{"gene":"ACTG1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2003,"finding":"Missense mutations in ACTG1 (gamma-actin) at conserved actin domains cause autosomal dominant progressive sensorineural hearing loss (DFNA20/26), with mutations predicted to interfere with actin bundling, gelation, polymerization, or myosin movement based on domain mapping.","method":"Sequencing of ACTG1 in affected families; molecular domain mapping of mutation positions","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genetic/sequencing identification with functional prediction; replicated across four families","pmids":["13680526"],"is_preprint":false},{"year":2003,"finding":"A Thr278Ile mutation in helix 9 of ACTG1 is predicted to impair actin polymerization by disrupting a conserved residue in close proximity to Met313 in helix 11, based on structural modeling of the known actin crystal structure.","method":"Linkage analysis, sequencing, and molecular modeling based on known actin crystal structure","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — structural modeling with genetic validation; single lab","pmids":["14684684"],"is_preprint":false},{"year":2006,"finding":"Six DFNA20/26 point mutations in gamma-actin, when engineered into yeast actin as the sole actin, cause growth deficiencies, mitochondrial morphology defects, abnormal actin cable/patch distribution, and vacuole morphological abnormalities; two purified mutants (T278I and V370A) show decreased thermal stability and increased nucleotide exchange rates; V370A actin aggregates and polymerizes faster than wild-type; no dominant negative effect was detected in mixtures with wild-type actin.","method":"Yeast actin mutagenesis (in vivo and in vitro); bulk polymerization assay; nucleotide exchange assay; thermal stability assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assays plus in vivo yeast genetics with multiple orthogonal methods in single study","pmids":["16690605"],"is_preprint":false},{"year":2006,"finding":"The V370A ACTG1 mutation alters a site for protein-protein interaction in gamma-actin and modestly alters gamma-actin-based cytoskeletal structures; functional analysis in yeast shows restricted cell growth at elevated temperature or under hyperosmolar stress.","method":"Yeast functional assay; molecular modeling","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — yeast functional assay with molecular modeling; single lab","pmids":["16773128"],"is_preprint":false},{"year":2009,"finding":"DFNA20/26 gamma-actin mutants K118N and E241K affect actin function differently: E241K forms spontaneous bundles in vitro, which are neutralized by tropomyosin, and E241K filament bundles are hypersensitive to cofilin-mediated severing; K118N has only a mild effect in yeast; both mutants show cytoplasmic aggregates when transiently expressed in NIH3T3 cells; expression in cochlear hair cells does not grossly alter cytoskeletal structures or stereocilia morphology.","method":"In vitro bulk polymerization and bundling assays; yeast cell biology; transient transfection of NIH3T3 cells; gene-gun-mediated cochlear hair cell expression","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution combined with multiple cell biological readouts, increasing biological complexity","pmids":["19477959"],"is_preprint":false},{"year":2009,"finding":"DFNA20/26 gamma-actin mutants T89I and V370A display enhanced susceptibility to cofilin-mediated filament disassembly, while P332A shows resistance; K118M, T278I, P332A, and V370A growth defects on glycerol in yeast are rescued by deletion of the cofilin-activating protein Aip1p, indicating filament instability can be partially compensated by reducing actin turnover.","method":"In vitro cofilin disassembly assays; yeast genetic epistasis (Aip1p deletion); mole-fraction mixing experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assays with genetic epistasis validation across multiple mutants","pmids":["19419963"],"is_preprint":false},{"year":2010,"finding":"Actg1 null (Actg1-/-) mice are viable during embryonic development but mostly die within 48 h of birth; Actg1-/- mice exhibit stunted growth, delayed cardiac outflow tract formation, and primary mouse embryonic fibroblasts show growth impairment and reduced cell viability but normal cell migration; total actin protein level is maintained in Actg1-/- cells via compensatory upregulation, indicating a distinct requirement for gamma-actin in cell growth and survival.","method":"Actg1 knockout mouse model; primary mouse embryonic fibroblast culture; cell viability and growth assays; migration assays","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined cellular and developmental phenotypes, multiple readouts","pmids":["20662086"],"is_preprint":false},{"year":2012,"finding":"De novo missense mutations in ACTG1 (and ACTB) cause Baraitser-Winter syndrome, characterized by craniofacial features, ocular colobomata, and neuronal migration defects, establishing that cytoplasmic actin isoforms play overlapping roles in neuronal migration and development.","method":"Whole-exome sequencing of proband-parent trios; Sanger sequencing validation in 15 additional affected individuals","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple probands with strong genetic evidence; recurrent mutations identified","pmids":["22366783"],"is_preprint":false},{"year":2012,"finding":"DFNA20/26 mutations K118M and K118N in gamma-actin reduce Arp2/3-dependent actin polymerization rates in vitro; TIRF microscopy shows K118M mutant forms fewer branches per filament and alters branch location toward the pointed end, identifying Lys-118 as important for the actin-Arp2/3 interaction.","method":"In vitro bulk polymerization assays with Arp2/3; TIRF microscopy single-filament branching analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal methods (bulk assay + single-molecule TIRF)","pmids":["22718764"],"is_preprint":false},{"year":2013,"finding":"ACTG1 mutations cause more moderate phenotypes than ACTB mutations in Baraitser-Winter syndrome, suggesting distinct developmental roles for beta- and gamma-cytoplasmic actins despite their structural similarity and overlapping expression.","method":"Clinical and genetic comparison of ACTB vs. ACTG1 mutation carriers; sequencing","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — genotype-phenotype correlation across multiple patients; no direct functional assay","pmids":["23756437"],"is_preprint":false},{"year":2013,"finding":"Loss of ASAP3 destabilizes ACTG1 (gamma-actin-1) protein and suppresses cancer cell migration/invasion, linking ASAP3 to ACTG1-dependent cytoskeletal maintenance and cell motility.","method":"ASAP3 knockdown; co-immunoprecipitation; western blotting; migration/invasion assays","journal":"Molecular medicine reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single knockdown with limited mechanistic follow-up","pmids":["24284654"],"is_preprint":false},{"year":2013,"finding":"A novel alternatively-spliced ACTG1 transcript containing exon 3a introduces an in-frame premature stop codon and is targeted for nonsense-mediated decay (NMD), representing a RUST (regulated unproductive splicing and translation) mechanism that down-regulates gamma-actin production; exon 3a expression is tissue-specific (predominantly skeletal muscle, cardiac muscle, diaphragm) and coincides with down-regulation of Actg1 during C2C12 myoblast differentiation.","method":"RT-PCR; C2C12 differentiation model; NMD inhibitor treatment; phylogenetic conservation analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating NMD-mediated regulation: inhibitor treatment, conservation, developmental time-course","pmids":["24098136"],"is_preprint":false},{"year":2017,"finding":"A recurrent de novo ACTG1 mutation encoding p.(Pro70Leu) causes isolated ocular coloboma; the mutant protein is incapable of incorporation into F-actin, directly implicating defective actin polymerization in optic fissure closure.","method":"Whole-exome sequencing; F-actin incorporation assay for mutant protein","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — F-actin incorporation assay directly tests polymerization; identified in two unrelated individuals","pmids":["28493397"],"is_preprint":false},{"year":2019,"finding":"RRAD binds to ACTG1 (demonstrated by co-immunoprecipitation); RRAD suppresses aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by downregulating ACTG1 expression; ACTG1 promotes HCC cell proliferation by regulating cell cycle progression and inhibits apoptosis through the mitochondrial apoptosis pathway.","method":"Co-immunoprecipitation; siRNA knockdown; cell cycle analysis; apoptosis assays; in vivo xenograft model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus functional knockdown with multiple readouts, single lab","pmids":["30881024"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9(D10A) knockout of ACTG1 in human melanoma cells shows that gamma-actin loss has more severe consequences on cell migration and invasion than beta-actin loss; ACTG1 KO increases bundled stress fiber formation but impairs lamellipodial activity and more severely disrupts focal adhesion formation and FA-dependent signaling compared to ACTB KO.","method":"CRISPR/Cas9(D10A) gene editing; migration and invasion assays; immunofluorescence; focal adhesion quantification","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — clean CRISPR KO with multiple orthogonal functional readouts; direct comparison of isoforms","pmids":["32326615"],"is_preprint":false},{"year":2020,"finding":"Several ACTG1 disease-causing mutants (p.I34M, p.M82I, p.K118M, p.I165V) form small intracellular aggregates in NIH/3T3 fibroblasts, while others (p.R37H, p.G48R, p.E241K, p.H275Y) distribute similarly to wild-type, suggesting that some but not all pathogenic mutations impair normal F-actin incorporation.","method":"Transfection of ACTG1 mutants in NIH/3T3 fibroblasts; fluorescence microscopy","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional implication; multiple mutants tested","pmids":["32341388"],"is_preprint":false},{"year":2021,"finding":"ACTG1 knockdown in human nucleus pulposus cells increases MMP3 expression, decreases collagen II levels, and promotes apoptosis; ACTG1 knockdown upregulates phospho-p65 (NF-κB) and suppresses phospho-Akt, placing ACTG1 upstream of NF-κB-p65 and Akt signaling in intervertebral disc homeostasis.","method":"siRNA knockdown in human nucleus pulposus cells; western blotting; apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, siRNA knockdown with pathway signaling readout; moderate mechanistic follow-up","pmids":["33545632"],"is_preprint":false},{"year":2021,"finding":"Silencing ACTG1 in prostate cancer cells inhibits proliferation, migration, and invasion; ERK protein expression is downregulated after ACTG1 knockdown, and ERK1/2 inhibition recapitulates EMT marker changes, placing ACTG1 upstream of MAPK/ERK signaling in prostate cancer metastasis.","method":"siRNA knockdown; wound healing, CCK8, and Transwell assays; western blotting; ERK1/2 inhibitor treatment","journal":"DNA and cell biology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, knockdown with pathway inhibitor; weak mechanistic resolution","pmids":["34767732"],"is_preprint":false},{"year":2022,"finding":"Crossing Actb-edited mice (expressing gamma-actin from the Actb locus) with Actg1-/- mice to generate bG/0 animals (sole cytoplasmic actin = gamma-actin from Actb nucleotide sequence) reveals that bG/0 mice have impaired survival and a unique myopathy despite normal gamma-actin protein levels, demonstrating nucleotide sequence-dependent (protein-independent) functions for the Actg1 locus; conversely, cell proliferation and auditory function defects of Actg1-/- are rescued in bG/0, indicating these require gamma-actin protein.","method":"Genetic mouse models (Actg1-/-, Actb-knockin of gamma-actin, bG/0 compound mice); survival analysis; auditory function testing; histology","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — rigorous genetic rescue experiment separating protein vs. nucleotide functions; multiple phenotypic readouts","pmids":["35594181"],"is_preprint":false},{"year":2023,"finding":"Exosomal PGAM1 binds to ACTG1 (gamma-actin) in HUVECs (demonstrated by GST pulldown and co-immunoprecipitation), promoting podosome formation and neovascular sprouting; this interaction facilitates angiogenesis and lung metastasis in prostate cancer.","method":"GST pulldown; co-immunoprecipitation; western blotting; gelatin degradation assay; in vivo tail-vein metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal biochemical binding assays combined with functional in vivo validation","pmids":["37542027"],"is_preprint":false},{"year":2023,"finding":"A trans-regulatory lncRNA (TRLA), epigenetically regulated by H3K4 acetylation, binds directly to ACTG1 mRNA (2-375 nt of TRLA) to increase ACTG1 expression, promoting granulosa cell migration, proliferation, and follicular remodeling; ACTG1 itself promotes migration and proliferation while inhibiting apoptosis of granulosa cells.","method":"RNA binding assay (TRLA:ACTG1 mRNA); siRNA/overexpression; ChIP for H3K4ac; migration, proliferation, and apoptosis assays","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — direct RNA-RNA binding assay combined with functional readouts; single lab","pmids":["37276900"],"is_preprint":false}],"current_model":"ACTG1-encoded gamma-actin (γ-actin) is a ubiquitous cytoplasmic actin isoform whose protein-level functions include Arp2/3-dependent filament branching, cofilin-regulated filament turnover, focal adhesion formation, cell migration/invasion, cell growth and survival, and neuronal migration during development, while the Actg1 nucleotide sequence also encodes protein-independent (locus-specific) functions required for normal survival and muscle integrity; disease-causing missense mutations (DFNA20/26, Baraitser-Winter syndrome) disrupt these actin regulatory interactions in isoform- and allele-specific ways."},"narrative":{"teleology":[{"year":2003,"claim":"Identification of ACTG1 as the gene mutated in DFNA20/26 established that γ-actin has a non-redundant role in auditory hair cell function, raising the question of which actin-regulatory interactions are disrupted.","evidence":"Sequencing of ACTG1 in four hearing-loss families with domain-level mapping of mutations","pmids":["13680526","14684684"],"confidence":"Medium","gaps":["No direct biochemical characterization of mutant protein properties","Mechanism of hearing loss at cellular level unknown"]},{"year":2006,"claim":"Biochemical and genetic analysis of DFNA20/26 mutants in yeast revealed that disease mutations cause intrinsic defects in actin stability, nucleotide exchange, and polymerization kinetics rather than acting as dominant negatives.","evidence":"Yeast sole-actin system; in vitro polymerization, nucleotide exchange, and thermal stability assays for T278I and V370A mutants","pmids":["16690605","16773128"],"confidence":"High","gaps":["Yeast actin differs from human γ-actin; relevance to mammalian hair cells unclear","Effect on actin-binding protein interactions not yet tested"]},{"year":2009,"claim":"Demonstration that DFNA20/26 mutations differentially alter cofilin-mediated filament severing — and that genetic suppression of the cofilin pathway rescues growth — established filament turnover dysregulation as a convergent disease mechanism.","evidence":"In vitro cofilin disassembly assays; yeast Aip1p deletion epistasis; bundling assays for E241K","pmids":["19419963","19477959"],"confidence":"High","gaps":["Molecular basis for mutation-specific directionality (enhanced vs. resistant severing) not resolved","No mammalian hair cell confirmation of cofilin-pathway relevance"]},{"year":2010,"claim":"Actg1 knockout mice demonstrated that γ-actin is specifically required for postnatal survival and cell growth/viability but dispensable for embryonic development and cell migration, distinguishing its role from compensatory actin isoforms.","evidence":"Actg1−/− mouse model with primary fibroblast assays for growth, viability, and migration","pmids":["20662086"],"confidence":"High","gaps":["Compensatory upregulation of other actins complicates interpretation of which phenotypes are γ-actin-specific","Hair cell and auditory phenotype not reported in this study"]},{"year":2012,"claim":"Discovery that de novo ACTG1 missense mutations cause Baraitser-Winter syndrome extended γ-actin's non-redundant roles to neuronal migration and craniofacial development, distinct from its auditory function.","evidence":"Whole-exome sequencing of proband-parent trios; replicated across 15+ individuals","pmids":["22366783","23756437"],"confidence":"High","gaps":["No functional assay in neural tissue to define migration mechanism","Phenotypic overlap with ACTB mutations leaves isoform-specific contributions unclear"]},{"year":2012,"claim":"Single-filament TIRF microscopy showed that the K118M mutation reduces Arp2/3-dependent branch nucleation frequency and alters branch position, pinpointing Lys-118 as critical for the actin–Arp2/3 interface.","evidence":"In vitro bulk Arp2/3-dependent polymerization and single-filament TIRF branching analysis","pmids":["22718764"],"confidence":"High","gaps":["No structural data directly showing how K118 contacts Arp2/3","Other DFNA20/26 mutations not tested for Arp2/3 interaction"]},{"year":2013,"claim":"Discovery of an alternatively spliced ACTG1 transcript containing exon 3a that is targeted for NMD revealed a RUST mechanism for tissue-specific (muscle-enriched) post-transcriptional down-regulation of γ-actin production.","evidence":"RT-PCR; NMD inhibitor treatment; C2C12 myoblast differentiation time-course; phylogenetic conservation","pmids":["24098136"],"confidence":"High","gaps":["In vivo role of exon 3a splicing regulation not tested","Trans-acting splicing regulators controlling exon 3a inclusion not identified"]},{"year":2020,"claim":"CRISPR knockout of ACTG1 in melanoma cells established that γ-actin is preferentially required over β-actin for lamellipodial dynamics, focal adhesion formation, and cell invasion, resolving a longstanding question about isoform-specific cytoskeletal roles.","evidence":"CRISPR/Cas9(D10A) knockout; migration, invasion, focal adhesion quantification; direct comparison with ACTB KO","pmids":["32326615"],"confidence":"High","gaps":["Single cell line (melanoma); generalizability to non-cancer cells unclear","Molecular basis for isoform-specific FA recruitment unknown"]},{"year":2022,"claim":"Genetic separation experiments using compound Actb-knockin/Actg1-null mice demonstrated that the Actg1 locus encodes protein-independent (nucleotide sequence-dependent) functions essential for survival and muscle integrity, while γ-actin protein is specifically required for auditory function and cell proliferation.","evidence":"bG/0 compound mice expressing only γ-actin protein from the Actb locus; survival, auditory, and histological analysis","pmids":["35594181"],"confidence":"High","gaps":["Identity of protein-independent gene products (regulatory RNA, translational cis-elements) not determined","Muscle pathology mechanism not resolved at molecular level"]},{"year":2023,"claim":"Identification of exosomal PGAM1 as a direct ACTG1-binding partner that promotes podosome formation linked γ-actin to tumor angiogenesis and metastasis through a specific extracellular signaling axis.","evidence":"GST pulldown and co-IP in HUVECs; gelatin degradation assay; in vivo tail-vein metastasis model","pmids":["37542027"],"confidence":"Medium","gaps":["Binding interface between PGAM1 and γ-actin not mapped","Whether PGAM1 interaction is isoform-specific (γ- vs. β-actin) not tested"]},{"year":null,"claim":"The molecular nature of the protein-independent, nucleotide sequence-dependent functions encoded by the Actg1 locus — whether arising from regulatory RNA, translational cis-elements, or chromatin context — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No candidate non-coding product from the Actg1 locus has been identified","Structural basis for isoform-specific interactions with Arp2/3, cofilin, and focal adhesion components remains undetermined","In vivo hair cell-specific rescue experiments have not been performed for individual DFNA20/26 mutations"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,4,5,8,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,14]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[4,14,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,14]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,16]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[14]}],"complexes":[],"partners":["ARP2/3","CFL1","PGAM1","RRAD","ASAP3"],"other_free_text":[]},"mechanistic_narrative":"ACTG1 encodes γ-cytoplasmic actin, a ubiquitously expressed actin isoform essential for cell growth, survival, focal adhesion formation, and directed cell migration, with preferential roles over β-actin in lamellipodial dynamics and invasion [PMID:32326615, PMID:20662086]. γ-Actin participates in Arp2/3-dependent filament branching and is regulated by cofilin-mediated severing; disease-causing mutations at residues such as Lys-118 impair Arp2/3-dependent branch nucleation, while others (T278I, V370A, T89I) destabilize filaments and increase susceptibility to cofilin disassembly [PMID:22718764, PMID:19419963, PMID:16690605]. Missense mutations in ACTG1 cause autosomal dominant sensorineural hearing loss (DFNA20/26) and Baraitser-Winter syndrome, the latter involving neuronal migration defects [PMID:13680526, PMID:22366783]. Genetic separation of protein versus nucleotide-sequence contributions reveals that the Actg1 locus also encodes protein-independent functions required for survival and muscle integrity, while γ-actin protein is specifically required for auditory function and cell proliferation [PMID:35594181]."},"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":414,"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":257,"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":232,"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":218,"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":"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":"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":"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":14,"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":14,"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":"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":"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":"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":"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":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":"26009829","id":"PMC_26009829","title":"Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s.","date":"2015","source":"Journal of acquired immune deficiency syndromes (1999)","url":"https://pubmed.ncbi.nlm.nih.gov/26009829","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57187,"output_tokens":4816,"usd":0.1219},"stage2":{"model":"claude-opus-4-6","input_tokens":8330,"output_tokens":2614,"usd":0.1605},"total_usd":0.2824,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Missense mutations in ACTG1 (gamma-actin) at conserved actin domains cause autosomal dominant progressive sensorineural hearing loss (DFNA20/26), with mutations predicted to interfere with actin bundling, gelation, polymerization, or myosin movement based on domain mapping.\",\n      \"method\": \"Sequencing of ACTG1 in affected families; molecular domain mapping of mutation positions\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic/sequencing identification with functional prediction; replicated across four families\",\n      \"pmids\": [\"13680526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A Thr278Ile mutation in helix 9 of ACTG1 is predicted to impair actin polymerization by disrupting a conserved residue in close proximity to Met313 in helix 11, based on structural modeling of the known actin crystal structure.\",\n      \"method\": \"Linkage analysis, sequencing, and molecular modeling based on known actin crystal structure\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — structural modeling with genetic validation; single lab\",\n      \"pmids\": [\"14684684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Six DFNA20/26 point mutations in gamma-actin, when engineered into yeast actin as the sole actin, cause growth deficiencies, mitochondrial morphology defects, abnormal actin cable/patch distribution, and vacuole morphological abnormalities; two purified mutants (T278I and V370A) show decreased thermal stability and increased nucleotide exchange rates; V370A actin aggregates and polymerizes faster than wild-type; no dominant negative effect was detected in mixtures with wild-type actin.\",\n      \"method\": \"Yeast actin mutagenesis (in vivo and in vitro); bulk polymerization assay; nucleotide exchange assay; thermal stability assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assays plus in vivo yeast genetics with multiple orthogonal methods in single study\",\n      \"pmids\": [\"16690605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The V370A ACTG1 mutation alters a site for protein-protein interaction in gamma-actin and modestly alters gamma-actin-based cytoskeletal structures; functional analysis in yeast shows restricted cell growth at elevated temperature or under hyperosmolar stress.\",\n      \"method\": \"Yeast functional assay; molecular modeling\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — yeast functional assay with molecular modeling; single lab\",\n      \"pmids\": [\"16773128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DFNA20/26 gamma-actin mutants K118N and E241K affect actin function differently: E241K forms spontaneous bundles in vitro, which are neutralized by tropomyosin, and E241K filament bundles are hypersensitive to cofilin-mediated severing; K118N has only a mild effect in yeast; both mutants show cytoplasmic aggregates when transiently expressed in NIH3T3 cells; expression in cochlear hair cells does not grossly alter cytoskeletal structures or stereocilia morphology.\",\n      \"method\": \"In vitro bulk polymerization and bundling assays; yeast cell biology; transient transfection of NIH3T3 cells; gene-gun-mediated cochlear hair cell expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution combined with multiple cell biological readouts, increasing biological complexity\",\n      \"pmids\": [\"19477959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DFNA20/26 gamma-actin mutants T89I and V370A display enhanced susceptibility to cofilin-mediated filament disassembly, while P332A shows resistance; K118M, T278I, P332A, and V370A growth defects on glycerol in yeast are rescued by deletion of the cofilin-activating protein Aip1p, indicating filament instability can be partially compensated by reducing actin turnover.\",\n      \"method\": \"In vitro cofilin disassembly assays; yeast genetic epistasis (Aip1p deletion); mole-fraction mixing experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assays with genetic epistasis validation across multiple mutants\",\n      \"pmids\": [\"19419963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Actg1 null (Actg1-/-) mice are viable during embryonic development but mostly die within 48 h of birth; Actg1-/- mice exhibit stunted growth, delayed cardiac outflow tract formation, and primary mouse embryonic fibroblasts show growth impairment and reduced cell viability but normal cell migration; total actin protein level is maintained in Actg1-/- cells via compensatory upregulation, indicating a distinct requirement for gamma-actin in cell growth and survival.\",\n      \"method\": \"Actg1 knockout mouse model; primary mouse embryonic fibroblast culture; cell viability and growth assays; migration assays\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined cellular and developmental phenotypes, multiple readouts\",\n      \"pmids\": [\"20662086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"De novo missense mutations in ACTG1 (and ACTB) cause Baraitser-Winter syndrome, characterized by craniofacial features, ocular colobomata, and neuronal migration defects, establishing that cytoplasmic actin isoforms play overlapping roles in neuronal migration and development.\",\n      \"method\": \"Whole-exome sequencing of proband-parent trios; Sanger sequencing validation in 15 additional affected individuals\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple probands with strong genetic evidence; recurrent mutations identified\",\n      \"pmids\": [\"22366783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DFNA20/26 mutations K118M and K118N in gamma-actin reduce Arp2/3-dependent actin polymerization rates in vitro; TIRF microscopy shows K118M mutant forms fewer branches per filament and alters branch location toward the pointed end, identifying Lys-118 as important for the actin-Arp2/3 interaction.\",\n      \"method\": \"In vitro bulk polymerization assays with Arp2/3; TIRF microscopy single-filament branching analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal methods (bulk assay + single-molecule TIRF)\",\n      \"pmids\": [\"22718764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ACTG1 mutations cause more moderate phenotypes than ACTB mutations in Baraitser-Winter syndrome, suggesting distinct developmental roles for beta- and gamma-cytoplasmic actins despite their structural similarity and overlapping expression.\",\n      \"method\": \"Clinical and genetic comparison of ACTB vs. ACTG1 mutation carriers; sequencing\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genotype-phenotype correlation across multiple patients; no direct functional assay\",\n      \"pmids\": [\"23756437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of ASAP3 destabilizes ACTG1 (gamma-actin-1) protein and suppresses cancer cell migration/invasion, linking ASAP3 to ACTG1-dependent cytoskeletal maintenance and cell motility.\",\n      \"method\": \"ASAP3 knockdown; co-immunoprecipitation; western blotting; migration/invasion assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single knockdown with limited mechanistic follow-up\",\n      \"pmids\": [\"24284654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel alternatively-spliced ACTG1 transcript containing exon 3a introduces an in-frame premature stop codon and is targeted for nonsense-mediated decay (NMD), representing a RUST (regulated unproductive splicing and translation) mechanism that down-regulates gamma-actin production; exon 3a expression is tissue-specific (predominantly skeletal muscle, cardiac muscle, diaphragm) and coincides with down-regulation of Actg1 during C2C12 myoblast differentiation.\",\n      \"method\": \"RT-PCR; C2C12 differentiation model; NMD inhibitor treatment; phylogenetic conservation analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating NMD-mediated regulation: inhibitor treatment, conservation, developmental time-course\",\n      \"pmids\": [\"24098136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A recurrent de novo ACTG1 mutation encoding p.(Pro70Leu) causes isolated ocular coloboma; the mutant protein is incapable of incorporation into F-actin, directly implicating defective actin polymerization in optic fissure closure.\",\n      \"method\": \"Whole-exome sequencing; F-actin incorporation assay for mutant protein\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — F-actin incorporation assay directly tests polymerization; identified in two unrelated individuals\",\n      \"pmids\": [\"28493397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RRAD binds to ACTG1 (demonstrated by co-immunoprecipitation); RRAD suppresses aerobic glycolysis (Warburg effect) in hepatocellular carcinoma by downregulating ACTG1 expression; ACTG1 promotes HCC cell proliferation by regulating cell cycle progression and inhibits apoptosis through the mitochondrial apoptosis pathway.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; cell cycle analysis; apoptosis assays; in vivo xenograft model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional knockdown 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 shows that gamma-actin loss has more severe consequences on cell migration and invasion than beta-actin loss; ACTG1 KO increases bundled stress fiber formation but impairs lamellipodial activity and more severely disrupts focal adhesion formation and FA-dependent signaling compared to ACTB KO.\",\n      \"method\": \"CRISPR/Cas9(D10A) gene editing; migration and invasion assays; immunofluorescence; focal adhesion quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with multiple orthogonal functional readouts; direct comparison of isoforms\",\n      \"pmids\": [\"32326615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Several ACTG1 disease-causing mutants (p.I34M, p.M82I, p.K118M, p.I165V) form small intracellular aggregates in NIH/3T3 fibroblasts, while others (p.R37H, p.G48R, p.E241K, p.H275Y) distribute similarly to wild-type, suggesting that some but not all pathogenic mutations impair normal F-actin incorporation.\",\n      \"method\": \"Transfection of ACTG1 mutants in NIH/3T3 fibroblasts; fluorescence microscopy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional implication; multiple mutants tested\",\n      \"pmids\": [\"32341388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ACTG1 knockdown in human nucleus pulposus cells increases MMP3 expression, decreases collagen II levels, and promotes apoptosis; ACTG1 knockdown upregulates phospho-p65 (NF-κB) and suppresses phospho-Akt, placing ACTG1 upstream of NF-κB-p65 and Akt signaling in intervertebral disc homeostasis.\",\n      \"method\": \"siRNA knockdown in human nucleus pulposus cells; western blotting; apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, siRNA knockdown with pathway signaling readout; moderate mechanistic follow-up\",\n      \"pmids\": [\"33545632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing ACTG1 in prostate cancer cells inhibits proliferation, migration, and invasion; ERK protein expression is downregulated after ACTG1 knockdown, and ERK1/2 inhibition recapitulates EMT marker changes, placing ACTG1 upstream of MAPK/ERK signaling in prostate cancer metastasis.\",\n      \"method\": \"siRNA knockdown; wound healing, CCK8, and Transwell assays; western blotting; ERK1/2 inhibitor treatment\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with pathway inhibitor; weak mechanistic resolution\",\n      \"pmids\": [\"34767732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crossing Actb-edited mice (expressing gamma-actin from the Actb locus) with Actg1-/- mice to generate bG/0 animals (sole cytoplasmic actin = gamma-actin from Actb nucleotide sequence) reveals that bG/0 mice have impaired survival and a unique myopathy despite normal gamma-actin protein levels, demonstrating nucleotide sequence-dependent (protein-independent) functions for the Actg1 locus; conversely, cell proliferation and auditory function defects of Actg1-/- are rescued in bG/0, indicating these require gamma-actin protein.\",\n      \"method\": \"Genetic mouse models (Actg1-/-, Actb-knockin of gamma-actin, bG/0 compound mice); survival analysis; auditory function testing; histology\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous genetic rescue experiment separating protein vs. nucleotide functions; multiple phenotypic readouts\",\n      \"pmids\": [\"35594181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Exosomal PGAM1 binds to ACTG1 (gamma-actin) in HUVECs (demonstrated by GST pulldown and co-immunoprecipitation), promoting podosome formation and neovascular sprouting; this interaction facilitates angiogenesis and lung metastasis in prostate cancer.\",\n      \"method\": \"GST pulldown; co-immunoprecipitation; western blotting; gelatin degradation assay; in vivo tail-vein metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal biochemical binding assays combined with functional in vivo validation\",\n      \"pmids\": [\"37542027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A trans-regulatory lncRNA (TRLA), epigenetically regulated by H3K4 acetylation, binds directly to ACTG1 mRNA (2-375 nt of TRLA) to increase ACTG1 expression, promoting granulosa cell migration, proliferation, and follicular remodeling; ACTG1 itself promotes migration and proliferation while inhibiting apoptosis of granulosa cells.\",\n      \"method\": \"RNA binding assay (TRLA:ACTG1 mRNA); siRNA/overexpression; ChIP for H3K4ac; migration, proliferation, and apoptosis assays\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RNA-RNA binding assay combined with functional readouts; single lab\",\n      \"pmids\": [\"37276900\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTG1-encoded gamma-actin (γ-actin) is a ubiquitous cytoplasmic actin isoform whose protein-level functions include Arp2/3-dependent filament branching, cofilin-regulated filament turnover, focal adhesion formation, cell migration/invasion, cell growth and survival, and neuronal migration during development, while the Actg1 nucleotide sequence also encodes protein-independent (locus-specific) functions required for normal survival and muscle integrity; disease-causing missense mutations (DFNA20/26, Baraitser-Winter syndrome) disrupt these actin regulatory interactions in isoform- and allele-specific ways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ACTG1 encodes γ-cytoplasmic actin, a ubiquitously expressed actin isoform essential for cell growth, survival, focal adhesion formation, and directed cell migration, with preferential roles over β-actin in lamellipodial dynamics and invasion [PMID:32326615, PMID:20662086]. γ-Actin participates in Arp2/3-dependent filament branching and is regulated by cofilin-mediated severing; disease-causing mutations at residues such as Lys-118 impair Arp2/3-dependent branch nucleation, while others (T278I, V370A, T89I) destabilize filaments and increase susceptibility to cofilin disassembly [PMID:22718764, PMID:19419963, PMID:16690605]. Missense mutations in ACTG1 cause autosomal dominant sensorineural hearing loss (DFNA20/26) and Baraitser-Winter syndrome, the latter involving neuronal migration defects [PMID:13680526, PMID:22366783]. Genetic separation of protein versus nucleotide-sequence contributions reveals that the Actg1 locus also encodes protein-independent functions required for survival and muscle integrity, while γ-actin protein is specifically required for auditory function and cell proliferation [PMID:35594181].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of ACTG1 as the gene mutated in DFNA20/26 established that γ-actin has a non-redundant role in auditory hair cell function, raising the question of which actin-regulatory interactions are disrupted.\",\n      \"evidence\": \"Sequencing of ACTG1 in four hearing-loss families with domain-level mapping of mutations\",\n      \"pmids\": [\"13680526\", \"14684684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical characterization of mutant protein properties\", \"Mechanism of hearing loss at cellular level unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Biochemical and genetic analysis of DFNA20/26 mutants in yeast revealed that disease mutations cause intrinsic defects in actin stability, nucleotide exchange, and polymerization kinetics rather than acting as dominant negatives.\",\n      \"evidence\": \"Yeast sole-actin system; in vitro polymerization, nucleotide exchange, and thermal stability assays for T278I and V370A mutants\",\n      \"pmids\": [\"16690605\", \"16773128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast actin differs from human γ-actin; relevance to mammalian hair cells unclear\", \"Effect on actin-binding protein interactions not yet tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that DFNA20/26 mutations differentially alter cofilin-mediated filament severing — and that genetic suppression of the cofilin pathway rescues growth — established filament turnover dysregulation as a convergent disease mechanism.\",\n      \"evidence\": \"In vitro cofilin disassembly assays; yeast Aip1p deletion epistasis; bundling assays for E241K\",\n      \"pmids\": [\"19419963\", \"19477959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for mutation-specific directionality (enhanced vs. resistant severing) not resolved\", \"No mammalian hair cell confirmation of cofilin-pathway relevance\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Actg1 knockout mice demonstrated that γ-actin is specifically required for postnatal survival and cell growth/viability but dispensable for embryonic development and cell migration, distinguishing its role from compensatory actin isoforms.\",\n      \"evidence\": \"Actg1−/− mouse model with primary fibroblast assays for growth, viability, and migration\",\n      \"pmids\": [\"20662086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory upregulation of other actins complicates interpretation of which phenotypes are γ-actin-specific\", \"Hair cell and auditory phenotype not reported in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that de novo ACTG1 missense mutations cause Baraitser-Winter syndrome extended γ-actin's non-redundant roles to neuronal migration and craniofacial development, distinct from its auditory function.\",\n      \"evidence\": \"Whole-exome sequencing of proband-parent trios; replicated across 15+ individuals\",\n      \"pmids\": [\"22366783\", \"23756437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assay in neural tissue to define migration mechanism\", \"Phenotypic overlap with ACTB mutations leaves isoform-specific contributions unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Single-filament TIRF microscopy showed that the K118M mutation reduces Arp2/3-dependent branch nucleation frequency and alters branch position, pinpointing Lys-118 as critical for the actin–Arp2/3 interface.\",\n      \"evidence\": \"In vitro bulk Arp2/3-dependent polymerization and single-filament TIRF branching analysis\",\n      \"pmids\": [\"22718764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural data directly showing how K118 contacts Arp2/3\", \"Other DFNA20/26 mutations not tested for Arp2/3 interaction\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of an alternatively spliced ACTG1 transcript containing exon 3a that is targeted for NMD revealed a RUST mechanism for tissue-specific (muscle-enriched) post-transcriptional down-regulation of γ-actin production.\",\n      \"evidence\": \"RT-PCR; NMD inhibitor treatment; C2C12 myoblast differentiation time-course; phylogenetic conservation\",\n      \"pmids\": [\"24098136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo role of exon 3a splicing regulation not tested\", \"Trans-acting splicing regulators controlling exon 3a inclusion not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR knockout of ACTG1 in melanoma cells established that γ-actin is preferentially required over β-actin for lamellipodial dynamics, focal adhesion formation, and cell invasion, resolving a longstanding question about isoform-specific cytoskeletal roles.\",\n      \"evidence\": \"CRISPR/Cas9(D10A) knockout; migration, invasion, focal adhesion quantification; direct comparison with ACTB KO\",\n      \"pmids\": [\"32326615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single cell line (melanoma); generalizability to non-cancer cells unclear\", \"Molecular basis for isoform-specific FA recruitment unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic separation experiments using compound Actb-knockin/Actg1-null mice demonstrated that the Actg1 locus encodes protein-independent (nucleotide sequence-dependent) functions essential for survival and muscle integrity, while γ-actin protein is specifically required for auditory function and cell proliferation.\",\n      \"evidence\": \"bG/0 compound mice expressing only γ-actin protein from the Actb locus; survival, auditory, and histological analysis\",\n      \"pmids\": [\"35594181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of protein-independent gene products (regulatory RNA, translational cis-elements) not determined\", \"Muscle pathology mechanism not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of exosomal PGAM1 as a direct ACTG1-binding partner that promotes podosome formation linked γ-actin to tumor angiogenesis and metastasis through a specific extracellular signaling axis.\",\n      \"evidence\": \"GST pulldown and co-IP in HUVECs; gelatin degradation assay; in vivo tail-vein metastasis model\",\n      \"pmids\": [\"37542027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between PGAM1 and γ-actin not mapped\", \"Whether PGAM1 interaction is isoform-specific (γ- vs. β-actin) not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular nature of the protein-independent, nucleotide sequence-dependent functions encoded by the Actg1 locus — whether arising from regulatory RNA, translational cis-elements, or chromatin context — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No candidate non-coding product from the Actg1 locus has been identified\", \"Structural basis for isoform-specific interactions with Arp2/3, cofilin, and focal adhesion components remains undetermined\", \"In vivo hair cell-specific rescue experiments have not been performed for individual DFNA20/26 mutations\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 4, 5, 8, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [4, 14, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ARP2/3\",\n      \"CFL1\",\n      \"PGAM1\",\n      \"RRAD\",\n      \"ASAP3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}