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ACTC1 encodes α-cardiac actin, a core sarcomeric thin filament protein essential for force generation and transmission in cardiomyocytes. Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous, autosomal dominant disorder characterised by left ventricular hypertrophy, myocyte disarray, and risk of arrhythmia and sudden death. Variants in ACTC1 are a rare cause (<5%) of familial and sporadic HCM, with evidence from multiple unrelated families and concordant functional studies supporting a strong gene–disease relationship.
In a multigenerational Italian family, a novel heterozygous ACTC1 c.62C>T (p.Ala21Val) variant cosegregated with familial HCM and left ventricular noncompaction in 4 affected individuals (II-1, II-2, I-4, I-5), presenting with palpitations, dyspnea, right bundle branch block, and ventricular tachycardia (4 probands) (PMID:29440008). All carriers displayed myocardial hypertrophy up to 22 mm and myofibrillar disarray on histology, consistent with autosomal dominant inheritance and high penetrance of p.Ala21Val.
Screening of 368 unrelated HCM patients identified de novo ACTC1 missense mutations (Pro164Ala and Ala331Pro) in two sporadic early-onset cases, and a familial Glu99Lys substitution in a weak actomyosin binding domain (3 probands) demonstrating recurrent ACTC1 involvement in HCM cohorts (PMID:10966831). In systematic gene panels of 79 preadolescent HCM patients, ACTC1 mutations accounted for <5% of sarcomeric variants, reinforcing the need for cascade testing in families of affected children (PMID:20031618).
Functional characterization in isogenic human induced pluripotent stem cell-derived cardiomyocytes carrying the E99K-ACTC1 mutation revealed calcium handling abnormalities and arrhythmogenic phenotypes. Dual dantrolene/ranolazine treatment restored calcium transients, supporting a direct pathogenic role and guiding therapeutic strategies (PMID:30392975).
In transgenic mice expressing ACTC1 E99K at 50% of total actin, in vitro motility and papillary muscle assays showed increased Ca²⁺ sensitivity and abolished phosphorylation-linked regulation, culminating in apical hypertrophy, sudden death, and late DCM-like remodeling (PMID:21622575). These data illustrate haploinsufficiency and allosteric disruption of actomyosin interactions as key disease mechanisms.
A case–control study in an Iranian cohort found no E101K or M123V ACTC1 mutations among 30 HCM and 100 DCM patients, indicating population-specific variant frequencies and the importance of ethnically diverse screening (PMID:26715934).
ClinGen classification: Strong association based on multiple segregation reports and robust functional concordance. Combination of familial cosegregation, de novo occurrences, experimental models, and pharmacological rescue underscores ACTC1’s clinical utility for genetic diagnosis, risk stratification, and targeted therapy in HCM.
Key Take-home: ACTC1 variants cause autosomal dominant HCM through altered Ca²⁺ sensitivity and actomyosin regulation; genetic testing enables family screening and informs precision therapeutics.
Gene–Disease AssociationStrongMultiple unrelated probands across 4 families with segregation and de novo occurrences; concordant functional data Genetic EvidenceModerate6 probands (4 familial, 2 de novo) with ACTC1 variants showing segregation and recurrence ([PMID:29440008], [PMID:10966831]) Functional EvidenceModeratehiPSC-CM and transgenic mouse models demonstrate Ca²⁺ handling deficits, arrhythmogenesis, and altered actomyosin interactions rescued by pharmacological agents ([PMID:30392975], [PMID:21622575]) |