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

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

Cécilia Légaré  1 , Gayle Overend  1 , Simon-Pierre Guay  1 , Darren G Monckton  1 , Jean Mathieu  1 , Cynthia Gagnon  1 , Luigi Bouchard  1
Affiliations

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

Cécilia Légaré et al. Neurol Genet. .

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 (rs = -0.224, p = 0.040; rs = -0.317, p = 0.003; and rs = -0.241, p = 0.027), whereas correlations were observed with epivariations downstream of the CTG repeats (rs = 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.

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Figures

Figure 1
Figure 1. Spearman correlation between DMPK DNA methylation and modal CTG repeat length in patients with myotonic dystrophy type 1 (DM1)
Each panel (A to E) represents a different CpG. Results corrected for age and sex.
See this image and copyright information in PMC

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