DNA methylation at the DMPK gene locus is associated with cognitive functions in myotonic dystrophy type 1

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. 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.