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: Eri Imagawa, Ken Higashimoto, Yasunari Sakai, Chikahiko Numakura, Nobuhiko Okamoto, Satoko Matsunaga, Akihide Ryo, Yoshinori Sato, Masafumi Sanefuji, Kenji Ihara, Yui Takada, Gen Nishimura, Hirotomo Saitsu, Takeshi Mizuguchi, Satoko Miyatake, Mitsuko Nakashima, Noriko Miyake, Hidenobu Soejima, Naomichi Matsumoto
• Journal: Human mutation (Hum Mutat) Vol. 38 Issue 6 Pg. 637-648 (06 2017) ISSN: 1098-1004 [Electronic] United States
• PMID: 28229514 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Cullin 1
• Cullin Proteins
• DNA-Binding Proteins
• EED protein, human
• Histones
• Neoplasm Proteins
• SUZ12 protein, human
• Transcription Factors
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2

Topics

• Abnormalities, Multiple (genetics, pathology)
• Adult
• Child
• Child, Preschool
• Congenital Hypothyroidism (genetics, pathology)
• Craniofacial Abnormalities (genetics, pathology)
• Cullin Proteins (genetics)
• DNA-Binding Proteins (genetics)
• Enhancer of Zeste Homolog 2 Protein (genetics)
• Female
• Hand Deformities, Congenital (genetics, pathology)
• Heterozygote
• Histones (genetics)
• Humans
• Male
• Methylation
• Mutation
• Neoplasm Proteins
• Pedigree
• Polycomb Repressive Complex 2 (genetics)
• Protein Interaction Maps
• Transcription Factors