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

Légaré, C., Overend, G. , Guay, S.-P., Monckton, D. G. , Mathieu, J., Gagnon, C. and Bouchard, L. (2019) gene DNA methylation levels are associated with muscular and respiratory profiles in DM1. Neurology Genetics, 5(3), e338. (doi: 10.1212/NXG.0000000000000338) (PMID:31334355) (PMCID:PMC6568328)

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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.

Item Type:Articles
Additional Information:This project has been supported by the Marigold Foundation, the Canadian Institutes of Health Research (CIHR) (#JNM108412), the Fondation du grand défi Pierre Lavoie, and Muscular Dystrophy UK.
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren and Overend, Dr Gayle
Authors: Légaré, C., Overend, G., Guay, S.-P., Monckton, D. G., Mathieu, J., Gagnon, C., and Bouchard, L.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Neurology Genetics
Publisher:Lippincott, Williams & Wilkins
ISSN (Online):2376-7839
Published Online:23 May 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Neurology Genetics 5(3): e338
Publisher Policy:Reproduced under a Creative Commons License

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