Abstract
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.
Highlights
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder characterized by a gradual loss of muscle, weakness, and delayed relaxation after muscle contraction [1].Extramuscular symptoms such as intellectual disability, cataracts, cardiac conduction abnormalities, and endocrine problems may be present [1]
The aim of our study was to assess (1) whether elevated methylation in peripheral blood can be detected in a larger number of DM1 patients using a sensitive method, (2) whether blood methylation levels remain stable over time and can be used as a predictive biomarker, and (3) whether or not methylation levels in the blood correlate with the methylation levels in the affected tissue
Elevated methylation levels downstream of the repeat have been reported in patients with shorter (
Summary
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystem disorder characterized by a gradual loss of muscle, weakness, and delayed relaxation after muscle contraction (myotonia) [1] Extramuscular symptoms such as intellectual disability, cataracts, cardiac conduction abnormalities, and endocrine problems may be present [1]. MBNL1 binds to the double stranded RNA hairpins formed by the CUG repeats and is sequestered [6], while the splice factor CUGBP1 is upregulated [7]. This leads to the abnormal splicing of a range of
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