Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder caused by the expansion of an unstable CTG•CAG repeat in the DMPK gene. This study examined whether differential expression of DNA repair genes in three different tissues from the same DM1 patient contributed to tissue-specific somatic instability of the repeat tract. RNA-Seq was used to quantify expression levels of eight DNA repair genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS2, LIG1, and FAN1). Results indicate that the expression levels varied significantly across tissues, with no inter-tissue correlations, suggesting independent regulation and patient-specific differences. Somatic expansion of the repeat tract in blood and muscle was effectively predicted by a complex ePALxAge interaction, while in muscle it was further influenced by MSH3 and PMS2 gene expression, confirming their role as tissue-specific genetic modifiers in DM1. Although only marginally significant, muscle expression of PMS2 and FAN1 appeared to affect age-at-onset: higher FAN1 expression was associated with reduced somatic expansion and later onset. Our findings also suggest a complex competitive balance between promoters and stabilizers of repeat instability, shaping muscle expansion dynamics and potentially modifying clinical onset. Overall, these results indicate that certain DNA repair genes exert stronger, tissue-dependent effects on somatic instability. We confirm that MSH3, PMS2, and FAN1 act as key modifiers not only of somatic expansion, especially in skeletal muscle, but also of DM1 severity. Although RT-qPCR data might be required to validate some of these results, these genes therefore represent promising therapeutic targets for modulating disease progression.