Genetic and biochemical analyses of mTOR related megalencephaly

• Project/Area Number: 16K15530
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Nagoya City University
• Principal Investigator: Saitoh Shinji 名古屋市立大学, 大学院医学研究科, 教授 (00281824)
• Co-Investigator(Kenkyū-buntansha): 中西 真 東京大学, 医科学研究所, 教授 (40217774)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 巨脳症 / mTOR / 次世代シーケンシング / 脳・神経

Outline of Final Research Achievements

Next generation sequencing based targeted panel analysis was performed on 28 patients with megalencephaly. We detected a pathogenic mutation in 13 of 27 patients (48.1%) including one patient with a mosaic mutation which was only detected in the affected brain tissue. Western blot analysis using lymphoblastoid cell lines established from peripheral leukocytes with phospho-S6 antibody was performed in 7 mutation-positive patients, and significantly increased phospho-S6 representing abnormal activation of mTOR pathway was found in all 7 patients. Increased phospho-S6 was also detected in 1 of 8 mutation-negative patients. Collectively, our combination of genetic and biochemical analyses is useful for diagnosis of genetic megalencephaly syndromes.

Research Products

• [Journal Article] IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis (2018)
  • Author(s): Shigemizu Daichi、Miya Fuyuki、Akiyama Shintaro、Okuda Shujiro、Boroevich Keith A、Fujimoto Akihiro、Nakagawa Hidewaki、Ozaki Kouichi、Niida Shumpei、Kanemura Yonehiro、Okamoto Nobuhiko、Saitoh Shinji、Kato Mitsuhiro、Yamasaki Mami、Matsunaga Tatsuo、Mutai Hideki、Kosaki Kenjiro、Tsunoda Tatsuhiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5608-5608
  • DOI: 10.1038/s41598-018-23978-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. (2017)
  • Author(s): Negishi Y, Miya F, Hattori A, Johmura Y, Nakagawa M, Ando N, Hori I, Togawa T, Aoyama K, Ohashi K, Fukumura S, Mizuno S, Umemura A, Kishimoto Y, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Nakanishi M, Saitoh S.
  • Journal Title: BMC Med Genet. Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12881-016-0363-6
  • Peer Reviewed / Open Access
• [Journal Article] A novel missense mutation in the HECT domain of NEDD4L identified in a girl with periventricular nodular heterotopia, polymicrogyria and cleft palate (2017)
  • Author(s): Kato Koji、Miya Fuyuki、Hori Ikumi、Ieda Daisuke、Ohashi Kei、Negishi Yutaka、Hattori Ayako、Okamoto Nobuhiko、Kato Mitsuhiro、Tsunoda Tatsuhiko、Yamasaki Mami、Kanemura Yonehiro、Kosaki Kenjiro、Saitoh Shinji
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 9 Pages: 861-863
  • DOI: 10.1038/jhg.2017.53
  • Peer Reviewed
• [Presentation] PI3K-AKT-mTOR経路異常による巨脳症の臨床的・分子遺伝学的・生化学的検討 (2017)
  • Author(s): 堀いくみ、根岸豊、宮冬樹、角田達彦、金村米博、小崎健次郎、齋藤伸治
  • Organizer: 第62回日本人類遺伝学会学術集会
• [Presentation] Combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway associated megalencephaly syndromes. (2016)
  • Author(s): Negishi Y, Miya F, Hattori A, Ando N, Hori I, Togawa T, Aoyama K, Ohashi K, Fukumura S, Mizuno S, Umemura A, Kishimoto Y, Okamoto N, Kato M, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-04-04
  • Int'l Joint Research