Abstract 18360: ACTN2 Mutations Are Associated With Cardiomyopathy and Cardiomyocyte Hypertrophy
Introduction: Alpha actinins belong to the spectrin gene superfamily, a diverse group of cytoskeletal proteins. In cardiac and skeletal muscle cells, they act as actin- and titin-binding proteins localized to the Z-disc and help anchor myofibrillar actin filaments. Mutations in ACTN2 (alpha-actinin-2) have been implicated in a heterogeneous group of cardiomyopathies, ranging from hypertrophic cardiomyopathy to dilated cardiomyopathies to left ventricular noncompaction. However, the precise molecular and cellular mechanisms of how ACTN2 causes cardiomyocyte hypertrophy and dysfunction is poorly understood.
Hypothesis: We wished to assess the molecular effects of ACTN2 mutations on cardiomyocyte biology.
Methods/Results: We identified patients in the Stanford Center for Inherited Cardiovascular Disease database with ACTN2 mutations. We identified patients with negative clinical panel sequencing and sequenced ACTN2. We found six families with rare or novel ACTN2 variants using a custom mutation pipeline optimized for rare variant discovery. A patient homozygous for a stop-gain mutation (p.Q860X) in ACTN2 and a family with a novel exon 8-10 deletion had findings of cardiomyopathy and cardiac arrest. In heart transplant tissue of the homozygous stop-gain patient, we saw no evidence of variation in ACTN2 expression, suggesting absence of nonsense mediated decay. We knocked down ACTN2 in neonatal rat ventricular cardiomyocytes with siRNA and observed a dramatic change in cell size and morphology (Fig. 1).
Conclusions: The molecular effects of ACTN2 on a cellular level and how it causes cardiomyopathy have been little explored. Here, we provide evidence that ACTN2 mutations lead to abnormalities in cardiomyocytes and myocardium biology.
Author Disclosures: H. Zhu: None. E. Ashley: None. M. Wheeler: None.
- © 2016 by American Heart Association, Inc.