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Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy

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Abstract

The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD1, OMIM 158900) is caused by contraction of the D4Z4 repeat array on 4qter. We show that this contraction causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with phenotypic FSHD1, who are clinically identical to FSHD1 but have an unaltered D4Z4, also have hypomethylation of D4Z4. These results strongly suggest that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1.

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Figure 1: Methylation-sensitive digestions after Southern blotting and hybridization with probe p13E-11.
Figure 2: Bar diagram of the methylation of D4Z4.

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Acknowledgements

We dedicate this work to the memory of Lodewijk Sandkuijl, who unexpectedly passed away during preparation of this manuscript. We thank R. ten Hove for contributing to the development of the methylation assays and C. Wijmenga and D. Smeets for providing material from individuals with ICF. Our FSHD research is made possible by the Prinses Beatrix Fonds, the Muscular Dystrophy Association USA, the FSH Society, the Stichting FSHD, the Shaw Family and the US National Institutes of Health.

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Author notes

  1. Lodewijk A Sandkuijl: Deceased.

Authors and Affiliations

  1. Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, P.O. Box 9502, Leiden, 2300 RA, The Netherlands

    Petra G M van Overveld, Richard J F L Lemmers, Lodewijk A Sandkuijl, Floor Bakels, Gert-Jan B van Ommen, Rune R Frants & Silvère M van der Maarel

  2. Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, P.O. Box 9502, Leiden, 2300 RA, The Netherlands

    Leo Enthoven

  3. Department of Biological Chemistry, College of Medicine, University of California, Irvine, California, USA

    Sara T Winokur

  4. Department of Neurology, University Medical Center St. Radboud, Nijmegen, The Netherlands

    George W Padberg

Authors
  1. Petra G M van Overveld
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  2. Richard J F L Lemmers
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  3. Lodewijk A Sandkuijl
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  4. Leo Enthoven
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  5. Sara T Winokur
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  6. Floor Bakels
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  7. George W Padberg
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  8. Gert-Jan B van Ommen
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  9. Rune R Frants
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  10. Silvère M van der Maarel
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Correspondence to Silvère M van der Maarel.

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The authors declare no competing financial interests.

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van Overveld, P., Lemmers, R., Sandkuijl, L. et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet 35, 315–317 (2003). https://doi.org/10.1038/ng1262

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  • DOI: https://doi.org/10.1038/ng1262

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