Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Am J Hum Genet. 2016 May 5;98(5):1020-1029. doi: 10.1016/j.ajhg.2016.03.013.

Marlinde L van den Boogaard ¹, Richard J L F Lemmers ¹, Judit Balog ¹, Mariëlle Wohlgemuth ², Mari Auranen ³, Satomi Mitsuhashi ⁴, Patrick J van der Vliet ¹, Kirsten R Straasheijm ¹, Rob F P van den Akker ¹, Marjolein Kriek ⁵, Marlies E Y Laurense-Bik ⁶, Vered Raz ¹, Monique M van Ostaijen-Ten Dam ⁷, Kerstin B M Hansson ⁶, Elly L van der Kooi ⁸, Sari Kiuru-Enari ³, Bjarne Udd ⁹, Maarten J D van Tol ⁷, Ichizo Nishino ⁴, Rabi Tawil ¹⁰, Stephen J Tapscott ¹¹, Baziel G M van Engelen ², Silvère M van der Maarel ¹²

Affiliations

1 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
2 Department of Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
3 Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
4 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
5 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
6 Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
7 Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
8 Medisch Centrum Leeuwarden, 8934AD, Leeuwarden, the Netherlands.
9 Neuromuscular Research Center, Department of Neurology, Tampere University Hospital and University of Tampere, 33520 Tampere, Finland.
10 Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
11 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
12 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. Electronic address: [email protected].

PMID: 27153398 DOI: 10.1016/j.ajhg.2016.03.013

Abstract

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA Methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

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