ACTA1 – Nemaline Myopathy 3

ACTA1 encodes alpha-skeletal muscle actin, the principal thin filament protein essential for sarcomere structure and muscle contraction. Nemaline myopathy 3 (NEM3) is a congenital, non-dystrophic myopathy marked by early-onset hypotonia, generalized muscle weakness, and rod-shaped inclusions on muscle biopsy. Pathogenic variants in ACTA1 underlie a significant fraction of NEM3 cases and present across a spectrum of clinical severity.

Inheritance is autosomal dominant, with most cases resulting from de novo heterozygous missense mutations in ACTA1. In a cohort of 14 unrelated probands, distinct ACTA1 variants were identified, including the recurrent c.355G>C (p.Glu119Gln) substitution ([PMID:29328520]). No multi-generation pedigrees have been described, consistent with sporadic dominant occurrence.

Missense changes cluster in actin regions critical for actin–myosin interactions, disrupting filament dynamics. Segregation data are limited, but each variant has been observed in an independent affected individual without presence in healthy relatives, supporting pathogenicity.

Functional assays in patient muscle fibers revealed a reduced maximal force-generating capacity and a decreased number of myosin heads binding to actin during activation, demonstrating sarcomere contractility defects as a key mechanism of weakness ([PMID:29328520]). Complementary in vitro studies show that mutant actin exhibits impaired polymerization and forms aberrant aggregates, indicative of a dominant-negative effect on filament assembly.

No studies have refuted the ACTA1–NEM3 relationship, and there is no evidence of conflicting genotype–phenotype correlations. The consistency of genetic findings across unrelated patients and concordant functional data confirm a robust association.

Key Take-home: Heterozygous missense ACTA1 mutations cause autosomal dominant NEM3 through dominant-negative disruption of sarcomere contractility, guiding molecular diagnosis and informing myosin-targeted therapeutic strategies.

References

• Ann Neurol • 2018 • Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3). [PMID:29328520]

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