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

作者：Imagawa Eri; Higashimoto Ken; Sakai Yasunari; Numakura Chikahiko; Okamoto Nobuhiko; Matsunaga Satoko; Ryo Akihide; Sato Yoshinori; Sanefuji Masafumi; Ihara Kenji; Takada Yui; Nishimura Gen; Saitsu Hirotomo; Mizuguchi Takeshi; Miyatake Satoko; Nakashima Mitsuko; Miyake Noriko; Soejima Hidenobu; Matsumoto Naomichi^*

来源：Human Mutation, 2017, 38(6): 637-648.

DOI：10.1002/humu.23200

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

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.

• 出版日期2017-6