Novel Junctophilin-2 Mutation A405S Is Associated With Basal Septal Hypertrophy and Diastolic Dysfunction

Junctophilin-2 (JPH2) is a structural calcium (Ca(2+)) handling protein, which approximates the cardiomyocyte transverse tubules (TTs) to the sarcoplasmic reticulum. This facilitates communication of the voltage-gated Ca(2+) channel and the ryanodine receptor RyR2. A human patient with hypertrophic cardiomyopathy was positive for a JPH2 mutation substituting alanine-405—located within the alpha helix domain—with a serine (A405S). Using a novel mouse echocardiography plane, we found that mice bearing this JPH2 mutation developed increased subvalvular septal thickness. Cardiomyocytes from the septa of these mice displayed irregular TTs and abnormal Ca(2+) handling including increased SERCA activity.