Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome
Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome
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DOI：
10.1002/humu.23200
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发表时间：
2017-06-01
期刊：
影响因子：
3.9
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Imagawa, Eri;Higashimoto, Ken;Matsumoto, Naomichi
韦弗综合征（WS）是一种罕见的先天性过度生长障碍引起的杂合子突变EZH 2（增强子zeste同源物2）或EED（胚胎外胚层发育）。EZH 2和EED是多梳阻遏复合物2（PRC 2）的核心组分，PRC 2具有组蛋白甲基转移酶活性并催化组蛋白H3在赖氨酸27处的三甲基化。在这里，我们通过全外显子组测序分析了8名临床疑似WS的先证者，并确定了3种突变：部分涉及EZH 2和CUL 1的25.4-kb缺失（个体1），错义突变（c.707G>C，p.Arg236Thr）（个体2），和从她的父亲（个体4）继承的SUZ 12（zeste 12同源物的抑制子）（个体3）中的错义突变（c.1829A>T，p.Glu610Val），具有嵌合突变。SUZ 12是PRC 2的另一个组成部分，SUZ 12的种系突变以前在人类中没有报道。体外功能分析表明，鉴定的EED和SUZ 12错义突变导致组蛋白H3的赖氨酸27的三甲基化降低。这些数据表明PRC 2组分的功能缺失突变是WS的重要原因。
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.