| Literature DB >> 27153398 |
Marlinde L van den Boogaard1, Richard J L F Lemmers1, Judit Balog1, Mariëlle Wohlgemuth2, Mari Auranen3, Satomi Mitsuhashi4, Patrick J van der Vliet1, Kirsten R Straasheijm1, Rob F P van den Akker1, Marjolein Kriek5, Marlies E Y Laurense-Bik6, Vered Raz1, Monique M van Ostaijen-Ten Dam7, Kerstin B M Hansson6, Elly L van der Kooi8, Sari Kiuru-Enari3, Bjarne Udd9, Maarten J D van Tol7, Ichizo Nishino4, Rabi Tawil10, Stephen J Tapscott11, Baziel G M van Engelen2, Silvère M van der Maarel12.
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.Entities:
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Year: 2016 PMID： 27153398 PMCID： PMC4863565 DOI： 10.1016/j.ajhg.2016.03.013
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025