title: Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome.
abstract: Weaver syndrome (WS) is a rare congenital overgrowth disorder caused by heterozygous mutations in EZH2 (enhancer of zeste homolog 2) or EED (embryonic ectoderm development). EZH2 and EED are core components of the polycomb repressive complex 2 (PRC2), which possesses histone methyltransferase activity and catalyzes trimethylation of histone H3 at lysine 27. Here, we analyzed eight probands with clinically suspected WS by whole-exome sequencing and identified three mutations: a 25.4-kb deletion partially involving EZH2 and CUL1 (individual 1), a missense mutation (c.707G>C, p.Arg236Thr) in EED (individual 2), and a missense mutation (c.1829A>T, p.Glu610Val) in SUZ12 (suppressor of zeste 12 homolog) (individual 3) inherited from her father (individual 4) with a mosaic mutation. SUZ12 is another component of PRC2 and germline mutations in SUZ12 have not been previously reported in humans. In vitro functional analyses demonstrated that the identified EED and SUZ12 missense mutations cause decreased trimethylation of lysine 27 of histone H3. These data indicate that loss-of-function mutations of PRC2 components are an important cause of WS.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Imagawa
authors.affiliation: Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Higashimoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Chikahiko
authors.initials: C
authors.lastname: Numakura
authors.affiliation: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ryo
authors.affiliation: Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sanefuji
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Oita University, Yufu, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Soejima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics* / Q000473:pathology; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D044842:Cullin Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D005260:Female; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D008745:Methylation; D009154:Mutation; D009363:Neoplasm Proteins; D010375:Pedigree; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D060066:Protein Interaction Maps; D014157:Transcription Factors
chemical_list: C100318:Cullin 1; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; C491488:EED protein, human; D006657:Histones; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: EED; EZH2; SUZ12; Weaver syndrome; loss-of-function mutation; polycomb repressive complex 2; trimethylation of histone H3 at lysine 27