"34266473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on Myh7 mRNA not mapped\", \"Whether YTHDF2-mediated decay is sufficient to modulate allelic imbalance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic epistasis in zebrafish showed that loss of MYH7 ortholog function activates mTOR and MAPK signaling as downstream mediators of cardiomyopathy, with pathway-specific rescue of distinct cellular phenotypes (nuclear size vs. cell shape), deconvolving signaling consequences of MYH7 loss.\",\n      \"evidence\": \"CRISPR/Cas9 zebrafish mutants with pharmacological and MMEJ-based genetic epistasis screens\",\n      \"pmids\": [\"34935644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Zebrafish-to-mammalian translatability of pathway hierarchy not confirmed\", \"Upstream sensor linking sarcomere dysfunction to mTOR/MAPK activation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The miR-143-3p–Sox6 axis was identified as a transcriptional regulatory circuit controlling Myh7 expression in cardiomyocytes, connecting obesity-associated microRNA dysregulation to pathological MHC isoform switching.\",\n      \"evidence\": \"miR-143-3p inhibitor in cardiomyocytes with qPCR for Sox6 and Myh7; obese mouse cardiac hypertrophy model\",\n      \"pmids\": [\"35765992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Sox6 binding to Myh7 promoter not demonstrated by ChIP in this study\", \"Whether miR-143-3p regulation is cardiac-specific or also operates in skeletal muscle not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genetic ablation of TP53 failed to rescue contractile dysfunction or survival in MYH7 E848G hiPSC-CMs despite elevated p53 activity, establishing that the apoptotic and contractile phenotypes are p53-independent consequences of the mutation.\",\n      \"evidence\": \"Isogenic hiPSC-CM MYH7 E848G model with TP53 knockout, engineered heart tissue force and apoptosis assays\",\n      \"pmids\": [\"36902340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alternative cell-death pathways mediating apoptosis not identified\", \"Whether p53-independent mechanism generalizes to other MYH7 variants unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multi-scale analysis of G256E established the super-relaxed state as a quantitative regulator of contractile output, showing that disruption of the myosin folded-back conformation increases available cross-bridges and causes hypercontractility with compensatory mitochondrial upregulation—a gain-of-function mechanism distinct from the force-loss seen with other head mutations.\",\n      \"evidence\": \"Biochemical super-relaxed state assay, myofibril mechanics, traction force microscopy, engineered heart tissues, and single-cell transcriptomics in gene-edited hiPSC-CMs\",\n      \"pmids\": [\"38683993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mavacamten or other myosin inhibitors fully restore super-relaxed fraction in G256E not tested in this study\", \"Long-term in vivo consequences of hypercontractile mechanism not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Deep mutational scanning across 113 codon positions revealed that reduced β-MHC protein abundance and impaired cell survival are shared features of pathogenic MYH7 missense variants, suggesting protein instability as a convergent pathomechanism beyond allele-specific kinetic changes.\",\n      \"evidence\": \"CRISPRa-based hiPSC-CM library with massively parallel variant abundance sequencing; validation in human HCM tissue\",\n      \"pmids\": [\"38362799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether protein instability reflects folding defects versus enhanced degradation not mechanistically resolved\", \"Functional consequences (force, kinetics) not measured for most variants in this screen\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Transgenic pig MYH7 R453C model identified TGF-β/Smad2/3, ERK1/2, and Nox4/ROS/NF-κB as mutation-specific downstream remodeling pathways, distinguishing MYH7 signaling from MYH6 and providing therapeutic targets.\",\n      \"evidence\": \"Transgenic pig (MYH7 vs. MYH6 R453C), RNA-seq, Western blotting, ROS measurement, H9C2 cell model\",\n      \"pmids\": [\"38862020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway activation causality versus correlation not fully disentangled\", \"Whether pathway specificity is mutation-position or isoform-dependent not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how sarcomere mechanical dysfunction is sensed and transduced to activate mTOR/MAPK/TGF-β pathways; whether protein instability versus altered kinetics is the dominant pathomechanism across the full MYH7 variant spectrum; and what determines the tissue-specific vulnerability (cardiac versus skeletal) of different domain mutations.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mechanosensor linking sarcomere dysfunction to signaling cascades has been identified\", \"Structural basis for domain-specific disease presentation (head = cardiac, rod/tail = skeletal) remains unexplained\", \"Therapeutic thresholds for allelic balance correction are unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2, 5, 19]}\n    ],\n    \"complexes\": [\n      \"thick filament (sarcomere)\"\n    ],\n    \"partners\": [\n      \"MYBPC3\",\n      \"MYH6\",\n      \"YTHDF2\",\n      \"SOX6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}