Abstract 1427: Pathogenesis of Hypertrophic Cardiomyopathy Caused by the Myozenin 2 Mutations Involves Calcineurin-Dependent and -Independent Mechanisms

TL;DRAbstract

Identification of myozenin-2 mutations (MYOZ2) has expanded the spectrum of causal mutations for hypertrophic cardiomyopathy (HCM) to include the Z disk proteins. The molecular mechanism(s) by which MYOZ2 mutations cause HCM are unknown. MYOZ2 is known to inhibit calcineurin phosphatase (PP2B). We posit mutant MYOZ2 lose their inhibitory effects on PP2B and hence, the ensuing cardiac phenotype results from enhanced activity of PP2B. To test this hypothesis, we generated lines of transgenic mice expressing either N-terminally flag-tagged wild type (MYOZ2-WT) or mutant MYOZ2-P48 or MYOZ2-M246 regulated by the α-myosin heavy chain promoter. Expression levels of the transgenic and endogenous MYOZ2 proteins were detected by immunoblotting using pan-specific anti-MYOZ2 and anti-Flag antibodies. The transgene proteins constituted 15 to 35% of the total MYOZ2 protein. The total MYOZ2 levels remained unchanged. Immunofluorescence staining showed both WT and mutant MYOZ2 proteins were incorporat

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