Straightjacket/α 2δ 3 deregulation is associated with cardiac conduction defects in Myotonic Dystrophy type 1

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a complex toxic CTG repeat disorder involving misbalance between two RNAbinding factors, MBNL1 and CELF1. How this pathogenic DM1 condition translates into cardiac conduction disorders remains unknown. Here, we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and identified associated gene deregulations using transcriptional profiling of cardiac cells. We detected increased transcript levels of straightjacket/α2δ3 that encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heart beating that could result from affected conduction, whereas cardiac knockdown improves these symptoms. We also show that ventricular α2δ3 expression is low in healthy mice and humans but significantly elevated in ventricular muscles from DM1 patients with conduction defects. Taken together, this suggests that keeping the straightjacket/α2δ3 transcript levels low in ventricular cardiomyocytes could be a strategy to prevent conduction defects in DM1 pathology.