{"gene":"ACTA1","run_date":"2026-06-09T22:02:39","timeline":{"discoveries":[{"year":2004,"finding":"Mutant ACTA1 proteins (e.g., V163L, V163M, R183G) show abnormal folding, altered polymerization capacity, and aggregation when expressed in C2C12 myoblasts; mutant actin isoforms were detected in insoluble actin filaments from patient muscle, providing direct evidence for a dominant-negative mechanism where mutant actin disrupts normal filament assembly.","method":"Transfection of C2C12 myoblasts with mutant actin-EGFP constructs, isoelectric focusing of patient muscle actin, fractionation into soluble/insoluble pools","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell transfection, patient muscle isoelectric focusing, fractionation) in a single study with direct functional readouts","pmids":["15198992"],"is_preprint":false},{"year":2005,"finding":"Alpha-cardiac actin is the predominant sarcomeric isoform in human donor hearts and early fetal skeletal muscle, while alpha-skeletal actin (ACTA1) becomes the exclusive isoform in skeletal muscle from infancy through adulthood; this differential expression was established by direct protein quantification and explains the absence of cardiac involvement in ACTA1 nemaline myopathy.","method":"Quantitative protein expression analysis (immunoblot/2D gel) of human heart and skeletal muscle samples across developmental stages","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein quantification across developmental stages, single lab but clear functional implication","pmids":["16288873"],"is_preprint":false},{"year":2006,"finding":"The ACTA1 K336E mutation reduces the sliding speed of actin in an in vitro motility assay by ~13% and reduces the affinity of actin for the Z-line protein alpha-actinin by 10-fold, establishing a specific functional defect in sarcomere protein interactions.","method":"In vitro motility assay on actin isolated from patient muscle biopsy; binding affinity measurement for alpha-actinin","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro motility assay and binding assay, but single lab and single patient sample","pmids":["16945537"],"is_preprint":false},{"year":2007,"finding":"ACTA1 CFTD mutations D292V and P332S cause muscle weakness through disruption of sarcomere function rather than structure: D292V abnormally stabilizes tropomyosin in the 'switched-off' position (as shown by in vitro motility), while both mutations are associated with normal sarcomeric ultrastructure, distinguishing them mechanistically from nemaline myopathy mutations.","method":"In vitro motility assay, mass spectrometry, 2D gel electrophoresis of patient muscle, electron microscopy, C2C12 expression models","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including in vitro motility, mass spectrometry, structural analysis; single lab but rigorous","pmids":["17387733"],"is_preprint":false},{"year":2011,"finding":"In transgenic mice expressing ACTA1 D286G, skeletal muscles contain ~25% mutant protein and are significantly weaker; when mutant protein load is increased to ~50% (by crossing with Acta1+/- knockouts), mice develop severe nemaline bodies, actin accumulations, and widespread sarcomeric disarray with early lethality, establishing that mutant ACTA1 protein load directly determines disease severity.","method":"Transgenic mouse model generation, mass spectrometry quantification of mutant protein, in vitro muscle mechanics, histopathology","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse models with dose-response relationship between mutant protein load and severity, multiple orthogonal measurements","pmids":["21303860"],"is_preprint":false},{"year":2012,"finding":"The ACTA1 D286G mutation acts as a 'poison-protein' by modifying the actin-actin interface (as computed by molecular energy state calculations), preventing proper myosin cross-bridge binding in the strong-binding state, thereby reducing force-generating capacity in single permeabilized muscle fibers.","method":"Single permeabilized muscle fiber mechanics from transgenic mice, molecular energy state computation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single fiber mechanics combined with computational modeling, single lab","pmids":["23029319"],"is_preprint":false},{"year":2013,"finding":"Transgenic over-expression of cardiac alpha-actin in postnatal skeletal muscle of ACTA1(D286G).Acta1+/- mice reduced lethality before 30 days from ~59% to ~12%, demonstrating that cardiac alpha-actin can functionally substitute for mutant skeletal alpha-actin and that increasing the ratio of wild-type to mutant actin is therapeutic for dominant ACTA1 disease.","method":"Transgenic mouse crosses, survival analysis, histopathology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue experiment in mouse model with clear survival endpoint, replication across two mouse models","pmids":["23736297"],"is_preprint":false},{"year":2016,"finding":"The ACTA1 H40Y mutation severely disrupts the DNase I-binding-loop structure and actin filament organization, causes mutant actin monomers to form distinctive homopolymers with abnormally high stiffness, and prevents proper myosin binding, establishing the molecular basis of contractile dysfunction.","method":"Molecular dynamics simulation, biophysical assays (filament mechanics, DNase I binding), in vitro motility","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical assays plus computational modeling, single lab","pmids":["27112274"],"is_preprint":false},{"year":2022,"finding":"Severe ACTA1-related nemaline myopathy patients show abnormal localization of nuclear envelope proteins lamin A/C, Nesprin-1, and Nesprin-2, with enlarged perinuclear space on electron microscopy, indicating that skeletal muscle alpha-actin contributes to maintaining nuclear shape and LINC complex integrity.","method":"Immunofluorescence localization of nuclear lamina proteins, electron microscopy of patient muscle biopsies","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization in patient tissue with functional interpretation, replicated across multiple patients","pmids":["35810298"],"is_preprint":false},{"year":2006,"finding":"The Val163Met ACTA1 mutation (causing intranuclear rod myopathy) introduces substitution at a residue adjacent to the nuclear export signal of actin, providing a structural basis for intranuclear rod formation; this was supported by the finding in [15198992] that V163L and V163M mutant actin accumulates in the nucleus in C2C12 transfection models.","method":"Mutation identification by sequencing, structural modeling of actin nuclear export signal proximity","journal":"Neuromuscular disorders : NMD","confidence":"Low","confidence_rationale":"Tier 4 / Weak — structural modeling only, no direct experimental validation of nuclear export signal disruption","pmids":["16427282"],"is_preprint":false},{"year":2013,"finding":"In the ACTA1 H40Y mouse model, skeletal muscle shows reduced maximal force (-40% absolute, -25% specific), improved fatigue resistance (+40%), and increased energy cost of contraction as measured by 31P-MRS, indicating impaired cross-bridge cycling and potentially altered mitochondrial function or actomyosin interaction kinetics.","method":"In vivo force measurements, 31P magnetic resonance spectroscopy, MRI of muscle anatomy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple non-invasive quantitative measurements in mouse model, single lab","pmids":["23613869"],"is_preprint":false}],"current_model":"ACTA1-encoded skeletal muscle alpha-actin is the predominant thin-filament component in adult skeletal muscle that cooperates with myosin for force generation; disease-causing mutations act dominantly through a poison-protein mechanism in which mutant actin (at ~25–50% of total actin) disrupts the actin-actin interface, prevents proper myosin strong-binding, can stabilize tropomyosin in the off-state, and may impair nuclear shape via the LINC complex, with disease severity directly proportional to mutant protein load; cardiac alpha-actin can functionally substitute for mutant skeletal alpha-actin in vivo."},"narrative":{"mechanistic_narrative":"ACTA1 encodes skeletal muscle alpha-actin, the predominant thin-filament protein of adult skeletal muscle sarcomeres, where it polymerizes into filaments that interact with myosin to generate contractile force and with Z-line proteins such as alpha-actinin to organize the sarcomere [PMID:16945537, PMID:23029319]. Its expression is developmentally regulated: alpha-cardiac actin predominates in fetal skeletal muscle and the heart, while ACTA1 becomes the exclusive skeletal isoform from infancy onward, accounting for the muscle-restricted phenotype of ACTA1 disease [PMID:16288873]. Dominant disease-causing mutations act through a poison-protein mechanism rather than loss of function: mutant actin misfolds, polymerizes abnormally, and aggregates into insoluble filaments and nemaline/intranuclear rods [PMID:15198992], modifies the actin-actin interface to block strong myosin cross-bridge binding [PMID:23029319, PMID:27112274], and in some cases stabilizes tropomyosin in the switched-off state without disrupting sarcomere ultrastructure [PMID:17387733]. Disease severity tracks directly with mutant protein load, and raising the wild-type-to-mutant ratio—including by substituting cardiac alpha-actin—is therapeutic in mouse models [PMID:21303860, PMID:23736297]. Beyond contraction, ACTA1 deficiency is associated with mislocalization of nuclear envelope and LINC-complex proteins and abnormal nuclear shape in patient muscle [PMID:35810298].","teleology":[{"year":2004,"claim":"Established that ACTA1 missense mutations act dominant-negatively at the protein level rather than through haploinsufficiency, by showing mutant actin misfolds and is incorporated into insoluble filaments.","evidence":"Mutant actin-EGFP transfection of C2C12 myoblasts plus isoelectric focusing and solubility fractionation of patient muscle","pmids":["15198992"],"confidence":"High","gaps":["Did not quantify how mutant load relates to severity","Did not resolve which specific binding interfaces are disrupted"]},{"year":2005,"claim":"Explained the muscle-restricted, heart-sparing phenotype of ACTA1 disease by mapping the developmental switch from cardiac to skeletal alpha-actin isoforms.","evidence":"Quantitative protein expression analysis of human heart and skeletal muscle across developmental stages","pmids":["16288873"],"confidence":"Medium","gaps":["Single-lab quantification","Does not establish functional interchangeability of the isoforms"]},{"year":2006,"claim":"Defined a concrete biochemical lesion by showing a mutation slows actin motility and weakens binding to the Z-line protein alpha-actinin.","evidence":"In vitro motility assay and alpha-actinin binding affinity on actin from a single patient biopsy","pmids":["16945537"],"confidence":"Medium","gaps":["Single patient sample","Modest motility effect of unclear clinical weight"]},{"year":2006,"claim":"Offered a structural rationale for intranuclear rod myopathy by placing a recurrent mutated residue adjacent to actin's nuclear export signal.","evidence":"Mutation sequencing and structural modeling of NES proximity, linked to nuclear accumulation seen in C2C12 transfection","pmids":["16427282"],"confidence":"Low","gaps":["Modeling only, no direct test of NES disruption","No measurement of altered nuclear export kinetics"]},{"year":2007,"claim":"Distinguished a functional disease class from structural nemaline myopathy by showing some mutations weaken muscle by stabilizing tropomyosin off-state without sarcomere disorganization.","evidence":"In vitro motility, mass spectrometry, 2D gels, electron microscopy and C2C12 expression of CFTD mutants","pmids":["17387733"],"confidence":"High","gaps":["Mechanism of tropomyosin stabilization not resolved at atomic level","Genotype-phenotype generality across mutations untested"]},{"year":2011,"claim":"Demonstrated that mutant ACTA1 protein dose, not mere presence, determines severity, by titrating mutant load via crosses with Acta1 knockouts.","evidence":"Transgenic D286G mouse models, mass-spectrometry quantification, muscle mechanics and histopathology","pmids":["21303860"],"confidence":"High","gaps":["Does not pinpoint the molecular step disrupted by excess mutant actin","Single mutation tested"]},{"year":2012,"claim":"Provided a mechanistic basis for force loss by showing the mutation alters the actin-actin interface to prevent strong myosin binding.","evidence":"Single permeabilized fiber mechanics from transgenic mice with molecular energy-state computation","pmids":["23029319"],"confidence":"Medium","gaps":["Interface modification inferred computationally","Single lab and single mutation"]},{"year":2013,"claim":"Established a therapeutic principle by rescuing lethality through cardiac alpha-actin substitution, raising the wild-type-to-mutant ratio.","evidence":"Transgenic mouse crosses over-expressing cardiac alpha-actin with survival analysis and histopathology","pmids":["23736297"],"confidence":"High","gaps":["Functional substitution incomplete (residual lethality)","Translation to human therapy untested"]},{"year":2013,"claim":"Linked an ACTA1 mutation to altered cross-bridge cycling and energy cost in vivo, beyond static force deficits.","evidence":"In vivo force measurement, 31P-MRS and MRI in the H40Y mouse model","pmids":["23613869"],"confidence":"Medium","gaps":["Mitochondrial vs actomyosin origin of energy cost unresolved","Single mutation model"]},{"year":2016,"claim":"Resolved how a specific mutation corrupts filament biophysics by disrupting the DNase-I-binding loop and forming abnormally stiff homopolymers that block myosin binding.","evidence":"Molecular dynamics simulation with filament mechanics, DNase I binding and in vitro motility assays","pmids":["27112274"],"confidence":"Medium","gaps":["Computational structural claims need experimental structures","Generalizability to other mutations unknown"]},{"year":2022,"claim":"Extended ACTA1 function beyond contraction by linking deficiency to nuclear envelope/LINC-complex mislocalization and abnormal nuclear shape.","evidence":"Immunofluorescence of lamin A/C, Nesprin-1/2 and electron microscopy in patient muscle biopsies","pmids":["35810298"],"confidence":"Medium","gaps":["Correlative patient-tissue data, not mechanistic","Direct interaction between alpha-actin and LINC components not demonstrated"]},{"year":null,"claim":"How distinct mutation classes map onto the spectrum of clinical phenotypes, and whether the nuclear/LINC defect is a primary mechanism or downstream consequence, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking interface mutations to phenotype severity","Causal role of LINC disruption in pathology untested","No human therapeutic validation of ratio-shifting strategy"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,5,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,5,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[2,5,10]}],"complexes":["sarcomere thin filament"],"partners":["MYH","ACTN2","TPM","LMNA","SYNE1","SYNE2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P68133","full_name":"Actin, alpha skeletal muscle","aliases":["Alpha-actin-1"],"length_aa":377,"mass_kda":42.1,"function":"Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P68133/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTA1","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACTA1","total_profiled":1310},"omim":[{"mim_id":"620278","title":"CONGENITAL MYOPATHY 2C, SEVERE INFANTILE, AUTOSOMAL DOMINANT; CMYO2C","url":"https://www.omim.org/entry/620278"},{"mim_id":"620265","title":"CONGENITAL MYOPATHY 2B, SEVERE INFANTILE, AUTOSOMAL RECESSIVE; CMYO2B","url":"https://www.omim.org/entry/620265"},{"mim_id":"620093","title":"ACTIN MATURATION PROTEASE; ACTMAP","url":"https://www.omim.org/entry/620093"},{"mim_id":"619731","title":"ACTIN-RELATED PROTEIN 10; ACTR10","url":"https://www.omim.org/entry/619731"},{"mim_id":"618692","title":"VESTIGIAL-LIKE FAMILY MEMBER 4; VGLL4","url":"https://www.omim.org/entry/618692"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":123974.2}],"url":"https://www.proteinatlas.org/search/ACTA1"},"hgnc":{"alias_symbol":["NEM3"],"prev_symbol":["ACTA"]},"alphafold":{"accession":"P68133","domains":[{"cath_id":"3.30.420.40","chopping":"9-139_341-374","consensus_level":"medium","plddt":94.9742,"start":9,"end":374},{"cath_id":"3.30.420.40","chopping":"144-181_274-337","consensus_level":"medium","plddt":97.4592,"start":144,"end":337},{"cath_id":"3.90.640.10","chopping":"183-265","consensus_level":"high","plddt":96.7371,"start":183,"end":265}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P68133","model_url":"https://alphafold.ebi.ac.uk/files/AF-P68133-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P68133-F1-predicted_aligned_error_v6.png","plddt_mean":95.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTA1","jax_strain_url":"https://www.jax.org/strain/search?query=ACTA1"},"sequence":{"accession":"P68133","fasta_url":"https://rest.uniprot.org/uniprotkb/P68133.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P68133/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P68133"}},"corpus_meta":[{"pmid":"1739966","id":"PMC_1739966","title":"L. 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9725238","citation_count":20,"is_preprint":false},{"pmid":"10618167","id":"PMC_10618167","title":"Listeria monocytogenes ActA protein interacts with phosphatidylinositol 4,5-bisphosphate in vitro.","date":"2000","source":"Cell motility and the cytoskeleton","url":"https://pubmed.ncbi.nlm.nih.gov/10618167","citation_count":20,"is_preprint":false},{"pmid":"11207557","id":"PMC_11207557","title":"Stability of the Listeria monocytogenes ActA protein in mammalian cells is regulated by the N-end rule pathway.","date":"1999","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11207557","citation_count":20,"is_preprint":false},{"pmid":"20850316","id":"PMC_20850316","title":"A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance.","date":"2010","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/20850316","citation_count":20,"is_preprint":false},{"pmid":"35234473","id":"PMC_35234473","title":"Circular RNA ACTA1 Acts as a Sponge for miR-199a-5p and miR-433 to Regulate Bovine Myoblast Development through the MAP3K11/MAP2K7/JNK Pathway.","date":"2022","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35234473","citation_count":19,"is_preprint":false},{"pmid":"16411913","id":"PMC_16411913","title":"Detection and quantification of Listeria monocytogenes by 5'-nuclease polymerase chain reaction targeting the actA gene.","date":"2006","source":"Letters in applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16411913","citation_count":19,"is_preprint":false},{"pmid":"23860362","id":"PMC_23860362","title":"Warkmycin, a novel angucycline antibiotic produced by Streptomyces sp. Acta 2930*.","date":"2013","source":"The Journal of antibiotics","url":"https://pubmed.ncbi.nlm.nih.gov/23860362","citation_count":19,"is_preprint":false},{"pmid":"25182138","id":"PMC_25182138","title":"Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/25182138","citation_count":18,"is_preprint":false},{"pmid":"22219381","id":"PMC_22219381","title":"Choosing orientation: influence of cargo geometry and ActA polarization on actin comet tails.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22219381","citation_count":18,"is_preprint":false},{"pmid":"22642587","id":"PMC_22642587","title":"Langkolide, a 32-membered macrolactone antibiotic produced by Streptomyces sp. Acta 3062.","date":"2012","source":"Journal of natural products","url":"https://pubmed.ncbi.nlm.nih.gov/22642587","citation_count":18,"is_preprint":false},{"pmid":"27112274","id":"PMC_27112274","title":"Myopathy-inducing mutation H40Y in ACTA1 hampers actin filament structure and function.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/27112274","citation_count":17,"is_preprint":false},{"pmid":"32989108","id":"PMC_32989108","title":"Asymmetric muscle weakness due to ACTA1 mosaic mutations.","date":"2020","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32989108","citation_count":17,"is_preprint":false},{"pmid":"25747004","id":"PMC_25747004","title":"Zebra body myopathy is caused by a mutation in the skeletal muscle actin gene (ACTA1).","date":"2015","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/25747004","citation_count":17,"is_preprint":false},{"pmid":"23613869","id":"PMC_23613869","title":"Combined MRI and ³¹P-MRS investigations of the ACTA1(H40Y) mouse model of nemaline myopathy show impaired muscle function and altered energy metabolism.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23613869","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46111,"output_tokens":2922,"usd":0.091081,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9861,"output_tokens":3163,"usd":0.06419,"stage2_stop_reason":"end_turn"},"total_usd":0.155271,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to distinguish between:\n1. Papers about **Listeria monocytogenes ActA** (a bacterial virulence protein) - these are NOT the human ACTA1 gene\n2. Papers about **human ACTA1** (skeletal muscle alpha-actin, also known as NEM3/ACTA) - these ARE the target gene\n3. Papers about circRNA ACTA1 - EXCLUDE (non-protein locus product)\n4. Symbol collisions (Rhizobium actA, Nocardia ACTA, etc.) - EXCLUDE\n\nThe human ACTA1 gene encodes skeletal muscle alpha-actin. Papers [7], [8], [29], [31], [36], [37], [47], [48], [53], [54], [60], [61], [67], [78], [82], [83], [85], [90], [94], [97], [98], [99], [100] are about the human ACTA1 protein. Papers [1]-[6], [9]-[28], [30], [32]-[35], [38]-[46], [49]-[52], [55]-[56], [59], [62]-[66], [68]-[77], [79]-[81], [84], [87]-[89] are primarily about Listeria ActA (bacterial protein). Papers [41], [57], [58], [64], [91]-[96] are collisions or non-protein products - EXCLUDE.\n\nNow extracting mechanistic discoveries from human ACTA1 papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Mutant ACTA1 proteins (e.g., V163L, V163M, R183G) show abnormal folding, altered polymerization capacity, and aggregation when expressed in C2C12 myoblasts; mutant actin isoforms were detected in insoluble actin filaments from patient muscle, providing direct evidence for a dominant-negative mechanism where mutant actin disrupts normal filament assembly.\",\n      \"method\": \"Transfection of C2C12 myoblasts with mutant actin-EGFP constructs, isoelectric focusing of patient muscle actin, fractionation into soluble/insoluble pools\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell transfection, patient muscle isoelectric focusing, fractionation) in a single study with direct functional readouts\",\n      \"pmids\": [\"15198992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Alpha-cardiac actin is the predominant sarcomeric isoform in human donor hearts and early fetal skeletal muscle, while alpha-skeletal actin (ACTA1) becomes the exclusive isoform in skeletal muscle from infancy through adulthood; this differential expression was established by direct protein quantification and explains the absence of cardiac involvement in ACTA1 nemaline myopathy.\",\n      \"method\": \"Quantitative protein expression analysis (immunoblot/2D gel) of human heart and skeletal muscle samples across developmental stages\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein quantification across developmental stages, single lab but clear functional implication\",\n      \"pmids\": [\"16288873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The ACTA1 K336E mutation reduces the sliding speed of actin in an in vitro motility assay by ~13% and reduces the affinity of actin for the Z-line protein alpha-actinin by 10-fold, establishing a specific functional defect in sarcomere protein interactions.\",\n      \"method\": \"In vitro motility assay on actin isolated from patient muscle biopsy; binding affinity measurement for alpha-actinin\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro motility assay and binding assay, but single lab and single patient sample\",\n      \"pmids\": [\"16945537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ACTA1 CFTD mutations D292V and P332S cause muscle weakness through disruption of sarcomere function rather than structure: D292V abnormally stabilizes tropomyosin in the 'switched-off' position (as shown by in vitro motility), while both mutations are associated with normal sarcomeric ultrastructure, distinguishing them mechanistically from nemaline myopathy mutations.\",\n      \"method\": \"In vitro motility assay, mass spectrometry, 2D gel electrophoresis of patient muscle, electron microscopy, C2C12 expression models\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including in vitro motility, mass spectrometry, structural analysis; single lab but rigorous\",\n      \"pmids\": [\"17387733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In transgenic mice expressing ACTA1 D286G, skeletal muscles contain ~25% mutant protein and are significantly weaker; when mutant protein load is increased to ~50% (by crossing with Acta1+/- knockouts), mice develop severe nemaline bodies, actin accumulations, and widespread sarcomeric disarray with early lethality, establishing that mutant ACTA1 protein load directly determines disease severity.\",\n      \"method\": \"Transgenic mouse model generation, mass spectrometry quantification of mutant protein, in vitro muscle mechanics, histopathology\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse models with dose-response relationship between mutant protein load and severity, multiple orthogonal measurements\",\n      \"pmids\": [\"21303860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ACTA1 D286G mutation acts as a 'poison-protein' by modifying the actin-actin interface (as computed by molecular energy state calculations), preventing proper myosin cross-bridge binding in the strong-binding state, thereby reducing force-generating capacity in single permeabilized muscle fibers.\",\n      \"method\": \"Single permeabilized muscle fiber mechanics from transgenic mice, molecular energy state computation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single fiber mechanics combined with computational modeling, single lab\",\n      \"pmids\": [\"23029319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transgenic over-expression of cardiac alpha-actin in postnatal skeletal muscle of ACTA1(D286G).Acta1+/- mice reduced lethality before 30 days from ~59% to ~12%, demonstrating that cardiac alpha-actin can functionally substitute for mutant skeletal alpha-actin and that increasing the ratio of wild-type to mutant actin is therapeutic for dominant ACTA1 disease.\",\n      \"method\": \"Transgenic mouse crosses, survival analysis, histopathology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue experiment in mouse model with clear survival endpoint, replication across two mouse models\",\n      \"pmids\": [\"23736297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The ACTA1 H40Y mutation severely disrupts the DNase I-binding-loop structure and actin filament organization, causes mutant actin monomers to form distinctive homopolymers with abnormally high stiffness, and prevents proper myosin binding, establishing the molecular basis of contractile dysfunction.\",\n      \"method\": \"Molecular dynamics simulation, biophysical assays (filament mechanics, DNase I binding), in vitro motility\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical assays plus computational modeling, single lab\",\n      \"pmids\": [\"27112274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Severe ACTA1-related nemaline myopathy patients show abnormal localization of nuclear envelope proteins lamin A/C, Nesprin-1, and Nesprin-2, with enlarged perinuclear space on electron microscopy, indicating that skeletal muscle alpha-actin contributes to maintaining nuclear shape and LINC complex integrity.\",\n      \"method\": \"Immunofluorescence localization of nuclear lamina proteins, electron microscopy of patient muscle biopsies\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization in patient tissue with functional interpretation, replicated across multiple patients\",\n      \"pmids\": [\"35810298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Val163Met ACTA1 mutation (causing intranuclear rod myopathy) introduces substitution at a residue adjacent to the nuclear export signal of actin, providing a structural basis for intranuclear rod formation; this was supported by the finding in [15198992] that V163L and V163M mutant actin accumulates in the nucleus in C2C12 transfection models.\",\n      \"method\": \"Mutation identification by sequencing, structural modeling of actin nuclear export signal proximity\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — structural modeling only, no direct experimental validation of nuclear export signal disruption\",\n      \"pmids\": [\"16427282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the ACTA1 H40Y mouse model, skeletal muscle shows reduced maximal force (-40% absolute, -25% specific), improved fatigue resistance (+40%), and increased energy cost of contraction as measured by 31P-MRS, indicating impaired cross-bridge cycling and potentially altered mitochondrial function or actomyosin interaction kinetics.\",\n      \"method\": \"In vivo force measurements, 31P magnetic resonance spectroscopy, MRI of muscle anatomy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple non-invasive quantitative measurements in mouse model, single lab\",\n      \"pmids\": [\"23613869\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTA1-encoded skeletal muscle alpha-actin is the predominant thin-filament component in adult skeletal muscle that cooperates with myosin for force generation; disease-causing mutations act dominantly through a poison-protein mechanism in which mutant actin (at ~25–50% of total actin) disrupts the actin-actin interface, prevents proper myosin strong-binding, can stabilize tropomyosin in the off-state, and may impair nuclear shape via the LINC complex, with disease severity directly proportional to mutant protein load; cardiac alpha-actin can functionally substitute for mutant skeletal alpha-actin in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTA1 encodes skeletal muscle alpha-actin, the predominant thin-filament protein of adult skeletal muscle sarcomeres, where it polymerizes into filaments that interact with myosin to generate contractile force and with Z-line proteins such as alpha-actinin to organize the sarcomere [#2, #5]. Its expression is developmentally regulated: alpha-cardiac actin predominates in fetal skeletal muscle and the heart, while ACTA1 becomes the exclusive skeletal isoform from infancy onward, accounting for the muscle-restricted phenotype of ACTA1 disease [#1]. Dominant disease-causing mutations act through a poison-protein mechanism rather than loss of function: mutant actin misfolds, polymerizes abnormally, and aggregates into insoluble filaments and nemaline/intranuclear rods [#0], modifies the actin-actin interface to block strong myosin cross-bridge binding [#5, #7], and in some cases stabilizes tropomyosin in the switched-off state without disrupting sarcomere ultrastructure [#3]. Disease severity tracks directly with mutant protein load, and raising the wild-type-to-mutant ratio—including by substituting cardiac alpha-actin—is therapeutic in mouse models [#4, #6]. Beyond contraction, ACTA1 deficiency is associated with mislocalization of nuclear envelope and LINC-complex proteins and abnormal nuclear shape in patient muscle [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that ACTA1 missense mutations act dominant-negatively at the protein level rather than through haploinsufficiency, by showing mutant actin misfolds and is incorporated into insoluble filaments.\",\n      \"evidence\": \"Mutant actin-EGFP transfection of C2C12 myoblasts plus isoelectric focusing and solubility fractionation of patient muscle\",\n      \"pmids\": [\"15198992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify how mutant load relates to severity\", \"Did not resolve which specific binding interfaces are disrupted\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Explained the muscle-restricted, heart-sparing phenotype of ACTA1 disease by mapping the developmental switch from cardiac to skeletal alpha-actin isoforms.\",\n      \"evidence\": \"Quantitative protein expression analysis of human heart and skeletal muscle across developmental stages\",\n      \"pmids\": [\"16288873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab quantification\", \"Does not establish functional interchangeability of the isoforms\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a concrete biochemical lesion by showing a mutation slows actin motility and weakens binding to the Z-line protein alpha-actinin.\",\n      \"evidence\": \"In vitro motility assay and alpha-actinin binding affinity on actin from a single patient biopsy\",\n      \"pmids\": [\"16945537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient sample\", \"Modest motility effect of unclear clinical weight\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Offered a structural rationale for intranuclear rod myopathy by placing a recurrent mutated residue adjacent to actin's nuclear export signal.\",\n      \"evidence\": \"Mutation sequencing and structural modeling of NES proximity, linked to nuclear accumulation seen in C2C12 transfection\",\n      \"pmids\": [\"16427282\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Modeling only, no direct test of NES disruption\", \"No measurement of altered nuclear export kinetics\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Distinguished a functional disease class from structural nemaline myopathy by showing some mutations weaken muscle by stabilizing tropomyosin off-state without sarcomere disorganization.\",\n      \"evidence\": \"In vitro motility, mass spectrometry, 2D gels, electron microscopy and C2C12 expression of CFTD mutants\",\n      \"pmids\": [\"17387733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of tropomyosin stabilization not resolved at atomic level\", \"Genotype-phenotype generality across mutations untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that mutant ACTA1 protein dose, not mere presence, determines severity, by titrating mutant load via crosses with Acta1 knockouts.\",\n      \"evidence\": \"Transgenic D286G mouse models, mass-spectrometry quantification, muscle mechanics and histopathology\",\n      \"pmids\": [\"21303860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not pinpoint the molecular step disrupted by excess mutant actin\", \"Single mutation tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided a mechanistic basis for force loss by showing the mutation alters the actin-actin interface to prevent strong myosin binding.\",\n      \"evidence\": \"Single permeabilized fiber mechanics from transgenic mice with molecular energy-state computation\",\n      \"pmids\": [\"23029319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interface modification inferred computationally\", \"Single lab and single mutation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a therapeutic principle by rescuing lethality through cardiac alpha-actin substitution, raising the wild-type-to-mutant ratio.\",\n      \"evidence\": \"Transgenic mouse crosses over-expressing cardiac alpha-actin with survival analysis and histopathology\",\n      \"pmids\": [\"23736297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional substitution incomplete (residual lethality)\", \"Translation to human therapy untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked an ACTA1 mutation to altered cross-bridge cycling and energy cost in vivo, beyond static force deficits.\",\n      \"evidence\": \"In vivo force measurement, 31P-MRS and MRI in the H40Y mouse model\",\n      \"pmids\": [\"23613869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial vs actomyosin origin of energy cost unresolved\", \"Single mutation model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how a specific mutation corrupts filament biophysics by disrupting the DNase-I-binding loop and forming abnormally stiff homopolymers that block myosin binding.\",\n      \"evidence\": \"Molecular dynamics simulation with filament mechanics, DNase I binding and in vitro motility assays\",\n      \"pmids\": [\"27112274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Computational structural claims need experimental structures\", \"Generalizability to other mutations unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended ACTA1 function beyond contraction by linking deficiency to nuclear envelope/LINC-complex mislocalization and abnormal nuclear shape.\",\n      \"evidence\": \"Immunofluorescence of lamin A/C, Nesprin-1/2 and electron microscopy in patient muscle biopsies\",\n      \"pmids\": [\"35810298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative patient-tissue data, not mechanistic\", \"Direct interaction between alpha-actin and LINC components not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct mutation classes map onto the spectrum of clinical phenotypes, and whether the nuclear/LINC defect is a primary mechanism or downstream consequence, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking interface mutations to phenotype severity\", \"Causal role of LINC disruption in pathology untested\", \"No human therapeutic validation of ratio-shifting strategy\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 5, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [2, 5, 10]}\n    ],\n    \"complexes\": [\"sarcomere thin filament\"],\n    \"partners\": [\"MYH\", \"ACTN2\", \"TPM\", \"LMNA\", \"SYNE1\", \"SYNE2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}