2. Academic Validation
  3. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome

Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome

  • Hum Mutat. 2017 Jun;38(6):637-648. doi: 10.1002/humu.23200.
Eri Imagawa 1,  Ken Higashimoto 2,  Yasunari Sakai 3,  Chikahiko Numakura 4,  Nobuhiko Okamoto 5,  Satoko Matsunaga 6,  Akihide Ryo 6,  Yoshinori Sato 7,  Masafumi Sanefuji 3,  Kenji Ihara 8,  Yui Takada 9,  Gen Nishimura 10,  Hirotomo Saitsu 11,  Takeshi Mizuguchi 1,  Satoko Miyatake 1,  Mitsuko Nakashima 1,  Noriko Miyake 1,  Hidenobu Soejima 2,  Naomichi Matsumoto 1
Affiliations

Affiliations

  • 1 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 2 Division of Molecular Genetics and Epigenetics, Department of Biomolecular Sciences, Faculty of Medicine, Saga University, Saga, Japan.
  • 3 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 4 Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
  • 5 Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
  • 6 Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.
  • 7 Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, Japan.
  • 8 Department of Pediatrics, Faculty of Medicine, Oita University, Yufu, Japan.
  • 9 Department of Pediatrics, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan.
  • 10 Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
  • 11 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
PMID: 28229514 DOI: 10.1002/humu.23200
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.

Keywords

EED; EZH2; SUZ12; Weaver syndrome; loss-of-function mutation; polycomb repressive complex 2; trimethylation of histone H3 at lysine 27.

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