title: Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.
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.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Marlinde L
authors.initials: ML
authors.lastname: van den Boogaard
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Richard J L F
authors.initials: RJLF
authors.lastname: Lemmers
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.affiliation: Department of Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Mariëlle
authors.initials: M
authors.lastname: Wohlgemuth
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Auranen
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van der Vliet
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Straasheijm
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Rob F P
authors.initials: RFP
authors.lastname: van den Akker
authors.affiliation: 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.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Kriek
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Marlies E Y
authors.initials: MEY
authors.lastname: Laurense-Bik
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Vered
authors.initials: V
authors.lastname: Raz
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: van Ostaijen-Ten Dam
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Kerstin B M
authors.initials: KBM
authors.lastname: Hansson
authors.affiliation: Medisch Centrum Leeuwarden, 8934AD, Leeuwarden, the Netherlands.
authors.forename: Elly L
authors.initials: EL
authors.lastname: van der Kooi
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00029 Helsinki, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Kiuru-Enari
authors.affiliation: Neuromuscular Research Center, Department of Neurology, Tampere University Hospital and University of Tampere, 33520 Tampere, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Maarten J D
authors.initials: MJD
authors.lastname: van Tol
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.affiliation: Department of Neurology, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Baziel G M
authors.initials: BGM
authors.lastname: van Engelen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands. Electronic address: s.m.van_der_maarel@lumc.nl.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics*; D019175:DNA Methylation; D063185:Epigenetic Repression / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D020080:Tandem Repeat Sequences / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000097584:DNA Methyltransferase 3B