The development of the molecular mechanism and treatment methods of Schaaf-Yang syndrome focusing on protein transport disorders

• Project/Area Number: 19K17308
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya City University
• Principal Investigator: HORI IKUMI 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (00745929)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: Schaaf-Yang症候群 / MAGEL2 / ゲノムインプリンティング / CRISPR/Cas9 / 父性発現遺伝子 / RT-PCR法 / in situ hybridization法 / 逆行性輸送

Outline of Research at the Start

Schaaf-Yang症候群 (SHFYNG) はPrader-Willi症候群 (PWS) の責任領域にあるMAGEL2の短縮変異が原因である。PWSよりも重度の知的障害を示し関節拘縮や脳症の合併を認める。しかし、MAGEL2の短縮型変異がSHFYNGを発症させる分子経路メカニズムはいまだに解明されていない。我々は6名の患者にMAGEL2の短縮型変異を同定している。本研究ではMAGEL2がエンドソームからトランスゴルジ網へ積荷蛋白の輸送を行う逆行性輸送に関与している点に着目し、蛋白輸送経路障害を中心としたSHFYNGの発症機序を解明する。

Outline of Final Research Achievements

The purpose of this study is to establish the clinical feature of Schaaf-Yang syndrome (SYS) by focusing on protein transport and to elucidate the molecular mechanism. Regarding patient accumulation, we conducted a national survey of SYS in Japan and created a patient registry.
Transgenic mice (Tg mice) and knockout (KO) mice has been created. Tg mice were embryonic lethal, but the phenotype of KO mice remained minimal. Based on the hypothesis that the effect on MAGEL2 differs depending on the type of mutation, we are creating a cell line library in vitro in which various mutations of MAGEL2 are introduced.

Academic Significance and Societal Importance of the Research Achievements

Schaaf-Yang症候群 (SHFYNG) はMAGEL2の短縮変異が原因である。重度の知的障害を示し関節拘縮や脳症の合併を認める。しかし、MAGEL2の短縮型変異がSHFYNGを発症させる分子経路メカニズムはいまだに解明されておらず、本研究は分子機構の解明に一歩近づいたと考えられる。蛋白輸送経路障害を中心としたSHFYNGの発症機序を解明することで、自閉症、パーキンソン病やアルツハイマー病などの神経変性疾患の分子機構の解明につながり、治療法開発の基盤となる。

Research Products

• [Journal Article] Peripheral nerves are involved in hypomyelinating leukodystrophy-3 caused by a homozygous AIMP1 variant (2021)
  • Author(s): Hori Ikumi、Ieda Daisuke、Ito Shogo、Ebe Seimi、Nakamura Yuji、Ohashi Kei、Aoyama Kohei、Hattori Ayako、Kokubo Minoru、Saitoh Shinji
  • Journal Title: Brain and Development Volume: 43 Issue: 4 Pages: 590-595
  • DOI: 10.1016/j.braindev.2020.12.008
  • Peer Reviewed / Open Access
• [Journal Article] De novo 2q36.3q37.1 deletion encompassing TRIP12 and NPPC yields distinct phenotypes (2020)
  • Author(s): Kondo Yuto、Aoyama Kohei、Suzuki Hisato、Hattori Ayako、Hori Ikumi、Ito Koichi、Yoshida Aya、Koroki Mari、Ueda Kentaro、Kosaki Kenjiro、Saitoh Shinji
  • Journal Title: Human Genome Variation Volume: 7 Issue: 1 Pages: 19-19
  • DOI: 10.1038/s41439-020-0107-1
  • Peer Reviewed / Open Access
• [Journal Article] Frequent epileptic apnoea in a patient with Pitt-Hopkins syndrome (2020)
  • Author(s): Yamada Hiroyuki、Tamasaki Akiko、Oguri Masayoshi、Hori Ikumi、Saitoh Shinji、Maegaki Yoshihiro
  • Journal Title: Epileptic Disorders Volume: 22 Issue: 5 Pages: 673-677
  • DOI: 10.1684/epd.2020.1212
  • NAID: 120006975634
  • Peer Reviewed / Open Access
• [Presentation] Mild Phenotypic features associated with non-truncating UBE3A mutations in Angelman syndrome. (2020)
  • Author(s): Yuji Nakamura, Kana Hosoki, Daisuke Ieda, Ikumi Hori, Yutaka Negishi, Ayako Hattori, Shinji Saitoh
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] 当院でエキソーム解析を実施した小児神経疾患症例の臨床的検討. (2020)
  • Author(s): 堀いくみ, 宮冬樹, 中島光子, 中村勇治, 家田大輔, 大橋圭, 根岸豊, 服部文子, 安藤直樹, 角田達彦, 才津浩智, 金村米博, 小崎健次郎, 齋藤伸治
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] Generation of a mouse model carrying a truncating mutation in Magel2 (2019)
  • Author(s): Daisuke Ieda
  • Organizer: 第61回日本小児神経学会、日本-台湾 新生児・小児神経ワークショップ