The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat
Open accessAbstract
Using methylation-sensitive restriction enzymes, we characterized the methylation pattern on the 5' side of the CTG repeat in the DMPK gene of normal individuals and of patients affected with myotonic dystrophy, showing expansions of the repetitive sequence. The gene segment analyzed corresponds to the genomic SacI-HindIII fragment carrying exons 11-15. There is constitutive methylation in intron 12 at restriction sites of SacII and HhaI, localized 1,159-1,232 bp upstream of the CTG repeat, whereas most, if not all, of the other sites of SacII, HhaI, and HpaII in this region are unmethylated, in normal individuals and most of the patients. In a number of young and severely affected patients, however, complete methylation of these restriction sites was found in the mutated allele. In most of these patients, the onset of the disease was congenital. Preliminary in vivo footprinting data gave evidence for protein-DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene.
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In congenital myotonic dystrophy, the region flanking the DM1 gene is hypermethylated and this methylation disrupts binding of adjacent CTCF binding sites.
“In congenital myotonic dystrophy, the region flanking the DM1 gene is hypermethylated and this methylation disrupts binding of adjacent CTCF binding sites (Filippova et al., 2001; Steinbach et al., 1998).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Steinbach et al., 1998
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DNA methylation and human disease
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CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus
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Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries
Sun, J. H., Zhou, L., Emerson, D. J., Phyo, S. A., Titus, K. R., Gong, W., Gilgenast, T. G., Beagan, J. A., Davidson, B. L., Tassone, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.005 · Cited by 249 · see citing works
“In congenital myotonic dystrophy, the region flanking the DM1 gene is hypermethylated and this methylation disrupts binding of adjacent CTCF binding sites (Filippova et al., 2001; Steinbach et al., 1998).”
Background
- Authors
- Steinbach, P., Gläser, D., Vogel, W., Wolf, M., & Schwemmle, S.
- Affiliations
- Universität Ulm (DE)
- Corresponding author
- Steinbach, Peter
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 1998-02
- Volume
- 62
- Issue
- 2
- Pages
- 278-285
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1376887
- OpenAlex
- W1987037915
- Cited by
- 116
- References
- 51
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 9 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 3 · 2012: 2
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- myotonic dystrophy, DMPK gene, DNA methylation, CTG repeat expansion, trinucleotide repeat instability, hypermethylation, Sp1 binding site, protein-DNA interactions, congenital myotonic dystrophy, disease onset
- MeSH terms
- Adolescent, Adult, Base Sequence, Cells, Cultured, Child, DNA, Dura Mater, Fetus, Humans, Middle Aged, Myotonic Dystrophy, Reference Values, Restriction Mapping, Protein Serine-Threonine Kinases, Genomic Imprinting, Trinucleotide Repeats, DNA Footprinting, DNA Methylation, Myotonin-Protein Kinase
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