O.20Mutations in ACTN2 gene cause a novel form of adult-onset distal myopathy

Abstract

We studied three families from the same village in northern Spain and one family from Sweden with an autosomal dominant distal myopathy with rimmed vacuolar pathology. Affected members shared a very similar clinical phenotype, a characteristic pattern of muscle involvement by MRI and common histologic features. In particular, all the patients showed an adult-onset, asymmetric muscle weakness, with atrophy of tibialis anterior and initial involvement of ankle dorsiflexion later progressing to proximal limb muscles. We identified an ACTN2 c.1459T>C (p.C487R) variant co-segregating with the disease in families 1–3. An ACTN2 c.392T>C (p.L131P) variant was identified in the affected members of family 4. In all the families enrolled, the private ACTN2 variants are fully penetrant and co-segregate with the disease. ACTN2 encodes for alpha actinin2, a protein highly expressed in the Z-disk of cardiac and skeletal sarcomeres, where it plays several structural and functional roles through a complex network of interactions with other sarcomeric proteins. Our findings demonstrate that ACTN2 mutations cause a new type of dominant late-onset and slowly progressive distal myopathy. Dominant ACTN2 mutations were previously associated with hypertrophic and dilated cardiomyopathies. At the same time as our studies, two ACTN2 mutations have been described as the cause of a congenital core myopathy patients. Additional studies are needed to improve our understanding of the genotype-phenotype correlation and to clarify the molecular mechanisms of the actinopathies.