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

被引：192

作者：

van den Boogaard, Marlinde L. ^{[1
]}

Lemmers, Richard J. L. F. ^{[1
]}

Balog, Judit ^{[1
]}

Wohlgemuth, Marielle ^{[2
]}

Auranen, Mari ^{[3
,4
]}

Mitsuhashi, Satomi ^{[5
]}

van der Vliet, Patrick J. ^{[1
]}

Straasheijm, Kirsten R. ^{[1
]}

van den Akker, Rob F. P. ^{[1
]}

Kriek, Marjolein ^{[1
,6
]}

Laurense-Bik, Marlies E. Y. ^{[6
]}

Raz, Vered ^{[1
]}

van Ostaijen-ten Dam, Monique M. ^{[7
]}

Hansson, Kerstin B. M. ^{[6
]}

van der Kooi, Elly L. ^{[8
]}

Kiuru-Enari, Sari ^{[3
,4
]}

Udd, Bjarne ^{[9
,10
]}

van Tol, Maarten J. D. ^{[7
]}

Nishino, Ichizo ^{[5
]}

Tawil, Rabi ^{[11
]}

Tapscott, Stephen J. ^{[12
]}

van Engelen, Baziel G. M. ^{[2
]}

van der Maarel, Silvere M. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZA Leiden, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6500 HB Nijmegen, Netherlands

[3] Univ Helsinki, Neurol, Clin Neurosci, Helsinki 00029, Finland

[4] Helsinki Univ Hosp, Helsinki 00029, Finland

[5] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Tokyo 1878502, Japan

[6] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2333 ZA Leiden, Netherlands

[7] Leiden Univ, Med Ctr, Dept Pediat, NL-2333 ZA Leiden, Netherlands

[8] Med Ctr Leeuwarden, NL-8934 AD Leeuwarden, Netherlands

[9] Tampere Univ Hosp, Neuromuscular Res Ctr, Dept Neurol, Tampere 33520, Finland

[10] Univ Tampere, Tampere 33520, Finland

[11] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA

[12] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 98卷 / 05期

关键词：

DNA METHYLTRANSFERASE GENE; MUSCULAR-DYSTROPHY; ICF SYNDROME; IMMUNODEFICIENCY SYNDROME; CHROMOSOME INSTABILITY; DISEASE SEVERITY; SKELETAL-MUSCLE; SATELLITE DNA; ADD DOMAIN; METHYLATION;

D O I：

10.1016/j.ajhg.2016.03.013

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1020 / 1029

页数：10

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