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

• Published in: American journal of human genetics Vol. 98; no. 5; pp. 1020 - 1029
• Main Authors: van den Boogaard, Marlinde L., Lemmers, Richard J.L.F., Balog, Judit, Wohlgemuth, Mariëlle, Auranen, Mari, Mitsuhashi, Satomi, van der Vliet, Patrick J., Straasheijm, Kirsten R., van den Akker, Rob F.P., Kriek, Marjolein, Laurense-Bik, Marlies E.Y., Raz, Vered, van Ostaijen-ten Dam, Monique M., Hansson, Kerstin B.M., van der Kooi, Elly L., Kiuru-Enari, Sari, Udd, Bjarne, van Tol, Maarten J.D., Nishino, Ichizo, Tawil, Rabi, Tapscott, Stephen J., van Engelen, Baziel G.M., van der Maarel, Silvère M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.05.2016; Cell Press; Elsevier
• Subjects: Adolescent; Adult; Aged; Amino Acid Sequence; Child; Child, Preschool; Chromatin; Chromatin - genetics; DNA (Cytosine-5-)-Methyltransferases - chemistry; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA Methylation; DNA Methyltransferase 3B; Epigenetic Repression - genetics; Female; Genes; Genetic disorders; Humans; Infant; Male; Middle Aged; Muscular dystrophy; Muscular Dystrophy, Facioscapulohumeral - genetics; Mutation; Mutation - genetics; Pedigree; Penetrance; Protein Conformation; Sequence Homology, Amino Acid; Tandem Repeat Sequences - genetics
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2016.03.013

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.