Combinatorial Effects of Ion Channel Mis-Splicing as a Cause of Myopathy in Myotonic Dystrophy

Authors

Larissa Nitschke
Thomas A Cooper

Publication Date

1-2-2024

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI176089

PMID

38165037

PMCID

PMC10760967

PubMedCentral® Posted Date

1-2-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Myotonic Dystrophy, RNA Splicing, Muscle, Skeletal, Alternative Splicing, Ion Channels, Myotonin-Protein Kinase, Trinucleotide Repeat Expansion

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated the therapeutic potential for calcium channel modulation to block the synergistic effects and rescue myopathy.