Affinage

ACTC1

Actin, alpha cardiac muscle 1 · UniProt P68032

Length
377 aa
Mass
42.0 kDa
Annotated
2026-06-09
30 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACTC1 (cardiac α-actin) is a sarcomeric thin-filament protein that drives cardiac and skeletal muscle contraction through actin–myosin interactions, and proper actin polymerization is required for sarcomere integrity, contractile function, and survival of cardiomyocytes (PMID:31430208, PMID:20962418). Pathogenic missense mutations act through distinct biophysical mechanisms depending on their location: E99K elevates myofibrillar Ca²⁺ sensitivity, producing hypercontractility with slowed relaxation and disproportionate energy cost, and links this gain in sensitivity to aberrant sarcoplasmic reticulum Ca²⁺ release and arrhythmogenesis (PMID:21622575, PMID:23604709, PMID:28887330). Both E99K and the DCM-causing E361G mutation uncouple thin-filament regulation from troponin I phosphorylation, abolishing the normal phosphorylation-dependent decrease in Ca²⁺ sensitivity that tunes relaxation kinetics (PMID:21622575, PMID:25418306). A separate class of mutation typified by G247D impairs actin polymerization and turnover, reduces Rho-GTPase activity and SRF signaling while increasing nuclear globular actin, and causes sarcomeric disarray and apoptosis (PMID:31434612, PMID:31430208). Structural mapping further indicates that mutations on the actin surface contacting the myosin head correspond to congenital heart defects, while mutations on a distinct myosin-interaction surface cause cardiomyopathy (PMID:26061005). ACTC1 expression is controlled post-transcriptionally by miR-139-5p and by promoter DNA methylation and transcription-factor binding at its promoter (PMID:27139165, PMID:28847732, PMID:40848833). Beyond the cardiac sarcomere, ACTC1 physically associates with the cardiac band 3 (AE1) anion exchanger at intercalated discs and with LMOD2 in skeletal muscle (PMID:12898519, PMID:40745266).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 Medium

    Established a physical partner of cardiac α-actin outside the contractile apparatus, placing ACTC1 at the intercalated disc.

    Evidence Yeast two-hybrid with band 3 cytoplasmic domain bait, reciprocal Co-IP from rat heart, confocal co-localization

    PMID:12898519

    Open questions at the time
    • Functional consequence of the ACTC1–band 3 interaction not tested
    • Interface residues unmapped
  2. 2010 Medium

    Demonstrated that ACTC1 expression itself is required to suppress cardiomyocyte apoptosis, moving the gene beyond a passive structural role.

    Evidence siRNA knockdown in H9C2 cells with TUNEL and Caspase-3/Bcl-2 readouts, plus patient tissue correlation

    PMID:20962418

    Open questions at the time
    • Mechanism linking actin loss to intrinsic apoptosis not defined
    • Single cell line
  3. 2011 High

    Defined the biophysical mechanism of the HCM E99K mutation as elevated myofibrillar Ca²⁺ sensitivity with loss of troponin I phosphorylation-dependent modulation.

    Evidence In vitro motility on reconstituted thin filaments and skinned papillary muscle in transgenic mouse and human carrier samples

    PMID:21622575

    Open questions at the time
    • Does not address downstream Ca²⁺ handling consequences
    • Mechanism by which E99K blocks phosphorylation coupling unresolved
  4. 2013 High

    Connected E99K's elevated Ca²⁺ sensitivity to whole-muscle hypercontractility, slowed relaxation, and energetic inefficiency, distinguishing myofilament from Ca²⁺-transient causes.

    Evidence Intact papillary muscle mechanics, myofibril Ca²⁺-jump, and myocyte Ca²⁺ imaging in E99K transgenic mice

    PMID:23604709

    Open questions at the time
    • Does not establish arrhythmic mechanism
    • Energetic penalty mechanism not detailed
  5. 2014 High

    Generalized the troponin I phosphorylation uncoupling mechanism to the DCM mutation E361G, defining the actin–troponin interface as the route by which phosphorylation regulates relaxation.

    Evidence Ca²⁺-jump on single transgenic myofibrils with pharmacological manipulation of troponin I phosphorylation

    PMID:25418306

    Open questions at the time
    • Does not explain how the same defect yields DCM vs HCM
    • Structural basis of uncoupling unresolved
  6. 2016 Medium

    Identified post-transcriptional control of ACTC1, showing a 3'UTR variant creates a miR-139-5p site that represses ACTC1 protein.

    Evidence Luciferase reporter with WT/mutant 3'UTR plus miR-139-5p mimic and inhibitor rescue

    PMID:27139165

    Open questions at the time
    • Endogenous physiological relevance of miR-139-5p regulation not shown
    • Tissue context limited
  7. 2017 Medium

    Linked E99K-driven myofilament Ca²⁺ sensitization to aberrant SR Ca²⁺ release and arrhythmogenesis, with strong genetic-background modification of penetrance.

    Evidence Isolated myocyte Ca²⁺ imaging (transients, sparks, waves) in young transgenic mice on two backgrounds

    PMID:28887330

    Open questions at the time
    • Molecular link between myofilament sensitivity and SR release unresolved
    • Background modifier genes unidentified
  8. 2017 Medium

    Identified promoter DNA methylation as a transcriptional regulator of Actc1, ruling out histone and chromatin-accessibility changes.

    Evidence Expression QTL mapping, bisulfite sequencing, ChIP and ATAC-seq across Collaborative Cross strains

    PMID:28847732

    Open questions at the time
    • Causality of methylation vs expression not directly tested
    • Responsible methyltransferases/factors unknown
  9. 2018 Medium

    Validated the Ca²⁺-handling mechanism of E99K HCM in a human isogenic cell model and showed pharmacological rescue.

    Evidence Isogenic hiPSC-CM 3D and 2D Ca²⁺ imaging with dantrolene/ranolazine rescue

    PMID:30392975

    Open questions at the time
    • Long-term and in vivo efficacy of rescue not assessed
    • Single lab
  10. 2019 Medium

    Defined a polymerization-based mechanism for G247D, linking impaired actin assembly to reduced Rho-GTPase/SRF signaling and nuclear actin accumulation, and to sarcomeric disarray and apoptosis.

    Evidence In vitro polymerization, Rho-GTPase pulldown, SRF luciferase, fractionation/IF, patient EM, proteomics and molecular dynamics in NRVCMs/C2C12

    PMID:31430208 PMID:31434612

    Open questions at the time
    • Direct demonstration of SRF target dysregulation in vivo lacking
    • Overexpression model may not reflect heterozygous dosage
  11. 2025 Low

    Established LMOD2 as a physical partner of ACTC1 with a role in myogenic differentiation and fiber-type composition.

    Evidence Co-IP in C2C12 cells with LMOD2 CRISPR knockout, RNA-seq and MyHC/PAX7 Western blots

    PMID:40745266

    Open questions at the time
    • Single Co-IP without reciprocal validation
    • Functional role of the ACTC1–LMOD2 complex specifically inferred, not directly tested
  12. 2025 Medium

    Implicated ACTC1 promoter variants in VSD by altering transcription-factor binding and promoter activity.

    Evidence Dual luciferase in HL-1 cardiomyocytes and EMSA across patient-specific variants

    PMID:40848833

    Open questions at the time
    • Specific transcription factors not identified
    • In vivo expression consequences not measured
  13. 2025 Low

    Reported a non-muscle oncogenic role, defining an ACTC1–BMP4 axis promoting prostate cancer proliferation and migration.

    Evidence Overexpression/knockdown with proliferation, migration, xenograft, transcriptomics, and BMP4 rescue

    PMID:41286808

    Open questions at the time
    • No direct biochemical link between ACTC1 and BMP4
    • Pathway placement inferred from transcriptomics only

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single thin-filament protein produces opposite clinical outcomes (HCM vs DCM vs congenital defect vs arrhythmia) from mutation position, and how its cytoskeletal/signaling roles in non-muscle cells relate to its sarcomeric function, remains unresolved.
  • No unified structural model relating mutation surface to clinical phenotype with functional validation
  • Non-muscle ACTC1 signaling mechanisms unmapped
  • Direct in vivo validation of regulatory inputs (miRNA, methylation, TF binding) on ACTC1 dosage lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1
Pathway
R-HSA-397014 Muscle contraction 2 R-HSA-162582 Signal Transduction 1
Partners
LMOD2SLC4A1
Complex memberships
sarcomere thin filament

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 The ACTC1 E99K mutation increases myofibrillar Ca²⁺ sensitivity 2.3-fold in transgenic mouse thin filaments (1.3-fold in human carrier samples) as measured by in vitro motility assay and skinned papillary muscle, and specifically abolishes the normal decrease in Ca²⁺ sensitivity linked to troponin I phosphorylation. In vitro motility assay on reconstituted thin filaments, skinned papillary muscle Ca²⁺ sensitivity measurements, transgenic mouse model expressing E99K at 50% of total heart actin The Journal of biological chemistry High 21622575
2014 The DCM-causing ACTC1 E361G mutation specifically abolishes Ca²⁺ sensitivity modulation by troponin I phosphorylation in intact cardiac myofibrils, without affecting length-dependent activation or response to EMD57033, confirming that troponin I phosphorylation acts through the actin-troponin interface to regulate relaxation kinetics. Ca²⁺-jump protocol on single transgenic mouse heart myofibrils; comparison of isometric tension and relaxation parameters (kREL, tLIN) in myofibrils with varying troponin I phosphorylation levels (propranolol-treated vs. control mice) Biophysical journal High 25418306
2013 ACTC1 E99K papillary muscle produces 3–4× greater isometric twitch force than non-transgenic muscle, relaxes 1.4× slower, and consumes disproportionately more energy (efficiency 11–16% vs. 15–18%), with hypercontractility attributable to elevated myofibrillar Ca²⁺ sensitivity (EC₅₀ 0.39 vs. 0.80 µmol/L) rather than altered Ca²⁺ transient amplitude. Intact papillary muscle mechanics (force, heat, work), isolated myofibril Ca²⁺-jump protocol, isolated myocyte Ca²⁺ transient imaging in ACTC E99K transgenic mouse model American journal of physiology. Heart and circulatory physiology High 23604709
2017 Young ACTC1 E99K transgenic mice prone to sudden cardiac death exhibit increased Ca²⁺ transient amplitude, greater Ca²⁺ spark mass, and increased propensity for spontaneous Ca²⁺ waves compared with non-transgenic littermates despite similar sarcoplasmic reticulum Ca²⁺ content, linking the actin mutation's elevated myofilament Ca²⁺ sensitivity to aberrant SR Ca²⁺ release and arrhythmogenesis. Penetrance of sudden death is strongly modified by genetic background (CBA/Ca vs. C57Bl6). Isolated ventricular myocyte Ca²⁺ imaging (transients, sparks, waves), confocal microscopy, collagen quantification, comparison of young vs. adult TG and NTG mice on two genetic backgrounds American journal of physiology. Heart and circulatory physiology Medium 28887330
2018 Isogenic hiPSC-CMs carrying the ACTC1 E99K mutation display arrhythmogenesis in both 3D engineered heart tissues and 2D monolayers, with Ca²⁺ handling defects identified as the mechanistic basis; dual dantrolene/ranolazine treatment rescued the phenotype, confirming that aberrant Ca²⁺ handling drives the E99K-associated HCM phenotype. Isogenic hiPSC-CM pairs (heterozygous and homozygous E99K), 3D engineered heart tissue and 2D monolayer Ca²⁺ imaging, pharmacological rescue with dantrolene and ranolazine Stem cell reports Medium 30392975
2019 The ACTC1 G247D (Gly247Asp) mutation causes actin polymerization/turnover defects (confirmed by in vitro actin polymerization assays), reduces GTP-bound Rho-GTPase activity, increases nuclear localization of globular actin, and thereby abolishes SRF-signaling activation in neonatal rat cardiomyocytes and C2C12 cells. In vitro actin polymerization assay, luciferase reporter (SM22-RE-driven), Rho-GTPase activity assay (GTP-pull-down), nuclear/cytoplasmic fractionation with immunofluorescence in NRVCMs overexpressing mutant vs. wild-type ACTC1 Biochemical and biophysical research communications Medium 31434612
2019 The ACTC1 G247D mutation leads to sarcomeric disarray, myofibrillar degeneration, increased apoptosis, and defective actin polymerization/turnover in both patient myocardial tissue and in neonatal rat ventricular cardiomyocytes overexpressing mutant ACTC1, demonstrating that normal ACTC1 polymerization is required for sarcomere integrity and contractile function. Ultrastructural analysis of patient cardiac tissue (electron microscopy), cardiac proteomics, overexpression of mutant vs. native ACTC1 in NRVCMs with structural and apoptosis readouts, molecular dynamics simulation, in vitro actin polymerization assay Circulation. Genomic and precision medicine Medium 31430208
2003 Alpha-cardiac actin (ACTC1) physically binds to the cardiac isoform of band 3 (AE1 anion exchanger) at the intercalated disc; interaction identified by yeast two-hybrid using the cytoplasmic domain of band 3 as bait, confirmed by reciprocal co-immunoprecipitation from rat heart and co-localized by confocal microscopy. Yeast two-hybrid screen, reciprocal co-immunoprecipitation from whole rat heart, confocal microscopy immunolocalization Journal of cellular biochemistry Medium 12898519
2010 siRNA-mediated knockdown of ACTC1 in H9C2 cardiomyocyte cells increases apoptosis with elevated Caspase-3 and reduced Bcl-2 expression, indicating that ACTC1 expression is required to suppress the intrinsic apoptotic pathway in cardiomyocytes. siRNA knockdown of Actc1 in H9C2 cells, TUNEL assay, Western blot for Caspase-3 and Bcl-2, corroborated by RT-PCR and immunohistochemistry of patient cardiac tissue samples Circulation journal : official journal of the Japanese Circulation Society Medium 20962418
2025 LMOD2 interacts with ACTC1 (confirmed by co-immunoprecipitation) and this interaction is involved in regulating myogenic differentiation; LMOD2 knockout alters muscle fiber type composition and suppresses myoblast proliferation in C2C12 cells. Co-immunoprecipitation in C2C12 cells, LMOD2 knockout by CRISPR, RNA-seq, Western blot for myosin heavy chain isoforms and PAX7 BMC genomics Low 40745266
2016 A 3'UTR mutation in ACTC1 (c.*1784T>C) creates a new binding site for miR-139-5p, which specifically reduces ACTC1 protein expression; miR-139-5p mimic further decreases expression while miR-139-5p inhibitor rescues the decline, identifying miR-139-5p as a post-transcriptional repressor of ACTC1 through this gain-of-function mutation. Luciferase reporter assay with wild-type and mutant ACTC1 3'UTR constructs, miR-139-5p mimic and inhibitor transfection, whole genome sequencing for variant discovery Scientific reports Medium 27139165
2017 Actc1 expression in early adult skeletal muscle is negatively correlated with DNA methylation around its transcriptional start site in a strain-dependent manner (Collaborative Cross mouse panel), while histone modification and chromatin accessibility marks at the locus are unaltered, identifying promoter methylation as a regulatory mechanism controlling Actc1 transcript levels. Expression QTL mapping in Collaborative Cross mice, bisulfite sequencing/methylation analysis, histone ChIP, ATAC-seq at Actc1 locus across strains with up to 24-fold expression variation Biochimica et biophysica acta. Gene regulatory mechanisms Medium 28847732
2025 ACTC1 overexpression in prostate cancer cells promotes proliferation and migration, and drives tumor growth in xenograft models; BMP4 was identified as a key downstream effector, and BMP4 overexpression rescued the inhibitory effects of ACTC1 knockdown, defining an ACTC1–BMP4 signaling axis. ACTC1 overexpression and siRNA knockdown in prostate cancer cell lines (proliferation and migration assays), xenograft tumor growth, transcriptomic/pathway analysis, BMP4 rescue experiment BMC cancer Low 41286808
2025 ACTC1 promoter variants found exclusively in VSD patients significantly alter ACTC1 promoter transcriptional activity in mouse cardiomyocytes (HL-1), and EMSA demonstrates that these variants affect transcription factor binding at the ACTC1 promoter, implicating disrupted transcription factor recruitment as a mechanism of reduced ACTC1 expression in VSD. Dual luciferase transcriptional activity assay in HL-1 mouse cardiomyocytes, electrophoretic mobility shift assay (EMSA), Sanger sequencing of 627 subjects, JASPAR database analysis Gene Medium 40848833
2015 Structural mapping of ACTC1 missense mutations causing congenital heart defects (p.Met84Thr, p.Glu101Lys, p.Met125Val) places them in the actin surface domain that contacts the myosin heavy chain head, distinct from mutations causing cardiomyopathy (p.Ala297Ser, p.Asp313His, p.Arg314His) which lie on a separate myosin-interaction surface, suggesting that the clinical consequence of an ACTC1 mutation depends on the actin–myosin interaction domain affected. Linkage analysis mapping disease locus to chr15q (ACTC1), Sanger sequencing identifying p.Met84Thr mutation, structural modelling of actin–myosin interface mapping mutation locations PloS one Low 26061005
2018 ACTC1 knockdown by siRNA in U87MG glioblastoma cells significantly inhibits cell migration (distance migrated reduced from ~3,600 µm to ~1,265 µm over 72 h), demonstrating a functional role for ACTC1 in glioblastoma cell motility. siRNA knockdown of ACTC1 in U87MG cells confirmed by ddPCR and immunocytochemistry; time-lapse cell tracking migration assay over 72 h Journal of the neurological sciences Low 30055382

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits. Stem cell reports 55 30392975
2011 Molecular mechanism of the E99K mutation in cardiac actin (ACTC Gene) that causes apical hypertrophy in man and mouse. The Journal of biological chemistry 55 21622575
2019 Cardiac α-Actin (ACTC1) Gene Mutation Causes Atrial-Septal Defects Associated With Late-Onset Dilated Cardiomyopathy. Circulation. Genomic and precision medicine 54 31430208
2020 Use of a human embryonic stem cell model to discover GABRP, WFDC2, VTCN1 and ACTC1 as markers of early first trimester human trophoblast. Molecular human reproduction 37 32359161
2010 Reduced ACTC1 expression might play a role in the onset of congenital heart disease by inducing cardiomyocyte apoptosis. Circulation journal : official journal of the Japanese Circulation Society 36 20962418
2013 Exome sequencing identifies a novel variant in ACTC1 associated with familial atrial septal defect. The Canadian journal of cardiology 28 24461919
2017 Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation. Biochimica et biophysica acta. Gene regulatory mechanisms 25 28847732
2014 The dilated cardiomyopathy-causing mutation ACTC E361G in cardiac muscle myofibrils specifically abolishes modulation of Ca(2+) regulation by phosphorylation of troponin I. Biophysical journal 25 25418306
2013 Mechanical and energetic properties of papillary muscle from ACTC E99K transgenic mouse models of hypertrophic cardiomyopathy. American journal of physiology. Heart and circulatory physiology 25 23604709
1989 The cardiac actin locus (Actc-1) is not on mouse chromosome 17 but is linked to beta 2-microglobulin on chromosome 2. Genomics 23 2570027
2016 Impact of apoptotic circulating tumor cells (aCTC) in metastatic breast cancer. Breast cancer research and treatment 21 27696083
2018 Actin, alpha, cardiac muscle 1 (ACTC1) knockdown inhibits the migration of glioblastoma cells in vitro. Journal of the neurological sciences 18 30055382
2016 A gain-of-function ACTC1 3'UTR mutation that introduces a miR-139-5p target site may be associated with a dominant familial atrial septal defect. Scientific reports 18 27139165
2015 A Novel Alpha Cardiac Actin (ACTC1) Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects. PloS one 18 26061005
2023 Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects. HGG advances 16 37457373
2013 Evaluating the association between pathological myopia and SNPs in RASGRF1. ACTC1 and GJD2 genes at chromosome 15q14 and 15q25 in a Chinese population. Ophthalmic genetics 14 23834555
2017 Age- and strain-related aberrant Ca2+ release is associated with sudden cardiac death in the ACTC E99K mouse model of hypertrophic cardiomyopathy. American journal of physiology. Heart and circulatory physiology 10 28887330
2020 Data on the role of cardiac α-actin (ACTC1) gene mutations on SRF-signaling. Data in brief 8 31921954
2003 alpha-cardiac actin (ACTC) binds to the band 3 (AE1) cardiac isoform. Journal of cellular biochemistry 7 12898519
2022 Mutational Assessment in NKX2-5 and ACTC1 Genes in Patients with Congenital Cardiac Septal Defect (CCSD) from Ethnic Kashmiri Population. International journal of environmental research and public health 5 36011517
2019 A cardiac α-actin (ACTC1) p. Gly247Asp mutation inhibits SRF-signaling in vitro in neonatal rat cardiomyocytes. Biochemical and biophysical research communications 5 31434612
2025 LMOD2 interaction with ACTC1 regulates myogenic differentiation. BMC genomics 4 40745266
2025 ACTC1 Variants Result in Isolated and Syndromic Cardiac Phenotypes. Clinical genetics 2 40421724
2023 Prinzmetal angina in a child with actin gene ACTC1 mutation. Cardiology in the young 2 37489518
2025 Identification and pathological significance of variants in the promoter region of ACTC1 gene in congenital ventricular septal defect. Gene 1 40848833
2025 ACTC1 promotes tumor progression by upregulating BMP4 expression in prostate cancer. BMC cancer 1 41286808
2024 A De Novo Mutation in ACTC1 and a TTN Variant Linked to a Severe Sporadic Infant Dilated Cardiomyopathy Case. Case reports in genetics 1 39759977
2026 Genetic variants of ACTC1 gene promoter in pediatric patients with sporadic patent ductus arteriosus and pathological significance. Pediatric research 0 42120536
2025 2-Ethylhexyl Diphenyl Phosphate Inhibited C2C12 Myoblast Differentiation by Regulating ACTC1. Journal of biochemical and molecular toxicology 0 40878268
2023 Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects. medRxiv : the preprint server for health sciences 0 36945405

Missed literature

Know a paper Affinage missed for ACTC1? Flag it for the maintainers and the community.

No submissions yet.