DMPK gene DNA methylation levels are associated with muscular and respiratory profiles in DM1

OBJECTIVE: To assess the effects of dystrophia myotonica protein kinase (DMPK) DNA methylation (DNAme) epivariation on muscular and respiratory profiles in patients with myotonic dystrophy type 1 (DM1). METHODS: Phenotypes were assessed with standardized measures. Pyrosequencing of bisulfite-treated DNA was used to quantify DNAme levels in blood from 90 patients with DM1 (adult form). Modal CTG repeat length was assessed using small-pool PCR. The presence of Acil-sensitive variant repeats was also tested. RESULTS: DNAme levels upstream of the CTG expansion (exon and intron 11) were correlated with modal CTG repeat length (r(s) = −0.224, p = 0.040; r(s) = −0.317, p = 0.003; and r(s) = −0.241, p = 0.027), whereas correlations were observed with epivariations downstream of the CTG repeats (r(s) = 0.227; p = 0.037). The presence of a variant repeat was associated with higher DNAme levels at multiple CpG sites (up to 10% higher; p = 0.001). Stepwise multiple linear regression modeling showed that DNAme contributed significantly and independently to explain phenotypic variability in ankle dorsiflexor (3 CpGs: p = 0.001, 0.013, and 0.001), grip (p = 0.089), and pinch (p = 0.028) strengths and in forced vital capacity (2 CpGs: p = 0.002 and 0.021) and maximal inspiratory pressure (p = 0.012). CONCLUSIONS: In addition to the CTG repeat length, DMPK epivariations independently explain phenotypic variability in DM1 and could thus improve prognostic accuracy for patients.