Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Alpha-actinin-2 (ACTN2) is crucial for muscle function.
• ACTN2 variants cause cardiomyopathy and rare dominant myopathies.
• Recessive ACTN2 myopathy has been suggested but not well-characterized.

Purpose of the Study:

• To clinically, imaging, and histologically characterize patients with a novel biallelic ACTN2 variant.
• To investigate the genetic basis and clinical spectrum of recessive ACTN2-related myopathy.

Main Methods:

• Clinical assessment and follow-up of seven patients from five families.
• Genetic analysis including haplotype analysis.
• Muscle biopsy and MRI imaging.
• In vitro splicing assay.

Main Results:

• Identified a recurring biallelic ACTN2 variant (c.1516A>G, p.Arg506Gly) in seven patients of Palestinian ethnicity.
• Patients presented with asymmetric, progressive, proximal and distal lower extremity predominant muscle weakness, without cardiomyopathy or respiratory issues.
• Muscle biopsies showed myopathic changes with disrupted architecture and Type I fiber predominance.
• MRI revealed distinct asymmetric muscle involvement patterns in the lower extremities.
• The variant did not impair normal splicing in vitro.

Conclusions:

• Establishes ACTN2 as a gene implicated in recessive muscle diseases.
• Expands the clinical spectrum of actinopathies to include adult-onset progressive myopathy.
• Suggests a founder ACTN2 variant in the Palestinian population.