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

Cécilia Légaré; Gayle Overend; Simon-Pierre Guay; Darren G Monckton; Jean Mathieu; Cynthia Gagnon; Luigi Bouchard

doi:10.1212/NXG.0000000000000338

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

Neurol Genet. 2019 May 23;5(3):e338. doi: 10.1212/NXG.0000000000000338. eCollection 2019 Jun.

Authors

Cécilia Légaré¹, Gayle Overend¹, Simon-Pierre Guay¹, Darren G Monckton¹, Jean Mathieu¹, Cynthia Gagnon¹, Luigi Bouchard¹

Affiliation

¹ Department of Biochemistry (C.L., S.-P.G., L.B.), Université de Sherbrooke, Sherbrooke; ECOGENE-21 Biocluster (C.L., S.-P.G., L.B.), Chicoutimi, Québec, Canada; Groupe de Recherche interdisciplinaire sur les maladies neuromusculaires (C.L., J.M., C.G., L.B.), Saguenay, Canada; Institute of Molecular (G.O., D.G.M.), Cell and Systems Biology, University of Glasgow, United Kingdom; and Centre de Recherche Charles-Le-Moyne-Saguenay-Lac-StJean sur les innovations en santé (J.M., C.G.), Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Canada.

Abstract

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.