{"gene":"ACTB","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2012,"finding":"De novo missense mutations in ACTB cause Baraitser-Winter syndrome, a neuronal migration disorder with craniofacial features and ocular colobomata, establishing that cytoplasmic β-actin is required for normal neuronal migration and cortical development.","method":"Whole-exome sequencing of proband-parent trios followed by Sanger sequencing of additional affected individuals","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — exome sequencing with trio-based validation in 18 affected individuals across multiple labs; recurrent de novo mutations at same residues replicated independently","pmids":["22366783"],"is_preprint":false},{"year":2013,"finding":"A de novo ACTB p.E117K missense variant alters cell adhesion and actin polymer formation, demonstrating that disease-associated ACTB mutations functionally impair actin polymerization dynamics.","method":"Exome sequencing to identify variant, followed by in vitro functional characterization of mutant actin including polymer formation assays and cell adhesion assays","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays (polymerization, adhesion) in single lab with two orthogonal methods on a specific variant","pmids":["23649928"],"is_preprint":false},{"year":2017,"finding":"Heterozygous ACTB loss-of-function mutations cause reduced cell proliferation, altered cell shape and migration, and decreased nuclear (but not cytoplasmic) β-actin levels, demonstrating that ACTB is required for normal cell proliferation, migration, and nuclear actin function.","method":"ACTB siRNA knockdown in wild-type fibroblasts and analysis of fibroblasts from affected individuals; cell shape, migration, and proliferation assays; subcellular fractionation to measure nuclear vs. cytoplasmic β-actin","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, patient cells, fractionation, functional assays) in a single rigorous study with ≥33 affected individuals","pmids":["29220674"],"is_preprint":false},{"year":2018,"finding":"β-actin protein per se is not required for general cellular functions, but is specifically necessary to maintain auditory stereocilia integrity, as mice with the Actb locus gene-edited to produce only γ-actin protein are viable but develop progressive high-frequency hearing loss and stereocilia degeneration.","method":"CRISPR gene editing of endogenous mouse Actb locus to translate γ-actin protein (knock-in); audiological testing and stereocilia morphology analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — precise knock-in allele replacing β-actin protein with γ-actin in vivo, orthogonal functional and morphological validation","pmids":["30012594"],"is_preprint":false},{"year":2022,"finding":"The ACTB p.S368fs frameshift mutation causes a C-terminal alteration that markedly reduces actin nucleation and polymerization rates and lowers affinity for profilin-1, with allosteric effects including reduced thermal stability, altered DNase-I binding, and changed nucleotide exchange kinetics, implicating disrupted actin-profilin interaction as the disease mechanism in ACTB-associated syndromic thrombocytopenia.","method":"Recombinant production of mutant β-actin; in vitro spontaneous actin assembly assays; profilin-1 affinity measurements; DNase-I inhibition assay; thermal denaturation; nucleotide exchange kinetics","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro biochemistry with multiple orthogonal assays (polymerization, affinity, stability, nucleotide exchange) in single rigorous study","pmids":["35313204"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9-mediated knockout of ACTB in human melanoma cells shows that β-actin and γ-actin play distinct roles: ACTB knockout alters focal adhesion (FA) formation and FA-dependent signaling, while ACTG1 knockout more severely impairs cell migration, invasion, and lamellipodia formation, and increases bundled stress fibers.","method":"CRISPR/Cas9(D10A)-mediated gene inactivation; migration and invasion assays; FA formation and signaling analysis; actin isoform distribution by immunofluorescence","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (migration, invasion, FA, signaling) in single lab","pmids":["32326615"],"is_preprint":false},{"year":2004,"finding":"A chromosomal translocation t(7;12) fuses the 5'-portion of ACTB (including its promoter) to the 3'-portion of GLI, placing GLI under the control of the ubiquitously expressed ACTB promoter and causing deregulated GLI expression and activation of the sonic hedgehog pathway.","method":"Cytogenetics, RT-PCR, molecular genetic analysis of genomic breakpoints, electron microscopy of tumor phenotype","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — fusion transcript confirmed in five independent tumors, genomic breakpoints characterized, mechanism (promoter swap) established","pmids":["15111311"],"is_preprint":false},{"year":2004,"finding":"The ACTB-GLI fusion at the genomic level results from juxtaposition of intronic or exonic sequences (with one case showing a micro-inversion at the junction) without large repeats, and the fusions are molecularly unbalanced; the first 41 amino acids of ACTB replace the first 177 amino acids of GLI1 in the putative fusion protein.","method":"RT-PCR, Sanger sequencing of genomic breakpoints, bioinformatic analysis of recombination sequences","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of five independent tumor breakpoints, replicated across multiple cases","pmids":["15555571"],"is_preprint":false},{"year":2021,"finding":"Functional analysis in a haploid S. cerevisiae pseudoheterozygote model demonstrates that the ACTB p.Ser348Leu variant causes a dominant growth defect at 22°C but not 30°C, consistent with the mutation having a dominant functional defect over wild-type actin.","method":"Yeast pseudoheterozygote model expressing yACT1-S348L alongside wild-type; growth assay at different temperatures","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vivo yeast reconstitution with temperature-sensitive dominant growth phenotype, but single lab and single method","pmids":["34970864"],"is_preprint":false},{"year":2024,"finding":"The ACTB p.S348L variant impairs the ability of mutant β-actin to localize to epithelial junctions and to bind PROFILIN1, compromising actin polymerization and causing aberrant epithelial cell adhesion and migration, which underlies the orofacial cleft phenotype in Baraitser-Winter syndrome.","method":"Patient-derived MDCK cell line models and Xenopus laevis embryo functional assays; junction localization imaging; profilin-1 binding assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple disease models (cell line + Xenopus) with orthogonal functional assays (localization, binding, cell behavior), single lab","pmids":["39271101"],"is_preprint":false},{"year":2021,"finding":"Nuclear respiratory factor-1 (NRF-1) directly binds to the coding region of the ACTB gene and transcriptionally activates β-actin expression under hypoxic conditions, as NRF-1 levels and β-actin levels change concordantly with NRF-1 overexpression or silencing.","method":"ChIP experiments demonstrating NRF-1 binding to ACTB/Actb coding regions; NRF-1 overexpression and knockdown with β-actin protein level measurement; hypoxia treatment of gastric cancer and normal cells","journal":"Molekuliarnaia biologiia","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP plus gain/loss-of-function, but single lab and limited orthogonal validation","pmids":["34097680"],"is_preprint":false},{"year":2026,"finding":"SETD3-mediated methylation of ACTB at H73 is required for ACTB's genomic distribution, and this modification enables colocalization of SMARCA4 (a SWI/SNF BAF complex subunit) with H73-methylated ACTB at specific loci, thereby regulating transcription of genes involved in cell adhesion and mRNA translation in colorectal cancer cells.","method":"Proteomic analysis of ACTB/SETD3-interacting complexes; ChIP-seq for SMARCA4 and H73-methylated ACTB; SETD3 knockout/knockdown; cell adhesion and translation phenotypic assays","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, ChIP-seq, KO, phenotypic assays) establishing a mechanistic axis (ACTB-SETD3-SMARCA4) in a single rigorous study","pmids":["41881543"],"is_preprint":false},{"year":2026,"finding":"ECE1c interacts with ACTB (demonstrated by co-immunoprecipitation) and activates the ROCK2 signaling pathway, together modulating cytoskeletal remodeling and promoting pseudopodia formation to increase glioblastoma cell invasiveness.","method":"Co-immunoprecipitation; immunofluorescence; Western blot; knockdown and overexpression experiments; tumor xenograft models","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus multiple functional assays (migration, invasion, pseudopodia) and in vivo validation, single lab","pmids":["42007117"],"is_preprint":false},{"year":1996,"finding":"FISH mapping localized the human β-cytoplasmic actin gene ACTB to chromosome 7p22, and identified and mapped related processed pseudogenes to other chromosomes (18, 15, 6).","method":"Fluorescence in situ hybridization (FISH); PCR of somatic cell hybrid DNAs","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct FISH localization with somatic cell hybrid confirmation, established chromosomal location","pmids":["8941379"],"is_preprint":false},{"year":2024,"finding":"Subsets of disease-causing ACTB missense variants cause dramatically dysregulated actin polymerization and depolymerization dynamics, and in iPSC-derived neuronal models these variants lead to neuronal migration defects, while ACTB nonsense/frameshift variants that cause rapid protein degradation result in milder phenotypes; heterozygous Actb knockout in mice causes altered neuronal cell morphology and abnormal expression of actin-related genes in newborn brains.","method":"Clinical genomics of 290 patients; iPSC-derived neuronal migration assays; actin polymerization/depolymerization dynamics; heterozygous Actb knockout mouse brain analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large patient cohort combined with iPSC, mouse, and biochemical models in a single preprint study; not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"Nine ACTB patient-associated missense mutations introduced into C. elegans act-2 (cytoplasmic actin orthologue) reveal a range of defects at the actin network, cell, morphogenesis, and behavioral levels, with severity correlating with clinical severity of patients' symptoms, establishing that these variants cause pathological actin dynamics.","method":"CRISPR insertion of patient mutations into C. elegans act-2; multiscale phenotypic characterization including actin network imaging, cell morphology, embryo morphogenesis, and behavioral assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic in vivo modeling of nine distinct variants with quantitative multiscale readouts; preprint, not peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"ACTB encodes cytoplasmic β-actin, a cytoskeletal protein whose polymerization dynamics, profilin binding, and subcellular localization (including at epithelial junctions and in the nucleus) are mechanistically linked to neuronal migration, cell adhesion, migration, proliferation, and stereocilia maintenance; gain-of-function missense mutations disrupt actin polymerization/depolymerization dynamics and cause Baraitser-Winter syndrome, loss-of-function causes a distinct pleiotropic developmental disorder with reduced nuclear β-actin and impaired cell migration/proliferation, SETD3-mediated H73 methylation of ACTB governs its genomic distribution and SMARCA4 colocalization to regulate transcription, and ACTB promoter-swap gene fusions (e.g., ACTB-GLI1) drive oncogenic transcription factor deregulation in mesenchymal tumors."},"narrative":{"mechanistic_narrative":"ACTB encodes cytoplasmic β-actin, a cytoskeletal protein whose polymerization dynamics underlie neuronal migration, cell adhesion, proliferation, and migration [PMID:22366783, PMID:29220674]. Its assembly behavior depends on interaction with profilin-1, which mutations in the actin C-terminus disrupt by lowering nucleation and polymerization rates and profilin affinity, with allosteric consequences for thermal stability, DNase-I binding, and nucleotide exchange [PMID:35313204]. Disease-associated missense variants act through dysregulated polymerization/depolymerization dynamics: distinct variants impair localization to epithelial junctions and profilin-1 binding, producing aberrant adhesion and migration [PMID:39271101], and they behave as dominant defects over wild-type actin [PMID:34970864]. β-actin functions both in the cytoplasm and in the nucleus, where its levels and activity are selectively reduced by loss-of-function mutations [PMID:29220674]; the protein is also subject to SETD3-mediated H73 methylation that governs its genomic distribution and enables SMARCA4 (SWI/SNF BAF) colocalization to regulate transcription of adhesion and translation genes [PMID:41881543]. De novo missense mutations in ACTB cause Baraitser-Winter syndrome, a neuronal migration disorder, whereas loss-of-function mutations produce a distinct pleiotropic developmental disorder [PMID:22366783, PMID:29220674]. β-actin protein is dispensable for general cellular function but specifically required to maintain auditory stereocilia integrity, distinguishing it functionally from γ-actin [PMID:30012594, PMID:32326615]. ACTB also acts oncogenically as a promoter donor: the t(7;12) ACTB-GLI fusion places GLI under the ubiquitous ACTB promoter, deregulating GLI expression and activating sonic hedgehog signaling [PMID:15111311, PMID:15555571].","teleology":[{"year":2004,"claim":"Established that ACTB can drive oncogenesis non-cytoskeletally, as a promoter-donating fusion partner rather than through its actin function.","evidence":"Cytogenetics, RT-PCR, and genomic breakpoint analysis of t(7;12) tumors with ACTB-GLI fusions","pmids":["15111311","15555571"],"confidence":"High","gaps":["Does not address whether the chimeric ACTB-GLI protein retains any actin-like property","Tumor-type specificity of the fusion not defined"]},{"year":2012,"claim":"Linked ACTB to human disease for the first time, showing cytoplasmic β-actin is required for normal neuronal migration and cortical development.","evidence":"Whole-exome trio sequencing identifying recurrent de novo missense mutations in Baraitser-Winter syndrome","pmids":["22366783"],"confidence":"High","gaps":["Genetic association did not define the molecular consequence of mutations on actin behavior","Cell-type basis of the migration defect not resolved"]},{"year":2013,"claim":"Provided first functional evidence that disease variants impair actin behavior, connecting genotype to a biochemical defect.","evidence":"In vitro polymer formation and cell adhesion assays of the p.E117K variant","pmids":["23649928"],"confidence":"Medium","gaps":["Single variant in a single lab","Did not identify the binding partners affected"]},{"year":2017,"claim":"Distinguished loss-of-function from gain-of-function disease and revealed a selective requirement for nuclear β-actin.","evidence":"siRNA knockdown, patient fibroblasts, subcellular fractionation, and proliferation/migration assays","pmids":["29220674"],"confidence":"High","gaps":["Mechanism by which nuclear but not cytoplasmic β-actin is selectively reduced unexplained","Nuclear actin's molecular targets not identified"]},{"year":2018,"claim":"Disentangled the β-actin protein from the ACTB locus, showing the protein sequence itself is dispensable except for stereocilia maintenance.","evidence":"CRISPR knock-in mouse translating γ-actin from the Actb locus, with audiology and stereocilia morphology","pmids":["30012594"],"confidence":"High","gaps":["Does not address roles encoded by ACTB regulatory/nucleotide sequence rather than protein","Molecular basis of stereocilia-specific requirement unknown"]},{"year":2020,"claim":"Defined non-redundant roles for β- versus γ-actin in adhesion and motility, refining which cellular processes depend specifically on ACTB.","evidence":"CRISPR/Cas9(D10A) knockout of ACTB and ACTG1 in melanoma cells with migration, invasion, and focal adhesion readouts","pmids":["32326615"],"confidence":"Medium","gaps":["Single cell line and single lab","Molecular basis of isoform-specific focal adhesion effects not defined"]},{"year":2021,"claim":"Identified upstream transcriptional control of ACTB, showing NRF-1 directly activates β-actin expression under hypoxia.","evidence":"ChIP, NRF-1 gain/loss-of-function, and β-actin protein measurement in gastric cancer and normal cells","pmids":["34097680"],"confidence":"Medium","gaps":["Single lab with limited orthogonal validation","Physiological role of hypoxic β-actin induction unclear"]},{"year":2021,"claim":"Demonstrated dominance of a disease variant over wild-type actin in vivo, supporting a dominant-functional disease mechanism.","evidence":"Yeast pseudoheterozygote expressing yACT1-S348L with temperature-dependent growth assays","pmids":["34970864"],"confidence":"Medium","gaps":["Single method in a yeast surrogate","Does not define the affected molecular interaction"]},{"year":2022,"claim":"Pinpointed disrupted actin-profilin interaction as a disease mechanism through reconstituted biochemistry.","evidence":"Recombinant mutant β-actin assembly, profilin-1 affinity, DNase-I binding, thermal stability, and nucleotide exchange assays for p.S368fs","pmids":["35313204"],"confidence":"High","gaps":["Biochemistry for one frameshift variant","Link from profilin defect to thrombocytopenia phenotype not directly tested"]},{"year":2024,"claim":"Connected the profilin-binding/junction-localization defect to a tissue phenotype, explaining orofacial clefting in Baraitser-Winter syndrome.","evidence":"Patient-derived MDCK lines and Xenopus embryos with junction localization and profilin-1 binding assays for p.S348L","pmids":["39271101"],"confidence":"Medium","gaps":["Single lab and single variant","Whether other variants share this junction-localization defect untested here"]},{"year":2026,"claim":"Revealed a chromatin function for β-actin in which SETD3-mediated H73 methylation directs its genomic distribution and partners it with SMARCA4 to regulate transcription.","evidence":"Proteomics, ChIP-seq of SMARCA4 and H73-methylated ACTB, SETD3 knockout, and adhesion/translation phenotypes in colorectal cancer cells","pmids":["41881543"],"confidence":"High","gaps":["How H73 methylation mechanistically recruits SMARCA4 not resolved","Generality beyond colorectal cancer cells untested"]},{"year":2026,"claim":"Implicated β-actin in a tumor-invasion signaling axis through interaction with ECE1c and ROCK2 activation.","evidence":"Reciprocal co-IP, knockdown/overexpression, pseudopodia and invasion assays, and xenograft models in glioblastoma","pmids":["42007117"],"confidence":"Medium","gaps":["Single lab","Direct biochemical mode of the ACTB-ECE1c interaction not mapped"]},{"year":null,"claim":"How allele-specific actin polymerization defects translate into the divergent neuronal-migration, adhesion, and tissue phenotypes across the ACTB variant spectrum remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking variant biophysics to organ-specific outcomes","Nuclear versus cytoplasmic contributions to each phenotype not separated","Preprint-stage iPSC, mouse, and C. elegans variant models await peer review"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,6]}],"complexes":["SWI/SNF (BAF) complex (via H73-methylated ACTB-SMARCA4 colocalization)"],"partners":["PFN1","SETD3","SMARCA4","ECE1","NRF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P60709","full_name":"Actin, cytoplasmic 1","aliases":["Beta-actin"],"length_aa":375,"mass_kda":41.7,"function":"Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells (PubMed:25255767, PubMed:29581253). Actin exists in both monomeric (G-actin) and polymeric (F-actin) forms, both forms playing key functions, such as cell motility and contraction (PubMed:29581253). In addition to their role in the cytoplasmic cytoskeleton, G- and F-actin also localize in the nucleus, and regulate gene transcription and motility and repair of damaged DNA (PubMed:29925947). Plays a role in the assembly of the gamma-tubulin ring complex (gTuRC), which regulates the minus-end nucleation of alpha-beta tubulin heterodimers that grow into microtubule protafilaments (PubMed:39321809, PubMed:38609661). Part of the ACTR1A/ACTB filament around which the dynactin complex is built (By similarity). The dynactin multiprotein complex activates the molecular motor dynein for ultra-processive transport along microtubules (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Nucleus","url":"https://www.uniprot.org/uniprotkb/P60709/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTB","classification":"Common Essential","n_dependent_lines":891,"n_total_lines":1208,"dependency_fraction":0.7375827814569537},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000075624","cell_line_id":"CID000002","localizations":[{"compartment":"cytoskeleton","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"TMSB10","stoichiometry":10.0},{"gene":"YWHAE","stoichiometry":10.0},{"gene":"CCT2","stoichiometry":10.0},{"gene":"CCT7","stoichiometry":10.0},{"gene":"HIST1H2AJ;HIST1H2AH;HIST1H2AG;H2AFJ","stoichiometry":10.0},{"gene":"TCP1","stoichiometry":10.0},{"gene":"CFL1","stoichiometry":10.0},{"gene":"PFN1","stoichiometry":10.0},{"gene":"CCT8","stoichiometry":10.0},{"gene":"CCT4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000002","total_profiled":1310},"omim":[{"mim_id":"621441","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 32; SPATA32","url":"https://www.omim.org/entry/621441"},{"mim_id":"620781","title":"TRANSMEMBRANE PROTEIN 208; TMEM208","url":"https://www.omim.org/entry/620781"},{"mim_id":"620475","title":"THROMBOCYTOPENIA 8, WITH DYSMORPHIC FEATURES AND DEVELOPMENTAL DELAY; THC8","url":"https://www.omim.org/entry/620475"},{"mim_id":"620470","title":"CONGENITAL SMOOTH MUSCLE HAMARTOMA, WITH OR WITHOUT HEMIHYPERTROPHY; CSMH","url":"https://www.omim.org/entry/620470"},{"mim_id":"620392","title":"ACTIN-BINDING TRANSCRIPTION MODULATOR; ABITRAM","url":"https://www.omim.org/entry/620392"}],"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/ACTB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P60709","domains":[{"cath_id":"3.30.420.40","chopping":"7-137_339-372","consensus_level":"medium","plddt":94.3218,"start":7,"end":372},{"cath_id":"3.30.420.40","chopping":"142-179_272-334","consensus_level":"medium","plddt":97.3954,"start":142,"end":334},{"cath_id":"3.90.640.10","chopping":"181-260","consensus_level":"high","plddt":96.8434,"start":181,"end":260}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P60709","model_url":"https://alphafold.ebi.ac.uk/files/AF-P60709-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P60709-F1-predicted_aligned_error_v6.png","plddt_mean":95.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTB","jax_strain_url":"https://www.jax.org/strain/search?query=ACTB"},"sequence":{"accession":"P60709","fasta_url":"https://rest.uniprot.org/uniprotkb/P60709.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P60709/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P60709"}},"corpus_meta":[{"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":"30459475","id":"PMC_30459475","title":"Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma.","date":"2018","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/30459475","citation_count":145,"is_preprint":false},{"pmid":"23266771","id":"PMC_23266771","title":"ACTB in cancer.","date":"2012","source":"Clinica chimica acta; 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A clinicopathologic and molecular study of 13 cases. Tumors harboring MALAT1-TFEB, ACTB-TFEB, and the novel NEAT1-TFEB translocations constantly express PDL1.","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/33208882","citation_count":46,"is_preprint":false},{"pmid":"26980027","id":"PMC_26980027","title":"Translocation t(7;12) as the sole chromosomal abnormality resulting in ACTB-GLI1 fusion in pediatric gastric pericytoma.","date":"2016","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26980027","citation_count":42,"is_preprint":false},{"pmid":"23289769","id":"PMC_23289769","title":"Familial or Sporadic Idiopathic Scoliosis - classification based on artificial neural network and GAPDH and ACTB transcription profile.","date":"2013","source":"Biomedical engineering 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  \"finding\": \"De novo missense mutations in ACTB cause Baraitser-Winter syndrome, a neuronal migration disorder with craniofacial features and ocular colobomata, establishing that cytoplasmic β-actin is required for normal neuronal migration and cortical development.\",\n      \"method\": \"Whole-exome sequencing of proband-parent trios followed by Sanger sequencing of additional affected individuals\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — exome sequencing with trio-based validation in 18 affected individuals across multiple labs; recurrent de novo mutations at same residues replicated independently\",\n      \"pmids\": [\"22366783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A de novo ACTB p.E117K missense variant alters cell adhesion and actin polymer formation, demonstrating that disease-associated ACTB mutations functionally impair actin polymerization dynamics.\",\n      \"method\": \"Exome sequencing to identify variant, followed by in vitro functional characterization of mutant actin including polymer formation assays and cell adhesion assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays (polymerization, adhesion) in single lab with two orthogonal methods on a specific variant\",\n      \"pmids\": [\"23649928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Heterozygous ACTB loss-of-function mutations cause reduced cell proliferation, altered cell shape and migration, and decreased nuclear (but not cytoplasmic) β-actin levels, demonstrating that ACTB is required for normal cell proliferation, migration, and nuclear actin function.\",\n      \"method\": \"ACTB siRNA knockdown in wild-type fibroblasts and analysis of fibroblasts from affected individuals; cell shape, migration, and proliferation assays; subcellular fractionation to measure nuclear vs. cytoplasmic β-actin\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, patient cells, fractionation, functional assays) in a single rigorous study with ≥33 affected individuals\",\n      \"pmids\": [\"29220674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"β-actin protein per se is not required for general cellular functions, but is specifically necessary to maintain auditory stereocilia integrity, as mice with the Actb locus gene-edited to produce only γ-actin protein are viable but develop progressive high-frequency hearing loss and stereocilia degeneration.\",\n      \"method\": \"CRISPR gene editing of endogenous mouse Actb locus to translate γ-actin protein (knock-in); audiological testing and stereocilia morphology analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — precise knock-in allele replacing β-actin protein with γ-actin in vivo, orthogonal functional and morphological validation\",\n      \"pmids\": [\"30012594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The ACTB p.S368fs frameshift mutation causes a C-terminal alteration that markedly reduces actin nucleation and polymerization rates and lowers affinity for profilin-1, with allosteric effects including reduced thermal stability, altered DNase-I binding, and changed nucleotide exchange kinetics, implicating disrupted actin-profilin interaction as the disease mechanism in ACTB-associated syndromic thrombocytopenia.\",\n      \"method\": \"Recombinant production of mutant β-actin; in vitro spontaneous actin assembly assays; profilin-1 affinity measurements; DNase-I inhibition assay; thermal denaturation; nucleotide exchange kinetics\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro biochemistry with multiple orthogonal assays (polymerization, affinity, stability, nucleotide exchange) in single rigorous study\",\n      \"pmids\": [\"35313204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9-mediated knockout of ACTB in human melanoma cells shows that β-actin and γ-actin play distinct roles: ACTB knockout alters focal adhesion (FA) formation and FA-dependent signaling, while ACTG1 knockout more severely impairs cell migration, invasion, and lamellipodia formation, and increases bundled stress fibers.\",\n      \"method\": \"CRISPR/Cas9(D10A)-mediated gene inactivation; migration and invasion assays; FA formation and signaling analysis; actin isoform distribution by immunofluorescence\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple functional readouts (migration, invasion, FA, signaling) in single lab\",\n      \"pmids\": [\"32326615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A chromosomal translocation t(7;12) fuses the 5'-portion of ACTB (including its promoter) to the 3'-portion of GLI, placing GLI under the control of the ubiquitously expressed ACTB promoter and causing deregulated GLI expression and activation of the sonic hedgehog pathway.\",\n      \"method\": \"Cytogenetics, RT-PCR, molecular genetic analysis of genomic breakpoints, electron microscopy of tumor phenotype\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fusion transcript confirmed in five independent tumors, genomic breakpoints characterized, mechanism (promoter swap) established\",\n      \"pmids\": [\"15111311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The ACTB-GLI fusion at the genomic level results from juxtaposition of intronic or exonic sequences (with one case showing a micro-inversion at the junction) without large repeats, and the fusions are molecularly unbalanced; the first 41 amino acids of ACTB replace the first 177 amino acids of GLI1 in the putative fusion protein.\",\n      \"method\": \"RT-PCR, Sanger sequencing of genomic breakpoints, bioinformatic analysis of recombination sequences\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of five independent tumor breakpoints, replicated across multiple cases\",\n      \"pmids\": [\"15555571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Functional analysis in a haploid S. cerevisiae pseudoheterozygote model demonstrates that the ACTB p.Ser348Leu variant causes a dominant growth defect at 22°C but not 30°C, consistent with the mutation having a dominant functional defect over wild-type actin.\",\n      \"method\": \"Yeast pseudoheterozygote model expressing yACT1-S348L alongside wild-type; growth assay at different temperatures\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vivo yeast reconstitution with temperature-sensitive dominant growth phenotype, but single lab and single method\",\n      \"pmids\": [\"34970864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The ACTB p.S348L variant impairs the ability of mutant β-actin to localize to epithelial junctions and to bind PROFILIN1, compromising actin polymerization and causing aberrant epithelial cell adhesion and migration, which underlies the orofacial cleft phenotype in Baraitser-Winter syndrome.\",\n      \"method\": \"Patient-derived MDCK cell line models and Xenopus laevis embryo functional assays; junction localization imaging; profilin-1 binding assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple disease models (cell line + Xenopus) with orthogonal functional assays (localization, binding, cell behavior), single lab\",\n      \"pmids\": [\"39271101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nuclear respiratory factor-1 (NRF-1) directly binds to the coding region of the ACTB gene and transcriptionally activates β-actin expression under hypoxic conditions, as NRF-1 levels and β-actin levels change concordantly with NRF-1 overexpression or silencing.\",\n      \"method\": \"ChIP experiments demonstrating NRF-1 binding to ACTB/Actb coding regions; NRF-1 overexpression and knockdown with β-actin protein level measurement; hypoxia treatment of gastric cancer and normal cells\",\n      \"journal\": \"Molekuliarnaia biologiia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP plus gain/loss-of-function, but single lab and limited orthogonal validation\",\n      \"pmids\": [\"34097680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SETD3-mediated methylation of ACTB at H73 is required for ACTB's genomic distribution, and this modification enables colocalization of SMARCA4 (a SWI/SNF BAF complex subunit) with H73-methylated ACTB at specific loci, thereby regulating transcription of genes involved in cell adhesion and mRNA translation in colorectal cancer cells.\",\n      \"method\": \"Proteomic analysis of ACTB/SETD3-interacting complexes; ChIP-seq for SMARCA4 and H73-methylated ACTB; SETD3 knockout/knockdown; cell adhesion and translation phenotypic assays\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, ChIP-seq, KO, phenotypic assays) establishing a mechanistic axis (ACTB-SETD3-SMARCA4) in a single rigorous study\",\n      \"pmids\": [\"41881543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ECE1c interacts with ACTB (demonstrated by co-immunoprecipitation) and activates the ROCK2 signaling pathway, together modulating cytoskeletal remodeling and promoting pseudopodia formation to increase glioblastoma cell invasiveness.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; Western blot; knockdown and overexpression experiments; tumor xenograft models\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus multiple functional assays (migration, invasion, pseudopodia) and in vivo validation, single lab\",\n      \"pmids\": [\"42007117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"FISH mapping localized the human β-cytoplasmic actin gene ACTB to chromosome 7p22, and identified and mapped related processed pseudogenes to other chromosomes (18, 15, 6).\",\n      \"method\": \"Fluorescence in situ hybridization (FISH); PCR of somatic cell hybrid DNAs\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct FISH localization with somatic cell hybrid confirmation, established chromosomal location\",\n      \"pmids\": [\"8941379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Subsets of disease-causing ACTB missense variants cause dramatically dysregulated actin polymerization and depolymerization dynamics, and in iPSC-derived neuronal models these variants lead to neuronal migration defects, while ACTB nonsense/frameshift variants that cause rapid protein degradation result in milder phenotypes; heterozygous Actb knockout in mice causes altered neuronal cell morphology and abnormal expression of actin-related genes in newborn brains.\",\n      \"method\": \"Clinical genomics of 290 patients; iPSC-derived neuronal migration assays; actin polymerization/depolymerization dynamics; heterozygous Actb knockout mouse brain analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large patient cohort combined with iPSC, mouse, and biochemical models in a single preprint study; not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nine ACTB patient-associated missense mutations introduced into C. elegans act-2 (cytoplasmic actin orthologue) reveal a range of defects at the actin network, cell, morphogenesis, and behavioral levels, with severity correlating with clinical severity of patients' symptoms, establishing that these variants cause pathological actin dynamics.\",\n      \"method\": \"CRISPR insertion of patient mutations into C. elegans act-2; multiscale phenotypic characterization including actin network imaging, cell morphology, embryo morphogenesis, and behavioral assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic in vivo modeling of nine distinct variants with quantitative multiscale readouts; preprint, not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ACTB encodes cytoplasmic β-actin, a cytoskeletal protein whose polymerization dynamics, profilin binding, and subcellular localization (including at epithelial junctions and in the nucleus) are mechanistically linked to neuronal migration, cell adhesion, migration, proliferation, and stereocilia maintenance; gain-of-function missense mutations disrupt actin polymerization/depolymerization dynamics and cause Baraitser-Winter syndrome, loss-of-function causes a distinct pleiotropic developmental disorder with reduced nuclear β-actin and impaired cell migration/proliferation, SETD3-mediated H73 methylation of ACTB governs its genomic distribution and SMARCA4 colocalization to regulate transcription, and ACTB promoter-swap gene fusions (e.g., ACTB-GLI1) drive oncogenic transcription factor deregulation in mesenchymal tumors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTB encodes cytoplasmic β-actin, a cytoskeletal protein whose polymerization dynamics underlie neuronal migration, cell adhesion, proliferation, and migration [#0, #2]. Its assembly behavior depends on interaction with profilin-1, which mutations in the actin C-terminus disrupt by lowering nucleation and polymerization rates and profilin affinity, with allosteric consequences for thermal stability, DNase-I binding, and nucleotide exchange [#4]. Disease-associated missense variants act through dysregulated polymerization/depolymerization dynamics: distinct variants impair localization to epithelial junctions and profilin-1 binding, producing aberrant adhesion and migration [#9], and they behave as dominant defects over wild-type actin [#8]. β-actin functions both in the cytoplasm and in the nucleus, where its levels and activity are selectively reduced by loss-of-function mutations [#2]; the protein is also subject to SETD3-mediated H73 methylation that governs its genomic distribution and enables SMARCA4 (SWI/SNF BAF) colocalization to regulate transcription of adhesion and translation genes [#11]. De novo missense mutations in ACTB cause Baraitser-Winter syndrome, a neuronal migration disorder, whereas loss-of-function mutations produce a distinct pleiotropic developmental disorder [#0, #2]. β-actin protein is dispensable for general cellular function but specifically required to maintain auditory stereocilia integrity, distinguishing it functionally from γ-actin [#3, #5]. ACTB also acts oncogenically as a promoter donor: the t(7;12) ACTB-GLI fusion places GLI under the ubiquitous ACTB promoter, deregulating GLI expression and activating sonic hedgehog signaling [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that ACTB can drive oncogenesis non-cytoskeletally, as a promoter-donating fusion partner rather than through its actin function.\",\n      \"evidence\": \"Cytogenetics, RT-PCR, and genomic breakpoint analysis of t(7;12) tumors with ACTB-GLI fusions\",\n      \"pmids\": [\"15111311\", \"15555571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address whether the chimeric ACTB-GLI protein retains any actin-like property\", \"Tumor-type specificity of the fusion not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ACTB to human disease for the first time, showing cytoplasmic β-actin is required for normal neuronal migration and cortical development.\",\n      \"evidence\": \"Whole-exome trio sequencing identifying recurrent de novo missense mutations in Baraitser-Winter syndrome\",\n      \"pmids\": [\"22366783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic association did not define the molecular consequence of mutations on actin behavior\", \"Cell-type basis of the migration defect not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided first functional evidence that disease variants impair actin behavior, connecting genotype to a biochemical defect.\",\n      \"evidence\": \"In vitro polymer formation and cell adhesion assays of the p.E117K variant\",\n      \"pmids\": [\"23649928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant in a single lab\", \"Did not identify the binding partners affected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished loss-of-function from gain-of-function disease and revealed a selective requirement for nuclear β-actin.\",\n      \"evidence\": \"siRNA knockdown, patient fibroblasts, subcellular fractionation, and proliferation/migration assays\",\n      \"pmids\": [\"29220674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which nuclear but not cytoplasmic β-actin is selectively reduced unexplained\", \"Nuclear actin's molecular targets not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Disentangled the β-actin protein from the ACTB locus, showing the protein sequence itself is dispensable except for stereocilia maintenance.\",\n      \"evidence\": \"CRISPR knock-in mouse translating γ-actin from the Actb locus, with audiology and stereocilia morphology\",\n      \"pmids\": [\"30012594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address roles encoded by ACTB regulatory/nucleotide sequence rather than protein\", \"Molecular basis of stereocilia-specific requirement unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined non-redundant roles for β- versus γ-actin in adhesion and motility, refining which cellular processes depend specifically on ACTB.\",\n      \"evidence\": \"CRISPR/Cas9(D10A) knockout of ACTB and ACTG1 in melanoma cells with migration, invasion, and focal adhesion readouts\",\n      \"pmids\": [\"32326615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line and single lab\", \"Molecular basis of isoform-specific focal adhesion effects not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified upstream transcriptional control of ACTB, showing NRF-1 directly activates β-actin expression under hypoxia.\",\n      \"evidence\": \"ChIP, NRF-1 gain/loss-of-function, and β-actin protein measurement in gastric cancer and normal cells\",\n      \"pmids\": [\"34097680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab with limited orthogonal validation\", \"Physiological role of hypoxic β-actin induction unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated dominance of a disease variant over wild-type actin in vivo, supporting a dominant-functional disease mechanism.\",\n      \"evidence\": \"Yeast pseudoheterozygote expressing yACT1-S348L with temperature-dependent growth assays\",\n      \"pmids\": [\"34970864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method in a yeast surrogate\", \"Does not define the affected molecular interaction\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pinpointed disrupted actin-profilin interaction as a disease mechanism through reconstituted biochemistry.\",\n      \"evidence\": \"Recombinant mutant β-actin assembly, profilin-1 affinity, DNase-I binding, thermal stability, and nucleotide exchange assays for p.S368fs\",\n      \"pmids\": [\"35313204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemistry for one frameshift variant\", \"Link from profilin defect to thrombocytopenia phenotype not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the profilin-binding/junction-localization defect to a tissue phenotype, explaining orofacial clefting in Baraitser-Winter syndrome.\",\n      \"evidence\": \"Patient-derived MDCK lines and Xenopus embryos with junction localization and profilin-1 binding assays for p.S348L\",\n      \"pmids\": [\"39271101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and single variant\", \"Whether other variants share this junction-localization defect untested here\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a chromatin function for β-actin in which SETD3-mediated H73 methylation directs its genomic distribution and partners it with SMARCA4 to regulate transcription.\",\n      \"evidence\": \"Proteomics, ChIP-seq of SMARCA4 and H73-methylated ACTB, SETD3 knockout, and adhesion/translation phenotypes in colorectal cancer cells\",\n      \"pmids\": [\"41881543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H73 methylation mechanistically recruits SMARCA4 not resolved\", \"Generality beyond colorectal cancer cells untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated β-actin in a tumor-invasion signaling axis through interaction with ECE1c and ROCK2 activation.\",\n      \"evidence\": \"Reciprocal co-IP, knockdown/overexpression, pseudopodia and invasion assays, and xenograft models in glioblastoma\",\n      \"pmids\": [\"42007117\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct biochemical mode of the ACTB-ECE1c interaction not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How allele-specific actin polymerization defects translate into the divergent neuronal-migration, adhesion, and tissue phenotypes across the ACTB variant spectrum remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking variant biophysics to organ-specific outcomes\", \"Nuclear versus cytoplasmic contributions to each phenotype not separated\", \"Preprint-stage iPSC, mouse, and C. elegans variant models await peer review\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 6]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF) complex (via H73-methylated ACTB-SMARCA4 colocalization)\"],\n    \"partners\": [\"PFN1\", \"SETD3\", \"SMARCA4\", \"ECE1\", \"NRF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}