Genetic analysis of mutations associated with polycomb repressive complex 2 in Weaver Syndrome

• Project/Area Number: 15H06533
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Yokohama City University
• Principal Investigator: IMAGAWA Eri 横浜市立大学, 医学研究科, 博士研究員 (60579895)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Weaver症候群 / ポリコーム蛋白質複合体2 / 全エクソーム解析 / 遺伝学

Outline of Final Research Achievements

In this study, we aimed to investigate a pathogenicity of a p.Arg236Thr in EED and a p.Glu610Val in SUZ12 , which was detected in a proband with clinically suspected Weaver Syndrome. The EED and SUZ12 proteins are components of polycomb repressive complex 2 (PRC2) that has histone methyltransferase activity and catalyzes the trimethylation of histone 3 at lysine 27 (H3K27me3). To investigate the functional effects of the mutations, we performed rescue experiments using the Tet-on system for 293 T-REx cells. The results showed that increased H3K27me3 signals were observed after wild-type EED or SUZ12 transfection, whereas the mutants failed to rescue and produced similar levels of H3K27me3 as the mock transfections. These results of reduced H3K27me3 levels indicate that the identified mutations might lead to PRC2 loss-of function. Finally, we summarized these results in the article on Human Mutation (Hum Mutat. 2017. Jun;38(6):637-648.) .

Research Products

• [Journal Article] Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome (2017)
  • Author(s): 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 Title: Human Mutation Volume: 印刷中 Issue: 6 Pages: 637-648
  • DOI: 10.1002/humu.23200
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant