{"gene":"ACTG1","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2003,"finding":"Missense mutations in ACTG1 (gamma-actin) cause autosomal dominant progressive sensorineural hearing loss (DFNA20/26); mutations are located in highly conserved actin domains including bundling, gelation, polymerization, and myosin movement binding domains, predicted to interfere with these functions.","method":"Sequencing of ACTG1 in affected families; molecular domain mapping","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple families with co-segregating mutations, domain-level functional prediction, but in vitro functional validation not performed in this paper","pmids":["13680526"],"is_preprint":false},{"year":2003,"finding":"A Thr278Ile mutation in ACTG1 identified in a DFNA20/26 family; molecular modelling predicts the mutation impairs actin polymerisation due to proximity to Met313 in helix 11 of the modelled protein structure.","method":"Linkage analysis, ACTG1 sequencing, molecular modelling of protein structure","journal":"Journal of medical genetics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — molecular modelling only, no in vitro functional validation reported in this paper","pmids":["14684684"],"is_preprint":false},{"year":2006,"finding":"Six DFNA20/26 point mutations engineered into yeast actin cause: growth defects, mitochondrial morphology abnormalities, abnormal actin cable/patch distribution, vacuole morphology abnormalities; two purified mutant actins show decreased thermal stability and increased nucleotide exchange rate (increased protein flexibility); V370A actin polymerizes abnormally (aggregates in low ionic strength, faster polymerization with enhanced nucleation); no dominant negative effect of mutant actin observed in mixtures.","method":"Yeast genetics (sole actin expression), in vitro actin biochemistry (thermal stability, nucleotide exchange, polymerization assays), fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with purified proteins plus in vivo yeast genetics with multiple orthogonal readouts in a single rigorous study","pmids":["16690605"],"is_preprint":false},{"year":2006,"finding":"A novel V370A ACTG1 mutation in a Norwegian DFNA20/26 family; functional analysis in yeast shows p.V370A restricts cell growth at elevated temperature or under hyperosmolar stress; molecular modelling suggests the mutation modestly alters a site for protein-protein interaction in gamma-actin.","method":"Linkage analysis, ACTG1 sequencing, yeast functional assay, molecular modelling","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast functional assay provides in vivo evidence; molecular modelling supports but does not prove mechanism; single lab","pmids":["16773128"],"is_preprint":false},{"year":2009,"finding":"DFNA20/26 gamma-actin mutants K118N and E241K assessed in yeast and mammalian cells: K118N has mild effect on yeast behaviour; E241K causes severe phenotype including inability to grow on glycerol, aberrant multi-vacuolar pattern, and thick F-actin bundles; E241K mutant spontaneously forms bundles in vitro (neutralized by tropomyosin); E241K filament bundles are hypersensitive to cofilin severing; in NIH3T3 cells both mutants incorporate into cytoskeletal structures but also form cytoplasmic aggregates; expression in cochlear hair cells causes no gross alteration in cytoskeletal structures or stereocilia morphology.","method":"Yeast genetics, in vitro F-actin bundling assay, cofilin severing assay, NIH3T3 cell transfection, cochlear hair cell gene-gun expression, fluorescence microscopy","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro and in vivo methods (biochemical reconstitution, yeast genetics, mammalian cell biology) in a single rigorous study","pmids":["19477959"],"is_preprint":false},{"year":2009,"finding":"DFNA20/26 actin mutations T89I and V370A cause F-actin filaments to be much more susceptible to cofilin disassembly in vitro; P332A filaments show enhanced resistance to cofilin; K118M mutant does not affect cofilin-G-actin interaction; in vivo, elimination of cofilin-activating protein Aip1p rescues inability of K118M, T278I, P332A, and V370A mutants to grow on glycerol, suggesting filament instability caused by these mutations can be compensated by decreasing cofilin-driven filament turnover.","method":"In vitro F-actin cofilin disassembly assay, yeast genetic epistasis (Aip1p deletion rescue)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assays with purified proteins combined with yeast epistasis rescue experiments in a single rigorous study","pmids":["19419963"],"is_preprint":false},{"year":2010,"finding":"Actg1 null (Actg1-/-) mice are fully viable during embryonic development but most die within 48 h of birth due to respiratory failure; Actg1-/- mice exhibit stunted growth and delayed cardiac outflow tract formation; primary mouse embryonic fibroblasts lacking gamma-actin show growth impairment and reduced cell viability; gamma-actin is not required for cell migration in these cells; total actin protein level is maintained in Actg1-/- cells through compensatory expression.","method":"Actg1 knockout mouse generation, mouse embryonic fibroblast primary culture, cell growth/viability assay, cell migration assay, western blot","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with multiple cellular phenotypic readouts including migration (negative result), proliferation, and viability; replicated across embryo and cell levels","pmids":["20662086"],"is_preprint":false},{"year":2012,"finding":"De novo missense mutations in ACTG1 cause Baraitser-Winter syndrome, characterized by craniofacial features, ocular colobomata, and neuronal migration defect; two recurrent de novo ACTG1 mutations identified including p.Ser155Phe, confirming ACTG1 is required for neuronal migration during cortical development.","method":"Whole-exome sequencing of proband-parent trios, Sanger sequencing validation in additional affected individuals","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic evidence from multiple families with de novo mutations; no direct in vitro functional mechanistic experiments reported; replicated across 17+ individuals","pmids":["22366783"],"is_preprint":false},{"year":2012,"finding":"DFNA20/26 deafness mutations K118M and K118N in gamma-actin reduce actin + Arp2/3 polymerization rates in vitro; TIRF microscopy of K118M shows reduced number of branches per filament and altered branch location (majority near pointed end rather than barbed end), revealing a role for Lys-118 in the actin-Arp2/3 interaction.","method":"In vitro bulk polymerization assay with Arp2/3 complex, TIRF microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins plus single-molecule TIRF microscopy, two orthogonal methods in one study","pmids":["22718764"],"is_preprint":false},{"year":2013,"finding":"Loss of ASAP3 destabilizes ACTG1 protein and suppresses cancer cell migration/invasion; ASAP3 and ACTG1 are linked in regulation of cytoskeletal maintenance and cell motility.","method":"ASAP3 knockdown, ACTG1 protein level assessment, cell migration/invasion assay","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, limited mechanistic detail in abstract","pmids":["24284654"],"is_preprint":false},{"year":2013,"finding":"A novel alternatively-spliced ACTG1 transcript including exon 3a introduces an in-frame premature termination codon and is targeted for nonsense-mediated decay (NMD), providing a post-transcriptional mechanism to downregulate gamma-actin expression; this exon is predominantly expressed in skeletal muscle, cardiac muscle, and diaphragm and is upregulated during C2C12 cell differentiation; NMD inhibitor treatment causes 7-fold increase in exon 3a-containing transcripts.","method":"RT-PCR, tissue expression profiling in mice, C2C12 differentiation assay, NMD inhibitor treatment","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (conservation analysis, tissue specificity, differentiation model, NMD inhibitor); single lab","pmids":["24098136"],"is_preprint":false},{"year":2017,"finding":"A recurrent de novo ACTG1 mutation p.(Pro70Leu) causes isolated ocular coloboma; the mutant protein is incapable of incorporation into F-actin, demonstrating that this residue is required for actin polymerization.","method":"Whole-exome sequencing, F-actin incorporation assay for mutant protein","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (F-actin incorporation) performed on mutant protein; single lab, limited detail in abstract","pmids":["28493397"],"is_preprint":false},{"year":2019,"finding":"RRAD binds to ACTG1 and suppresses aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by downregulating ACTG1; ACTG1 promotes HCC cell proliferation by regulating the cell cycle and inhibits apoptosis through the mitochondrial apoptosis pathway in vitro; RRAD retards tumor growth by downregulating ACTG1 in vivo.","method":"Co-immunoprecipitation (RRAD-ACTG1 interaction), ACTG1 overexpression/knockdown, cell cycle analysis, apoptosis assay, glucose metabolism assay, xenograft in vivo model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional cellular assays with multiple readouts; single lab","pmids":["30881024"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9(D10A) knockout of ACTG1 in human melanoma cells (A375): gamma-actin loss increases bundled stress fiber formation but impairs lamellipodial activity; CR-ACTG1 cells show greater impairment of cell migration and invasion than CR-ACTB cells; absence of gamma-actin causes more severe alteration of focal adhesion (FA) formation and FA-dependent signaling than beta-actin loss; expression of the other isoform is upregulated to compensate.","method":"CRISPR/Cas9(D10A) gene editing, cell migration assay, invasion assay, focal adhesion staining, fluorescence microscopy, western blot","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR knockout with multiple orthogonal phenotypic readouts (migration, invasion, stress fibers, lamellipodia, focal adhesions); direct comparison to ACTB knockout in same system","pmids":["32326615"],"is_preprint":false},{"year":2020,"finding":"Several ACTG1 missense mutations (p.I34M, p.M82I, p.K118M, p.I165V) cause intracellular aggregate formation when expressed in NIH/3T3 fibroblasts, indicating inability to polymerize into F-actin; other mutants (p.R37H, p.G48R, p.E241K, p.H275Y) distribute similarly to wild-type.","method":"Transient transfection of mutant ACTG1 in NIH/3T3 cells, fluorescence microscopy for intracellular localization","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell biology localization assay; multiple mutants tested; single lab","pmids":["32341388"],"is_preprint":false},{"year":2021,"finding":"ACTG1 knockdown in human nucleus pulposus cells upregulates MMP3 and decreases collagen II; ACTG1 knockdown increases P-P65 (NF-κB) and suppresses P-Akt, indicating ACTG1 regulates IDD through the NF-κB-p65 and Akt signaling pathways.","method":"siRNA knockdown of ACTG1, western blot for pathway components, MMP3 and collagen II expression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single method (siRNA knockdown + western blot), single lab, pathway assignment based on protein level changes","pmids":["33545632"],"is_preprint":false},{"year":2021,"finding":"ACTG1 knockdown in prostate cancer cells inhibits proliferation, migration, and invasion; ERK protein expression is downregulated after ACTG1 knockdown; ERK1/2 inhibitor treatment decreases epithelial-mesenchymal transition marker expression, indicating ACTG1 influences PCa metastasis through the MAPK/ERK signaling pathway.","method":"ACTG1 siRNA knockdown, wound healing assay, CCK8 proliferation assay, Transwell invasion assay, western blot, ERK1/2 inhibitor treatment","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple functional readouts with pathway inhibitor validation; single lab","pmids":["34767732"],"is_preprint":false},{"year":2022,"finding":"Actg1 has both nucleotide-dependent and protein-dependent functions: bG/0 mice (gamma-actin protein expressed only from the Actb locus, no Actg1 locus) show survival defect and myopathy despite normal gamma-actin protein levels, demonstrating nucleotide-dependent (locus-specific) functions for Actg1; bG/0 genotype rescues Actg1-/- defects in cell proliferation and auditory function, implicating gamma-actin protein (not nucleotide sequence) in fibroblast growth and hearing.","method":"Mouse genetics (Actb/Actg1 cross to generate bG/0 line), survival analysis, auditory function testing, muscle histology, cell proliferation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — elegant genetic rescue experiment dissecting protein versus nucleotide functions with multiple orthogonal readouts (survival, auditory, myopathy, cell proliferation)","pmids":["35594181"],"is_preprint":false},{"year":2023,"finding":"Exosomal PGAM1 from prostate cancer cells binds to ACTG1 (gamma-actin) in human umbilical vein endothelial cells (HUVECs), promoting podosome formation and neovascular sprouting; PGAM1-ACTG1 interaction was demonstrated by GST pulldown and co-immunoprecipitation.","method":"GST pulldown, co-immunoprecipitation, western blot, gelatin degradation assay (invadopodia/podosome formation), in vivo xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays (GST pulldown + Co-IP) plus functional cellular assays; single lab","pmids":["37542027"],"is_preprint":false}],"current_model":"ACTG1 encodes cytoplasmic gamma-actin, a ubiquitous cytoskeletal protein whose functions include F-actin polymerization (regulated by interactions with Arp2/3 complex, cofilin, and tropomyosin), cell proliferation and survival (demonstrated in knockout mice and fibroblasts), focal adhesion formation and lamellipodial activity in cell migration (shown by CRISPR knockout in melanoma cells), neuronal migration during cortical development (demonstrated by disease-causing de novo mutations causing Baraitser-Winter syndrome), and auditory hair cell cytoskeletal maintenance (demonstrated by deafness-causing DFNA20/26 mutations that alter actin filament stability and regulatory protein interactions); the Actg1 locus also harbors nucleotide-sequence-dependent functions distinct from its encoded protein, revealed by genetic rescue experiments in mice."},"narrative":{"mechanistic_narrative":"ACTG1 encodes cytoplasmic gamma-actin, a ubiquitous cytoskeletal protein that polymerizes into F-actin to support cell proliferation, survival, and tissue morphogenesis [PMID:20662086, PMID:35594181]. Gamma-actin function depends on its incorporation into filaments and on regulated interactions with actin-binding machinery: it polymerizes through the Arp2/3 complex (with Lys-118 controlling branch number and position) [PMID:22718764], is bundled and stabilized by tropomyosin, and is severed by cofilin [PMID:19477959, PMID:19419963]. In cell migration, gamma-actin loss in melanoma cells increases bundled stress fibers but impairs lamellipodial activity, focal adhesion formation, and FA-dependent signaling more severely than beta-actin loss, with the other isoform upregulated to compensate [PMID:32326615]; consistent isoform compensation maintains total actin in Actg1-null cells, which nonetheless show impaired growth and viability [PMID:20662086]. Genetic dissection in mice distinguishes a protein-encoded role (fibroblast proliferation and auditory function) from nucleotide-sequence-dependent, locus-specific functions of the Actg1 locus required for survival and muscle integrity [PMID:35594181], and a regulatory alternative-splicing isoform (exon 3a) downregulates gamma-actin post-transcriptionally via nonsense-mediated decay, predominantly in muscle [PMID:24098136]. Dominant ACTG1 missense mutations cause autosomal dominant sensorineural hearing loss (DFNA20/26) by destabilizing filaments and altering cofilin and Arp2/3 regulation [PMID:16690605, PMID:19419963, PMID:22718764], while de novo missense mutations cause Baraitser-Winter syndrome with neuronal migration defects [PMID:22366783] and isolated ocular coloboma through loss of F-actin incorporation [PMID:28493397]. In cancer contexts, gamma-actin levels are controlled by binding partners including RRAD and exosomal PGAM1, linking ACTG1 to proliferation, the Warburg effect, and podosome-driven neovascularization [PMID:30881024, PMID:37542027].","teleology":[{"year":2003,"claim":"Established that ACTG1 is a human disease gene, linking gamma-actin to dominant progressive hearing loss and mapping the disease mutations onto functionally critical actin domains.","evidence":"Sequencing of affected DFNA20/26 families and molecular domain mapping","pmids":["13680526","14684684"],"confidence":"Medium","gaps":["No in vitro functional validation of mutant actin","Mechanism of cochlear pathology not addressed"]},{"year":2006,"claim":"Provided the first biochemical mechanism for DFNA20/26 mutations by showing they destabilize actin and perturb polymerization, while ruling out a simple dominant-negative model.","evidence":"Yeast genetics with mutant actins plus in vitro thermal stability, nucleotide exchange, and polymerization assays on purified protein","pmids":["16690605","16773128"],"confidence":"High","gaps":["Studied in yeast actin background rather than human gamma-actin","Did not resolve how instability translates to hair-cell loss"]},{"year":2009,"claim":"Connected mutant filament instability to specific regulatory interactions, showing deafness mutants are hypersensitive to cofilin severing and that reducing cofilin-driven turnover compensates.","evidence":"In vitro cofilin disassembly and bundling assays, tropomyosin neutralization, and yeast Aip1p-deletion epistasis rescue","pmids":["19477959","19419963"],"confidence":"High","gaps":["Hair-cell expression of E241K showed no gross stereocilia change, leaving in vivo relevance incomplete","Effect of cofilin modulation untested in mammalian hair cells"]},{"year":2010,"claim":"Defined the organismal and cellular requirement for gamma-actin protein, separating roles in survival and proliferation from migration.","evidence":"Actg1 knockout mice and primary MEF assays for growth, viability, and migration with western blot for compensation","pmids":["20662086"],"confidence":"High","gaps":["Negative migration result conflicts with later melanoma data, leaving cell-type dependence unresolved","Compensatory isoform identity not fully dissected"]},{"year":2012,"claim":"Extended the ACTG1 disease spectrum to a developmental disorder, implicating gamma-actin in neuronal migration during cortical development.","evidence":"Whole-exome trio sequencing identifying recurrent de novo mutations in Baraitser-Winter syndrome","pmids":["22366783"],"confidence":"Medium","gaps":["No direct functional assay of mutant protein","Mechanism of migration defect not established"]},{"year":2012,"claim":"Pinpointed a residue-level mechanism by showing Lys-118 governs the gamma-actin/Arp2/3 interaction controlling branch formation.","evidence":"In vitro Arp2/3 polymerization assays and TIRF single-molecule microscopy of K118 mutants","pmids":["22718764"],"confidence":"High","gaps":["Linkage between altered branching and hearing loss not demonstrated in vivo"]},{"year":2013,"claim":"Identified a post-transcriptional control circuit and an early cancer-relevant partner regulating gamma-actin abundance.","evidence":"RT-PCR/NMD-inhibitor analysis of an exon-3a splice isoform; ASAP3 knockdown with ACTG1 protein and motility readouts","pmids":["24098136","24284654"],"confidence":"Medium","gaps":["ASAP3 link is a single low-detail knockdown study without reciprocal validation","Functional consequence of exon-3a NMD regulation in vivo unknown"]},{"year":2017,"claim":"Showed a coloboma-causing mutation abolishes F-actin incorporation, directly tying a residue to polymerization competence and an ocular phenotype.","evidence":"Whole-exome sequencing plus F-actin incorporation assay of mutant protein","pmids":["28493397"],"confidence":"Medium","gaps":["Single-lab assay","Developmental basis of coloboma not modeled"]},{"year":2020,"claim":"Resolved the cell-type-specific migration role, demonstrating gamma-actin is more critical than beta-actin for lamellipodia and focal adhesion signaling in melanoma cells.","evidence":"CRISPR/Cas9(D10A) ACTG1 knockout in A375 with migration, invasion, stress-fiber, lamellipodia, and focal-adhesion readouts versus ACTB knockout; aggregation assays for many mutants in NIH/3T3","pmids":["32326615","32341388"],"confidence":"High","gaps":["Molecular basis of isoform-specific focal adhesion role unknown","Aggregation mutant screen does not define interaction partners affected"]},{"year":2021,"claim":"Implicated ACTG1 in proliferation and disease-relevant signaling axes (MAPK/ERK, NF-kB-p65, Akt) across prostate cancer and intervertebral disc degeneration.","evidence":"siRNA knockdown with functional motility/proliferation assays and pathway western blots, including ERK inhibitor validation","pmids":["34767732","33545632"],"confidence":"Medium","gaps":["Pathway links inferred from protein-level changes, not direct biochemistry","Whether effects are cytoskeletal or signaling-intrinsic unresolved"]},{"year":2022,"claim":"Separated protein-encoded from nucleotide-sequence-dependent functions of the Actg1 locus, showing protein drives proliferation and hearing while locus-specific sequence supports survival and muscle integrity.","evidence":"Mouse genetic rescue (bG/0 line) with survival, auditory, myopathy, and proliferation readouts","pmids":["35594181"],"confidence":"High","gaps":["Identity of the nucleotide-dependent function (e.g., regulatory element vs codon usage) not defined","Molecular basis of myopathy unresolved"]},{"year":2023,"claim":"Identified a physical partner mediating tumor-microenvironment cytoskeletal remodeling, with exosomal PGAM1 binding gamma-actin to drive podosome formation and angiogenesis.","evidence":"GST pulldown and co-immunoprecipitation plus gelatin degradation and xenograft assays","pmids":["37542027"],"confidence":"Medium","gaps":["Single-lab interaction data","Binding interface and structural basis undefined"]},{"year":null,"claim":"How gamma-actin's biochemical properties produce its tissue-specific essentiality (hearing, neuronal migration, muscle) and the molecular identity of the Actg1 locus nucleotide-dependent function remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking specific mutations to tissue-specific phenotypes","Nucleotide-dependent locus function not molecularly defined","Signaling pathway links largely correlative"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6,13,17]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,5,8]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,13,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,13]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,11,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,12,18]}],"complexes":[],"partners":["ARPC","CFL1","TPM1","RRAD","PGAM1","ASAP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P63261","full_name":"Actin, cytoplasmic 2","aliases":["Gamma-actin"],"length_aa":375,"mass_kda":41.8,"function":"Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells. May play a role in the repair of noise-induced stereocilia gaps thereby maintains hearing sensitivity following loud noise damage (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/P63261/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTG1","classification":"Common Essential","n_dependent_lines":1033,"n_total_lines":1208,"dependency_fraction":0.8551324503311258},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000184009","cell_line_id":"CID001175","localizations":[{"compartment":"cytoskeleton","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"PFN2","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":10.0},{"gene":"PFN1","stoichiometry":10.0},{"gene":"ENAH","stoichiometry":10.0},{"gene":"CAP1","stoichiometry":10.0},{"gene":"TWF2","stoichiometry":10.0},{"gene":"BAIAP2","stoichiometry":4.0},{"gene":"MRFAP1","stoichiometry":4.0},{"gene":"BAIAP2L1","stoichiometry":4.0},{"gene":"TWF1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001175","total_profiled":1310},"omim":[{"mim_id":"620475","title":"THROMBOCYTOPENIA 8, WITH DYSMORPHIC FEATURES AND DEVELOPMENTAL DELAY; THC8","url":"https://www.omim.org/entry/620475"},{"mim_id":"616594","title":"ARF GTPase-ACTIVATING PROTEIN WITH SH3 DOMAIN, ANKYRIN REPEAT, AND PH DOMAIN 3; ASAP3","url":"https://www.omim.org/entry/616594"},{"mim_id":"614583","title":"BARAITSER-WINTER SYNDROME 2; BRWS2","url":"https://www.omim.org/entry/614583"},{"mim_id":"612149","title":"RNA-BINDING FOX1 HOMOLOG 2; RBFOX2","url":"https://www.omim.org/entry/612149"},{"mim_id":"610311","title":"MEDIATOR COMPLEX SUBUNIT 28; MED28","url":"https://www.omim.org/entry/610311"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACTG1"},"hgnc":{"alias_symbol":[],"prev_symbol":["ACTG","DFNA20","DFNA26"]},"alphafold":{"accession":"P63261","domains":[{"cath_id":"3.30.420.40","chopping":"7-138_337-373","consensus_level":"medium","plddt":94.383,"start":7,"end":373},{"cath_id":"3.30.420.40","chopping":"142-179_273-334","consensus_level":"medium","plddt":97.4882,"start":142,"end":334},{"cath_id":"3.90.640.10","chopping":"181-260","consensus_level":"high","plddt":96.373,"start":181,"end":260}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P63261","model_url":"https://alphafold.ebi.ac.uk/files/AF-P63261-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P63261-F1-predicted_aligned_error_v6.png","plddt_mean":95.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTG1","jax_strain_url":"https://www.jax.org/strain/search?query=ACTG1"},"sequence":{"accession":"P63261","fasta_url":"https://rest.uniprot.org/uniprotkb/P63261.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P63261/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P63261"}},"corpus_meta":[{"pmid":"21606537","id":"PMC_21606537","title":"Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21606537","citation_count":415,"is_preprint":false},{"pmid":"18687253","id":"PMC_18687253","title":"Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s.","date":"2008","source":"Journal of the American College of Cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/18687253","citation_count":259,"is_preprint":false},{"pmid":"22366783","id":"PMC_22366783","title":"De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22366783","citation_count":234,"is_preprint":false},{"pmid":"9182469","id":"PMC_9182469","title":"Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team.","date":"1997","source":"Annals of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9182469","citation_count":219,"is_preprint":false},{"pmid":"13680526","id":"PMC_13680526","title":"Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26).","date":"2003","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/13680526","citation_count":163,"is_preprint":false},{"pmid":"8843206","id":"PMC_8843206","title":"Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection. AIDS Clinical Trials Group (ACTG) 116B/117 Study Team. 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HIV","url":"https://pubmed.ncbi.nlm.nih.gov/26424232","citation_count":18,"is_preprint":false},{"pmid":"32341388","id":"PMC_32341388","title":"Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32341388","citation_count":17,"is_preprint":false},{"pmid":"30668695","id":"PMC_30668695","title":"Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353.","date":"2019","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30668695","citation_count":17,"is_preprint":false},{"pmid":"35594181","id":"PMC_35594181","title":"Nucleotide- and Protein-Dependent Functions of Actg1.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35594181","citation_count":16,"is_preprint":false},{"pmid":"37276900","id":"PMC_37276900","title":"A novel trans-acting lncRNA of ACTG1 that induces the remodeling of ovarian follicles.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37276900","citation_count":16,"is_preprint":false},{"pmid":"19419963","id":"PMC_19419963","title":"Allele-specific effects of human deafness gamma-actin mutations (DFNA20/26) on the actin/cofilin interaction.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19419963","citation_count":16,"is_preprint":false},{"pmid":"24098136","id":"PMC_24098136","title":"A novel actin mRNA splice variant regulates ACTG1 expression.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24098136","citation_count":16,"is_preprint":false},{"pmid":"25694653","id":"PMC_25694653","title":"Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230.","date":"2015","source":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","url":"https://pubmed.ncbi.nlm.nih.gov/25694653","citation_count":16,"is_preprint":false},{"pmid":"31231230","id":"PMC_31231230","title":"Post-mortem Characterisation of a Case With an ACTG1 Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31231230","citation_count":15,"is_preprint":false},{"pmid":"17041858","id":"PMC_17041858","title":"A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086.","date":"2006","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17041858","citation_count":15,"is_preprint":false},{"pmid":"11527035","id":"PMC_11527035","title":"Audiologic aspects of the search for DFNA20: a gene causing late-onset, progressive, sensorineural hearing loss.","date":"2001","source":"Ear and hearing","url":"https://pubmed.ncbi.nlm.nih.gov/11527035","citation_count":14,"is_preprint":false},{"pmid":"15097300","id":"PMC_15097300","title":"Daily low-dose subcutaneous interleukin-2 added to single- or dual-nucleoside therapy in HIV infection does not protect against CD4+ T-cell decline or improve other indices of immune function: results of a randomized controlled clinical trial (ACTG 248).","date":"2004","source":"Journal of acquired immune deficiency syndromes (1999)","url":"https://pubmed.ncbi.nlm.nih.gov/15097300","citation_count":14,"is_preprint":false},{"pmid":"21121053","id":"PMC_21121053","title":"Use of biological knowledge to inform the analysis of gene-gene interactions involved in modulating virologic failure with efavirenz-containing treatment regimens in ART-naïve ACTG clinical trials participants.","date":"2011","source":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","url":"https://pubmed.ncbi.nlm.nih.gov/21121053","citation_count":14,"is_preprint":false},{"pmid":"29620237","id":"PMC_29620237","title":"A novel missense mutation in the ACTG1 gene in a family with congenital autosomal dominant deafness: A case report.","date":"2018","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/29620237","citation_count":13,"is_preprint":false},{"pmid":"25582793","id":"PMC_25582793","title":"Predictors and outcomes of Mycobacterium tuberculosis bacteremia among patients with HIV and tuberculosis co-infection enrolled in the ACTG A5221 STRIDE study.","date":"2015","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25582793","citation_count":13,"is_preprint":false},{"pmid":"20415638","id":"PMC_20415638","title":"Treatment with recombinant growth hormone is associated with modest improvement in CD4 lymphocyte reconstitution in HIV-infected persons on antiretroviral therapy: results of ACTG A5174.","date":"2010","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/20415638","citation_count":13,"is_preprint":false},{"pmid":"12519370","id":"PMC_12519370","title":"A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.","date":"2003","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12519370","citation_count":12,"is_preprint":false},{"pmid":"10933617","id":"PMC_10933617","title":"Virologic and CD4+ cell responses to new nucleoside regimens: switching to stavudine or adding lamivudine after prolonged zidovudine treatment of human immunodeficiency virus infection. ACTG 302 Study Team. AIDS Clinical Trials Group.","date":"2000","source":"AIDS research and human retroviruses","url":"https://pubmed.ncbi.nlm.nih.gov/10933617","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57755,"output_tokens":4831,"usd":0.122865,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13086,"output_tokens":3828,"usd":0.080565,"stage2_stop_reason":"end_turn"},"total_usd":0.20343,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutations in ACTG1 (gamma-actin) cause autosomal dominant progressive sensorineural hearing loss (DFNA20/26); mutations are located in highly conserved actin domains including bundling, gelation, polymerization, and myosin movement binding domains, predicted to interfere with these functions.\",\n      \"method\": \"Sequencing of ACTG1 in affected families; molecular domain mapping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple families with co-segregating mutations, domain-level functional prediction, but in vitro functional validation not performed in this paper\",\n      \"pmids\": [\"13680526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A Thr278Ile mutation in ACTG1 identified in a DFNA20/26 family; molecular modelling predicts the mutation impairs actin polymerisation due to proximity to Met313 in helix 11 of the modelled protein structure.\",\n      \"method\": \"Linkage analysis, ACTG1 sequencing, molecular modelling of protein structure\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — molecular modelling only, no in vitro functional validation reported in this paper\",\n      \"pmids\": [\"14684684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Six DFNA20/26 point mutations engineered into yeast actin cause: growth defects, mitochondrial morphology abnormalities, abnormal actin cable/patch distribution, vacuole morphology abnormalities; two purified mutant actins show decreased thermal stability and increased nucleotide exchange rate (increased protein flexibility); V370A actin polymerizes abnormally (aggregates in low ionic strength, faster polymerization with enhanced nucleation); no dominant negative effect of mutant actin observed in mixtures.\",\n      \"method\": \"Yeast genetics (sole actin expression), in vitro actin biochemistry (thermal stability, nucleotide exchange, polymerization assays), fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with purified proteins plus in vivo yeast genetics with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"16690605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A novel V370A ACTG1 mutation in a Norwegian DFNA20/26 family; functional analysis in yeast shows p.V370A restricts cell growth at elevated temperature or under hyperosmolar stress; molecular modelling suggests the mutation modestly alters a site for protein-protein interaction in gamma-actin.\",\n      \"method\": \"Linkage analysis, ACTG1 sequencing, yeast functional assay, molecular modelling\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast functional assay provides in vivo evidence; molecular modelling supports but does not prove mechanism; single lab\",\n      \"pmids\": [\"16773128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DFNA20/26 gamma-actin mutants K118N and E241K assessed in yeast and mammalian cells: K118N has mild effect on yeast behaviour; E241K causes severe phenotype including inability to grow on glycerol, aberrant multi-vacuolar pattern, and thick F-actin bundles; E241K mutant spontaneously forms bundles in vitro (neutralized by tropomyosin); E241K filament bundles are hypersensitive to cofilin severing; in NIH3T3 cells both mutants incorporate into cytoskeletal structures but also form cytoplasmic aggregates; expression in cochlear hair cells causes no gross alteration in cytoskeletal structures or stereocilia morphology.\",\n      \"method\": \"Yeast genetics, in vitro F-actin bundling assay, cofilin severing assay, NIH3T3 cell transfection, cochlear hair cell gene-gun expression, fluorescence microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro and in vivo methods (biochemical reconstitution, yeast genetics, mammalian cell biology) in a single rigorous study\",\n      \"pmids\": [\"19477959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DFNA20/26 actin mutations T89I and V370A cause F-actin filaments to be much more susceptible to cofilin disassembly in vitro; P332A filaments show enhanced resistance to cofilin; K118M mutant does not affect cofilin-G-actin interaction; in vivo, elimination of cofilin-activating protein Aip1p rescues inability of K118M, T278I, P332A, and V370A mutants to grow on glycerol, suggesting filament instability caused by these mutations can be compensated by decreasing cofilin-driven filament turnover.\",\n      \"method\": \"In vitro F-actin cofilin disassembly assay, yeast genetic epistasis (Aip1p deletion rescue)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assays with purified proteins combined with yeast epistasis rescue experiments in a single rigorous study\",\n      \"pmids\": [\"19419963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Actg1 null (Actg1-/-) mice are fully viable during embryonic development but most die within 48 h of birth due to respiratory failure; Actg1-/- mice exhibit stunted growth and delayed cardiac outflow tract formation; primary mouse embryonic fibroblasts lacking gamma-actin show growth impairment and reduced cell viability; gamma-actin is not required for cell migration in these cells; total actin protein level is maintained in Actg1-/- cells through compensatory expression.\",\n      \"method\": \"Actg1 knockout mouse generation, mouse embryonic fibroblast primary culture, cell growth/viability assay, cell migration assay, western blot\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with multiple cellular phenotypic readouts including migration (negative result), proliferation, and viability; replicated across embryo and cell levels\",\n      \"pmids\": [\"20662086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"De novo missense mutations in ACTG1 cause Baraitser-Winter syndrome, characterized by craniofacial features, ocular colobomata, and neuronal migration defect; two recurrent de novo ACTG1 mutations identified including p.Ser155Phe, confirming ACTG1 is required for neuronal migration during cortical development.\",\n      \"method\": \"Whole-exome sequencing of proband-parent trios, Sanger sequencing validation in additional affected individuals\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic evidence from multiple families with de novo mutations; no direct in vitro functional mechanistic experiments reported; replicated across 17+ individuals\",\n      \"pmids\": [\"22366783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DFNA20/26 deafness mutations K118M and K118N in gamma-actin reduce actin + Arp2/3 polymerization rates in vitro; TIRF microscopy of K118M shows reduced number of branches per filament and altered branch location (majority near pointed end rather than barbed end), revealing a role for Lys-118 in the actin-Arp2/3 interaction.\",\n      \"method\": \"In vitro bulk polymerization assay with Arp2/3 complex, TIRF microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins plus single-molecule TIRF microscopy, two orthogonal methods in one study\",\n      \"pmids\": [\"22718764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of ASAP3 destabilizes ACTG1 protein and suppresses cancer cell migration/invasion; ASAP3 and ACTG1 are linked in regulation of cytoskeletal maintenance and cell motility.\",\n      \"method\": \"ASAP3 knockdown, ACTG1 protein level assessment, cell migration/invasion assay\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, limited mechanistic detail in abstract\",\n      \"pmids\": [\"24284654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel alternatively-spliced ACTG1 transcript including exon 3a introduces an in-frame premature termination codon and is targeted for nonsense-mediated decay (NMD), providing a post-transcriptional mechanism to downregulate gamma-actin expression; this exon is predominantly expressed in skeletal muscle, cardiac muscle, and diaphragm and is upregulated during C2C12 cell differentiation; NMD inhibitor treatment causes 7-fold increase in exon 3a-containing transcripts.\",\n      \"method\": \"RT-PCR, tissue expression profiling in mice, C2C12 differentiation assay, NMD inhibitor treatment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (conservation analysis, tissue specificity, differentiation model, NMD inhibitor); single lab\",\n      \"pmids\": [\"24098136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A recurrent de novo ACTG1 mutation p.(Pro70Leu) causes isolated ocular coloboma; the mutant protein is incapable of incorporation into F-actin, demonstrating that this residue is required for actin polymerization.\",\n      \"method\": \"Whole-exome sequencing, F-actin incorporation assay for mutant protein\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (F-actin incorporation) performed on mutant protein; single lab, limited detail in abstract\",\n      \"pmids\": [\"28493397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RRAD binds to ACTG1 and suppresses aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by downregulating ACTG1; ACTG1 promotes HCC cell proliferation by regulating the cell cycle and inhibits apoptosis through the mitochondrial apoptosis pathway in vitro; RRAD retards tumor growth by downregulating ACTG1 in vivo.\",\n      \"method\": \"Co-immunoprecipitation (RRAD-ACTG1 interaction), ACTG1 overexpression/knockdown, cell cycle analysis, apoptosis assay, glucose metabolism assay, xenograft in vivo model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional cellular assays with multiple readouts; single lab\",\n      \"pmids\": [\"30881024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9(D10A) knockout of ACTG1 in human melanoma cells (A375): gamma-actin loss increases bundled stress fiber formation but impairs lamellipodial activity; CR-ACTG1 cells show greater impairment of cell migration and invasion than CR-ACTB cells; absence of gamma-actin causes more severe alteration of focal adhesion (FA) formation and FA-dependent signaling than beta-actin loss; expression of the other isoform is upregulated to compensate.\",\n      \"method\": \"CRISPR/Cas9(D10A) gene editing, cell migration assay, invasion assay, focal adhesion staining, fluorescence microscopy, western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR knockout with multiple orthogonal phenotypic readouts (migration, invasion, stress fibers, lamellipodia, focal adhesions); direct comparison to ACTB knockout in same system\",\n      \"pmids\": [\"32326615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Several ACTG1 missense mutations (p.I34M, p.M82I, p.K118M, p.I165V) cause intracellular aggregate formation when expressed in NIH/3T3 fibroblasts, indicating inability to polymerize into F-actin; other mutants (p.R37H, p.G48R, p.E241K, p.H275Y) distribute similarly to wild-type.\",\n      \"method\": \"Transient transfection of mutant ACTG1 in NIH/3T3 cells, fluorescence microscopy for intracellular localization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell biology localization assay; multiple mutants tested; single lab\",\n      \"pmids\": [\"32341388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACTG1 knockdown in human nucleus pulposus cells upregulates MMP3 and decreases collagen II; ACTG1 knockdown increases P-P65 (NF-κB) and suppresses P-Akt, indicating ACTG1 regulates IDD through the NF-κB-p65 and Akt signaling pathways.\",\n      \"method\": \"siRNA knockdown of ACTG1, western blot for pathway components, MMP3 and collagen II expression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA knockdown + western blot), single lab, pathway assignment based on protein level changes\",\n      \"pmids\": [\"33545632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACTG1 knockdown in prostate cancer cells inhibits proliferation, migration, and invasion; ERK protein expression is downregulated after ACTG1 knockdown; ERK1/2 inhibitor treatment decreases epithelial-mesenchymal transition marker expression, indicating ACTG1 influences PCa metastasis through the MAPK/ERK signaling pathway.\",\n      \"method\": \"ACTG1 siRNA knockdown, wound healing assay, CCK8 proliferation assay, Transwell invasion assay, western blot, ERK1/2 inhibitor treatment\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple functional readouts with pathway inhibitor validation; single lab\",\n      \"pmids\": [\"34767732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Actg1 has both nucleotide-dependent and protein-dependent functions: bG/0 mice (gamma-actin protein expressed only from the Actb locus, no Actg1 locus) show survival defect and myopathy despite normal gamma-actin protein levels, demonstrating nucleotide-dependent (locus-specific) functions for Actg1; bG/0 genotype rescues Actg1-/- defects in cell proliferation and auditory function, implicating gamma-actin protein (not nucleotide sequence) in fibroblast growth and hearing.\",\n      \"method\": \"Mouse genetics (Actb/Actg1 cross to generate bG/0 line), survival analysis, auditory function testing, muscle histology, cell proliferation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — elegant genetic rescue experiment dissecting protein versus nucleotide functions with multiple orthogonal readouts (survival, auditory, myopathy, cell proliferation)\",\n      \"pmids\": [\"35594181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exosomal PGAM1 from prostate cancer cells binds to ACTG1 (gamma-actin) in human umbilical vein endothelial cells (HUVECs), promoting podosome formation and neovascular sprouting; PGAM1-ACTG1 interaction was demonstrated by GST pulldown and co-immunoprecipitation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, western blot, gelatin degradation assay (invadopodia/podosome formation), in vivo xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays (GST pulldown + Co-IP) plus functional cellular assays; single lab\",\n      \"pmids\": [\"37542027\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTG1 encodes cytoplasmic gamma-actin, a ubiquitous cytoskeletal protein whose functions include F-actin polymerization (regulated by interactions with Arp2/3 complex, cofilin, and tropomyosin), cell proliferation and survival (demonstrated in knockout mice and fibroblasts), focal adhesion formation and lamellipodial activity in cell migration (shown by CRISPR knockout in melanoma cells), neuronal migration during cortical development (demonstrated by disease-causing de novo mutations causing Baraitser-Winter syndrome), and auditory hair cell cytoskeletal maintenance (demonstrated by deafness-causing DFNA20/26 mutations that alter actin filament stability and regulatory protein interactions); the Actg1 locus also harbors nucleotide-sequence-dependent functions distinct from its encoded protein, revealed by genetic rescue experiments in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTG1 encodes cytoplasmic gamma-actin, a ubiquitous cytoskeletal protein that polymerizes into F-actin to support cell proliferation, survival, and tissue morphogenesis [#6, #17]. Gamma-actin function depends on its incorporation into filaments and on regulated interactions with actin-binding machinery: it polymerizes through the Arp2/3 complex (with Lys-118 controlling branch number and position) [#8], is bundled and stabilized by tropomyosin, and is severed by cofilin [#4, #5]. In cell migration, gamma-actin loss in melanoma cells increases bundled stress fibers but impairs lamellipodial activity, focal adhesion formation, and FA-dependent signaling more severely than beta-actin loss, with the other isoform upregulated to compensate [#13]; consistent isoform compensation maintains total actin in Actg1-null cells, which nonetheless show impaired growth and viability [#6]. Genetic dissection in mice distinguishes a protein-encoded role (fibroblast proliferation and auditory function) from nucleotide-sequence-dependent, locus-specific functions of the Actg1 locus required for survival and muscle integrity [#17], and a regulatory alternative-splicing isoform (exon 3a) downregulates gamma-actin post-transcriptionally via nonsense-mediated decay, predominantly in muscle [#10]. Dominant ACTG1 missense mutations cause autosomal dominant sensorineural hearing loss (DFNA20/26) by destabilizing filaments and altering cofilin and Arp2/3 regulation [#2, #5, #8], while de novo missense mutations cause Baraitser-Winter syndrome with neuronal migration defects [#7] and isolated ocular coloboma through loss of F-actin incorporation [#11]. In cancer contexts, gamma-actin levels are controlled by binding partners including RRAD and exosomal PGAM1, linking ACTG1 to proliferation, the Warburg effect, and podosome-driven neovascularization [#12, #18].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that ACTG1 is a human disease gene, linking gamma-actin to dominant progressive hearing loss and mapping the disease mutations onto functionally critical actin domains.\",\n      \"evidence\": \"Sequencing of affected DFNA20/26 families and molecular domain mapping\",\n      \"pmids\": [\"13680526\", \"14684684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro functional validation of mutant actin\", \"Mechanism of cochlear pathology not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided the first biochemical mechanism for DFNA20/26 mutations by showing they destabilize actin and perturb polymerization, while ruling out a simple dominant-negative model.\",\n      \"evidence\": \"Yeast genetics with mutant actins plus in vitro thermal stability, nucleotide exchange, and polymerization assays on purified protein\",\n      \"pmids\": [\"16690605\", \"16773128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Studied in yeast actin background rather than human gamma-actin\", \"Did not resolve how instability translates to hair-cell loss\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected mutant filament instability to specific regulatory interactions, showing deafness mutants are hypersensitive to cofilin severing and that reducing cofilin-driven turnover compensates.\",\n      \"evidence\": \"In vitro cofilin disassembly and bundling assays, tropomyosin neutralization, and yeast Aip1p-deletion epistasis rescue\",\n      \"pmids\": [\"19477959\", \"19419963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hair-cell expression of E241K showed no gross stereocilia change, leaving in vivo relevance incomplete\", \"Effect of cofilin modulation untested in mammalian hair cells\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the organismal and cellular requirement for gamma-actin protein, separating roles in survival and proliferation from migration.\",\n      \"evidence\": \"Actg1 knockout mice and primary MEF assays for growth, viability, and migration with western blot for compensation\",\n      \"pmids\": [\"20662086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative migration result conflicts with later melanoma data, leaving cell-type dependence unresolved\", \"Compensatory isoform identity not fully dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the ACTG1 disease spectrum to a developmental disorder, implicating gamma-actin in neuronal migration during cortical development.\",\n      \"evidence\": \"Whole-exome trio sequencing identifying recurrent de novo mutations in Baraitser-Winter syndrome\",\n      \"pmids\": [\"22366783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional assay of mutant protein\", \"Mechanism of migration defect not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Pinpointed a residue-level mechanism by showing Lys-118 governs the gamma-actin/Arp2/3 interaction controlling branch formation.\",\n      \"evidence\": \"In vitro Arp2/3 polymerization assays and TIRF single-molecule microscopy of K118 mutants\",\n      \"pmids\": [\"22718764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Linkage between altered branching and hearing loss not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a post-transcriptional control circuit and an early cancer-relevant partner regulating gamma-actin abundance.\",\n      \"evidence\": \"RT-PCR/NMD-inhibitor analysis of an exon-3a splice isoform; ASAP3 knockdown with ACTG1 protein and motility readouts\",\n      \"pmids\": [\"24098136\", \"24284654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ASAP3 link is a single low-detail knockdown study without reciprocal validation\", \"Functional consequence of exon-3a NMD regulation in vivo unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed a coloboma-causing mutation abolishes F-actin incorporation, directly tying a residue to polymerization competence and an ocular phenotype.\",\n      \"evidence\": \"Whole-exome sequencing plus F-actin incorporation assay of mutant protein\",\n      \"pmids\": [\"28493397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab assay\", \"Developmental basis of coloboma not modeled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the cell-type-specific migration role, demonstrating gamma-actin is more critical than beta-actin for lamellipodia and focal adhesion signaling in melanoma cells.\",\n      \"evidence\": \"CRISPR/Cas9(D10A) ACTG1 knockout in A375 with migration, invasion, stress-fiber, lamellipodia, and focal-adhesion readouts versus ACTB knockout; aggregation assays for many mutants in NIH/3T3\",\n      \"pmids\": [\"32326615\", \"32341388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of isoform-specific focal adhesion role unknown\", \"Aggregation mutant screen does not define interaction partners affected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated ACTG1 in proliferation and disease-relevant signaling axes (MAPK/ERK, NF-kB-p65, Akt) across prostate cancer and intervertebral disc degeneration.\",\n      \"evidence\": \"siRNA knockdown with functional motility/proliferation assays and pathway western blots, including ERK inhibitor validation\",\n      \"pmids\": [\"34767732\", \"33545632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway links inferred from protein-level changes, not direct biochemistry\", \"Whether effects are cytoskeletal or signaling-intrinsic unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Separated protein-encoded from nucleotide-sequence-dependent functions of the Actg1 locus, showing protein drives proliferation and hearing while locus-specific sequence supports survival and muscle integrity.\",\n      \"evidence\": \"Mouse genetic rescue (bG/0 line) with survival, auditory, myopathy, and proliferation readouts\",\n      \"pmids\": [\"35594181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the nucleotide-dependent function (e.g., regulatory element vs codon usage) not defined\", \"Molecular basis of myopathy unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a physical partner mediating tumor-microenvironment cytoskeletal remodeling, with exosomal PGAM1 binding gamma-actin to drive podosome formation and angiogenesis.\",\n      \"evidence\": \"GST pulldown and co-immunoprecipitation plus gelatin degradation and xenograft assays\",\n      \"pmids\": [\"37542027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction data\", \"Binding interface and structural basis undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How gamma-actin's biochemical properties produce its tissue-specific essentiality (hearing, neuronal migration, muscle) and the molecular identity of the Actg1 locus nucleotide-dependent function remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking specific mutations to tissue-specific phenotypes\", \"Nucleotide-dependent locus function not molecularly defined\", \"Signaling pathway links largely correlative\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 13, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 13, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 11, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 12, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARPC\", \"CFL1\", \"TPM1\", \"RRAD\", \"PGAM1\", \"ASAP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}