Projects per year
Abstract
CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10 −12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.
Original language | English |
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Pages (from-to) | 488-505 |
Number of pages | 18 |
Journal | American Journal of Human Genetics |
Volume | 100 |
Issue number | 3 |
DOIs | |
Publication status | Published - 2 Mar 2017 |
Keywords
- DMPK
- DNA/CpG methylation
- SIX5/DMAHP
- congenital myotonic dystrophy
- epigenetics
- maternal transmission/maternal inheritance
- myotonic dystrophy
- parent-of-origin effect(s)
- pre-natal diagnosis
- trinucleotide instability
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Dive into the research topics of 'CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy'. Together they form a unique fingerprint.Projects
- 3 Finished
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FWOAL777: Human pluripotent stem cells as disease models for trinucleotide instability in myotonic dystrophy type I
1/01/15 → 31/12/18
Project: Fundamental
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GIFT95: Human embryonic stem cells and induced pluripotent cells as models for research of human genetic diseases
1/09/09 → 31/08/16
Project: Fundamental
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OZRMETH3: Research at the interface between human genetics and reproduction.
Sermon, K., Seneca, S., Bonduelle, M., De Rycke, M., Devroey, P., Goossens, E., Lissens, W., Spits, C., Stouffs, K., Tournaye, H., Dee, K., Vandermaelen, D., Van Haute, L., Van Saen, D., Van Den Abbeel, E., Liebaers, I., De Meirleir, L., Nekkebroeck, J. & Van De Velde, H.
1/01/09 → 31/12/24
Project: Fundamental