Combinatorial effects of ion channel mis-splicing as a cause of myopathy in myotonic dystrophy

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.

Figure 1. The combined effects of ion channels from mis-spliced RNA cause myotonia and muscle weakness in DM1.

In unaffected muscle tissues, MBNL correctly regulates splicing of the alternative exons in CLCN1 and CACNA1S. This process results in expression of the adult isoforms of the chloride and calcium channels, which, together with SERCA1 and RyR1, facilitate proper muscle contraction and relaxation. In DM1, MBNL sequestration on expanded CUG repeats causes the dysregulation of CLCN1 and CACNA1S alternative splicing. The inclusion of a CLCN1 fetal exon leads to a frameshift and premature stop codon, causing ClC-1 loss. Mis-splicing also leads to expression of the Ca_v1.1 fetal isoform, which has an increased calcium current compared with the adult isoform. The combined loss of ClC-1 and expression of the fetal Ca_v1.1 isoform leads to severe myopathy that can be rescued pharmacologically by blocking the calcium channel using verapamil.