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Published on: December 5, 2019
Nemaline myopathy caused by absence of alpha-skeletal muscle actin
Kristen J Nowak1, Caroline A Sewry, Carmen Navarro
1Centre for Medical Research, University of Western Australia, Nedlands, Australia, and Centre for Inherited Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, UK.
Insights
Seven infants with congenital myopathy, caused by ACTA1 gene mutations, experienced severe outcomes. Residual alpha-cardiac actin correlated with better function, suggesting a therapeutic target for this rare genetic muscle disease.
Area of Science:
- Genetics
- Molecular Biology
- Neuromuscular Disorders
Background:
- Congenital myopathies are a group of inherited muscle diseases presenting at birth.
- Nemaline myopathy is characterized by the presence of specific protein aggregates (nemaline bodies) in muscle fibers.
- Mutations in the alpha-skeletal muscle actin gene (ACTA1) are a known cause of severe congenital myopathies.
Observation:
- This study investigated seven patients from six families with severe congenital myopathy.
- Patients exhibited significant muscle weakness, with most requiring mechanical ventilation and many succumbing in early infancy.
- Genetic sequencing identified homozygous null mutations in the ACTA1 gene in all affected individuals.
Findings:
- Three distinct homozygous ACTA1 null mutations were identified, including p.Arg41X, p.Tyr364fsX, and p.Asp181fsX10.
- Muscle biopsies revealed an absence of alpha-skeletal muscle actin protein.
- Alpha-cardiac actin was present in all biopsies, and its expression level correlated with residual muscle function.
Implications:
- The findings confirm that recessive nemaline myopathy can result from the absence of alpha-skeletal muscle actin.
- The level of retained alpha-cardiac actin may influence disease severity in ACTA1-related myopathies.
- This understanding opens avenues for potential therapeutic strategies targeting actin isoform expression.
Objective:
To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator-dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected.
Methods:
The alpha-skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry, western blotting, or both.
Results:
Three homozygous ACTA1 null mutations were identified: p.Arg41X in the French patient, p.Tyr364fsX in the Spanish patient, and p.Asp181fsX10 in all five British patients. An absence of alpha-skeletal muscle actin protein but presence of alpha-cardiac actin was shown in all muscle biopsies examined, with more alpha-cardiac actin in the biopsy from the child with the greatest muscle function. Muscle biopsies from all patients exhibited nemaline bodies whereas three also contained zebra bodies.
Interpretation:
The seven patients have recessive nemaline myopathy caused by absence of alpha-skeletal muscle actin. The level of retention of alpha-cardiac actin, the skeletal muscle fetal actin isoform, may determine alpha-skeletal muscle actin disease severity. This has implications for possible future therapy.
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