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.