Abstract

DM1 is a dominantly inherited neuromuscular disorder resulting from expansion of a CTG repeat in the 3' untranslated region of myotonic dystrophy protein kinase (DMPK). Mutant RNA transcripts containing expanded, non-translated repeats accumulate in nuclear foci, causing abnormal regulation of alternative splicing (AS) which is a molecular hallmark of the disease. Agents that promote mutant DMPK transcript degradation are in early phase clinical trials. Therefore, development of primary and secondary outcomes to determine therapeutic response is necessary.

This cross-sectional study of 45 Southern blot genotyped DM1 patients underwent vastus lateralis needle muscle biopsy with the following clinical outcome measures: grip dynamometry, ankle dorsiflexion strength and six-minute walk test.

Validation of splicing deregulation in two RNA transcripts identified from an international collaboration to sequence the DM1 skeletal muscle transcriptome, differentiates DM1 patients with severe phenotype from healthy controls and mild DM1 patients with no functional impairment: Insulin receptor (INSR) AS one way ANOVA p<0.05; nuclear factor I/X (NFIX) AS one way ANOVA p<0.05. In addition linear regression of INSR and NFIX AS correlated with all clinical outcome measures (p<0.05, r values 0.3–0.5).

This supports the potential use of these AS events in skeletal muscle as secondary outcomes in clinical trials.