Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1

• DOI: 10.7554/elife.51114
• Publication Date: 2019-12-12T12:00:19Z
• Authors: Emilie Auxerre-Pl...; Masayuki Nakamori; Yoan Renaud; Aline Huguet; Caroline Choquet; Cristiana Dondi; Lucile Miquerol; Masanori P Takahashi; Geneviève Gourdon; Guillaume Junion; Teresa Jagla; Monika Zmojdzian; Krzysztof Jagla
• Keywords: 0301 basic medicine; medicine; QH301-705.5; [SDV]Life Sciences [q-bio]; Science; heart; Mice; 03 medical and health sciences; Cardiac Conduction System Disease; Animals; Drosophila Proteins; Humans; Myotonic Dystrophy; [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Biology (General); Human Biology and Medicine; myotonic dystrophy type 1; D. melanogaster; TU-tagging; Q; R; human biology; [SDV] Life Sciences [q-bio]; conduction defects; Disease Models, Animal; Gene Expression Regulation; Medicine; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Drosophila; Calcium Channels

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a CTG repeat disorder involving misbalance between two RNA binding factors, MBNL1 and CELF1. However, how DM1 condition translates into conduction disorders remains poorly understood. Here we simulated MBNL1 and CELF1 misbalance in theDrosophilaheart and performed TU-tagging-based RNAseq of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels, including increased expression of straightjacket/α2δ3, which encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heartbeat, a hallmark of abnormal conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. 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. These findings suggest that reducing ventricular straightjacket/α2δ3 levels could offer a strategy to prevent conduction defects in DM1.