A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients

Abstract Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.

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Heart Rate Variability Declines with Increasing Age and CTG Repeat Length in Patients with Myotonic Dystrophy Type 1

Annals of Noninvasive Electrocardiology ◽

10.1046/j.1542-474x.2003.08310.x ◽

2003 ◽

Vol 8 (3) ◽

pp. 227-232 ◽

Cited By ~ 19

Author(s):

Bradley A. Hardin ◽

Miriam R. Lowe ◽

Deepak Bhakta ◽

William J. Groh

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Myotonic Dystrophy ◽

Repeat Length ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Ctg Repeat

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Stable Longitudinal Methylation Levels at the CpG Sites Flanking the CTG Repeat of DMPK in Patients with Myotonic Dystrophy Type 1

Genes ◽

10.3390/genes11080936 ◽

2020 ◽

Vol 11 (8) ◽

pp. 936

Author(s):

Mathis Hildonen ◽

Kirsten Lykke Knak ◽

Morten Dunø ◽

John Vissing ◽

Zeynep Tümer

Keyword(s):

Myotonic Dystrophy ◽

Autosomal Dominant ◽

Maternal Inheritance ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Muscle Loss ◽

Multisystem Disorder ◽

Ctg Repeat ◽

Over Time

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder mainly characterized by gradual muscle loss, weakness, and delayed relaxation after muscle contraction. It is caused by an expanded CTG repeat in the 3′ UTR of DMPK, which is transcribed into a toxic gain-of-function mRNA that affects the splicing of a range of other genes. The repeat is unstable, with a bias towards expansions both in somatic cells and in the germline, which results in a tendency for earlier onset with each generation, as longer repeat lengths generally correlate with earlier onset. Previous studies have found hypermethylation in the regions flanking the repeat in congenital onset DM1 and in some patients with non-congenital DM1. We used pyrosequencing to investigate blood methylation levels in 68 patients with non-congenital DM1, compare the methylation levels between the blood and muscle, and assess whether methylation levels change over time in the blood. We found higher methylation levels in the blood of DM1 patients than in healthy controls and especially in the patients who had inherited the disease allele maternally. The methylation levels remained relatively stable over time and are a strong biomarker of the disease, as well as of the maternal inheritance of the disease.

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