Key result
ACTN2 mutations A119T and G111V caused small changes in protein structure, reduced F-actin binding affinity, and affected Z-disc localization and dynamic behavior in adult cardiomyocytes.
The A119T and G111V mutations in ACTN2 cause mild structural and functional impairments that may contribute to the mild phenotype of hypertrophic cardiomyopathy.
These ACTN2 mutation effects warrant no clinical action in hypertrophic cardiomyopathy; leaves open their role in human disease pathogenesis.
α-Actinin-2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients, A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain (ABD) of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localization and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease.
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Haywood et al. (2016) studied Hypertrophic cardiomyopathy. ACTN2 mutations A119T and G111V vs. Wild-type ACTN2 was evaluated on Secondary and tertiary structure, F-actin binding affinity, and Z-disc localization. ACTN2 mutations A119T and G111V caused small changes in protein structure, reduced F-actin binding affinity, and affected Z-disc localization and dynamic behavior in adult cardiomyocytes.
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