https://orcid.org/0000-0002-8498-3133
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Abstract
Aim: Myotonic dystrophy type 1 (DM1) is caused by an unstable trinucleotide (CTG) expansion at the DMPK gene locus. Cognitive dysfunctions are often observed in the condition. We investigated the association between DMPK blood DNA methylation (DNAm) and cognitive functions in DM1, considering expansion length and variant repeats (VRs). Method: Data were obtained from 115 adult-onset DM1 patients. Molecular analyses consisted of pyrosequencing, small pool PCR and Southern blot hybridization. Cognitive functions were assessed by validated neuropsychological tests. Results: For patients without VRs (n = 103), blood DNAm at baseline independently contributed to predict cognitive functions 9 years later. Patients with VRs (n = 12) had different DNAm and cognitive profiles. Conclusion: DNAm allows to better understand DM1-related cognitive dysfunction etiology.
Aim: Myotonic dystrophy type 1 (DM1) is a rare neuromuscular genetic disease caused by an abnormal expansion of a small DNA sequence (CTG) within the DMPK gene locus. Cognitive dysfunctions are often observed in DM1. DNA methylation (DNAm) is an epigenetic process regulating gene expression with potential phenotypic impacts. Our study aimed to investigate whether DNAm levels measured in blood at the DMPK gene locus are associated with cognitive functions in DM1, in addition to the length of the CTG expansion. Method: Data were obtained from 115 adult-onset DM1 patients followed up over a 9-year period. Cognitive functions were assessed by validated neuropsychological tests. Results: For patients without CTG repeat interruptions (n = 103), blood DNAm at baseline independently predicted cognitive functions 9 years later. Patients with CTG repeat interruptions (n = 12) had different DNAm and cognitive profiles. Conclusion: DNAm might allow us to better understand DM1-related cognitive dysfunction.
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0328
Acknowledgements
The authors acknowledge all research participants, and the staff of the Groupe the recherche interdisciplinaire sur les maladies neuromusculaires (GRIMN) who participated to the follow-up and data collection. We also thank V Desgagné (Research Assistant), who carefully revised the manuscript.
Financial&competing interests disclosure
During this study, E Breton was recipient of a financial support from the Faculté de médecine et des Sciences de la Santé from the Université de Sherbrooke, and from the Fondation du Grand Défi Pierre Lavoie. E Breton and C Légaré are also supported by a doctoral training award from the Fonds de recherche en Santé du Québec (FRQS) and C Légaré received a funding from the Fondation du Grand Défi Pierre Lavoie and Corporation de recherche et d’action sur les maladies héréditaires (CORAMH). During this research, SP Guay was the recipient of a doctoral research award from the Canadian Institutes for Health and Research (CIHR). CG and LB are senior research scholars from the FRQS. L Bouchard is a member of the CR-CHUS, a FRQS-funded research center. C Gagnon and B Gallais are members of the Centre de recherche Charles-Le-Moyne-Saguenay-Lac-Saint-Jean, which is affiliated to the Université de Sherbrooke. G Overend and DG Monckton were supported by an award from Muscular Dystrophy UK and donations from the Myotonic Dystrophy Support Group. Within the last 3 years DG Monckton has been a scientific consultant and/or received an honoraria/stock options from AMO Pharma, Charles River, Vertex Pharmaceuticals, Triplet Therapeutics, LoQus23 and Small Molecule RNA, research contracts with AMO Pharma and Vertex Pharmaceuticals. DG Monckton is on the Scientific Advisory Board of Myotonic (formerly the Myotonic Dystrophy Foundation) and EuroDyMA (European Dystrophia Myotonica Association), is a scientific advisor to the Myotonic Dystrophy Support Group and is a vice president of Muscular Dystrophy UK. He has received research funding from Muscular Dystrophy UK and the Myotonic Dystrophy Support Group. C Gagnon received an honorarium from Biogen Idec and a funding from Bioblast Pharma inc. B Gallais has received an honorarium from Expansion Therapeutics, Inc and from Biogen Idec. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.