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

eLife

Caroline Choquet¹  Teresa Jagla¹  Cristiana Dondi²  Masanori P Takahashi²  Geneviève Gourdon³  Masayuki Nakamori⁴  Monika Zmojdzian⁵  Emilie Auxerre-Plantié⁵  Lucile Miquerol⁵  Krzysztof Jagla⁵  Yoan Renaud⁵  Guillaume Junion⁶  Aline Huguet⁶ 

[1]Centre de Recherche en Myologie, Inserm UMRS974, Sorbonne Universités, Institut de Myologie, Paris, France

[2]Aix-Marseille Univ, CNRS UMR 7288, IBDM, Marseille, France

[3]Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan

[4]Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan

[5]GReD, CNRS UMR6293, INSERM U1103, University of Clermont Auvergne, Clermont-Ferrand, France

[6]Imagine Institute, Inserm UMR1163, Paris, France

关键词: myotonic dystrophy type 1;    Drosophila;    heart;    conduction defects;    TU-tagging;   

DOI  :  10.7554/eLife.51114

来源: DOAJ

【 摘 要 】

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 the Drosophila heart 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.

【 授权许可】

Unknown