The search for novel causative genes of malignant hyperthermia

• Project/Area Number: 17K16733
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Anesthesiology
• Research Institution: Hiroshima University
• Principal Investigator: Noda Yuko 広島大学, 病院(医), 医科診療医 (00790065)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 悪性高熱症 / リアノジン受容体 / ジヒドロピリジン受容体 / 次世代シークエンサー / 遺伝子 / 遺伝学 / 臨床

Outline of Final Research Achievements

We analyzed gene variants of ryanodine receptor (RYR1) and dihydropyridine receptor (CACNA1S) in patients with malignant hyperthermia and family history of malignant hyperthermia.
We identified 16 known mutations in RYR1 and CACNA1S and 17 variants with a high possibility of a new causative mutation.We also performed functional analysis of variants with a high possibility of a new causative mutation and confirmed whether it was the causative mutation or not.
Samples with no mutation in RYR1 and CACNA1S were submitted to the exome sequence to try to find a new causative variants. By submitting a total of 16 samples, we were able to narrow down the candidates for the causative variants.

Academic Significance and Societal Importance of the Research Achievements

悪性高熱症は主にリアノジン受容体(RYR1)の遺伝子変異が原因であると言われているが，発症した患者のうち実際にRYR1から遺伝子変異が確認されない症例も多い．これはRYR1以外に未知の遺伝子要因が存在していることを示唆しているが，その探索は遅々として進んでおらず，今回の研究は，悪性高熱症の新たな原因遺伝子を探索し，悪性高熱症の遺伝子診断の確立に少なからず寄与できた．

Research Products

• [Journal Article] 帝王切開を脊髄くも膜下麻酔で２度行った血友病A確定保因者の麻酔管理 (2017)
  • Author(s): 野田祐子
  • Journal Title: 麻酔と蘇生 Volume: 53 Pages: 55-58
  • NAID: 120006348328
  • Peer Reviewed
• [Presentation] Functional Analysis of Newly Found Ryanodine Receptor 1 Variants in Malignant Hyperthermia Susceptible Patients. (2019)
  • Author(s): Yuko Noda, Toshimichi Yasuda, Hirotsugu Miyoshi, Keiko Mukaida, Hiroshi Hamada
  • Organizer: ASA 2019 American Society of Anesthesiologists Annual Meeting
  • Int'l Joint Research
• [Presentation] 悪性高熱症の原因であるp.R2508Cを組み込んだリアノジン受容体の温度上昇による細胞内Ca動態は野生型と変わらない (2017)
  • Author(s): 野田祐子
  • Organizer: 日本麻酔科学会第64回学術集会
• [Presentation] 30年前に悪性高熱症を診断され最近になってCACNA1Sに遺伝子変異が認められた1症例 (2017)
  • Author(s): 神﨑理英子 野田祐子
  • Organizer: 日本臨床麻酔学会第37回大会
• [Presentation] デブランチ胸部ステントグラフト内挿術後に生じた冠攣縮性狭心症の1例 (2017)
  • Author(s): 野田祐子
  • Organizer: 日本心臓血管麻酔学会第22回学術大会