ACTA1 – Congenital Fiber-Type Disproportion Myopathy

Autosomal dominant mutations in ACTA1 have been implicated in congenital fiber-type disproportion (CFTD), a myopathy characterized by marked type 1 fiber atrophy without nemaline bodies and early-onset muscle weakness. A spectrum of heterozygous missense and small in-frame variants has been reported in unrelated patients presenting severe hypotonia and respiratory insufficiency from birth.

Genetic evidence includes at least 8 probands with de novo or sporadic ACTA1 variants causing CFTD (3 probands) (PMID:15468086), 4 patients identified in a cohort of 28 infants with pathological CFTD features (PMID:20179953), and a single case with a de novo Met327Lys allele (PMID:35757965). Segregation data are limited to singleton presentations without additional affected relatives. The variant spectrum in CFTD is dominated by heterozygous missense changes in conserved actin residues.

Functional studies across multiple systems support a dominant-negative mechanism. In vitro motility and biochemical assays of D292V and P332S variants show abnormal actin–tropomyosin interactions and preserved sarcomeric ultrastructure (PMID:17387733). Expression of human-equivalent mutations in Drosophila Act88F muscle disrupts Z-disc organization and flight muscle sarcomeres (PMID:20452215). In C2C12 cells, Met327Lys actin exhibits reduced expression and apoptosis induction relative to wild-type controls, aligning with histopathological CFTD features (PMID:35757965).

No studies have refuted the association, but congenital myotonic dystrophy may mimic CFTD histology, necessitating DMPK testing in ambiguous cases (PMID:20179953).

Overall, ACTA1 demonstrates Moderate clinical validity for autosomal dominant CFTD based on multiple unrelated probands with consistent pathology and concordant functional data. Additional family segregation and larger cohorts would strengthen the evidence.

Key Take-home: Heterozygous ACTA1 missense variants cause dominant congenital fiber-type disproportion through a dominant-negative disruption of sarcomeric actin function, informing molecular diagnosis and potential therapeutic targeting of actomyosin interactions.

References

• Annals of neurology | 2004 | Actin mutations are one cause of congenital fibre type disproportion. PMID:15468086
• Acta neuropathologica | 2010 | Congenital myotonic dystrophy can show congenital fiber type disproportion pathology. PMID:20179953
• Molecular genetics & genomic medicine | 2022 | A case of congenital fiber-type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation. PMID:35757965
• Annals of neurology | 2007 | The pathogenesis of ACTA1-related congenital fiber type disproportion. PMID:17387733
• Neuromuscular disorders : NMD | 2010 | Drosophila indirect flight muscle specific Act88F actin mutants as a model system for studying congenital myopathies of the human ACTA1 skeletal muscle actin gene. PMID:20452215

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