Elucidation of mechanism of cardiac calcium channel (CaV1.2) abnormality in long QT syndrome

• Project/Area Number: 17K15999
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Fukuyama Megumi 滋賀医科大学, 医学部, 助教 (60625771)
• Research Collaborator: Ohno Seiko ; Horie Minoru
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: QT延長症候群8型 / CACNA1C遺伝子 / QT延長症候群 / CACNA1C遺伝子変異 / リアノジン受容体遺伝子 / 循環器 / 家族性不整脈症候群 / 遺伝子

Outline of Final Research Achievements

In a cohort of about 5000 of inherited lethal arrhythmic patients we collected, 892 LQTS patients who identified no mutation genes while exhibiting QT prolongation were extracted and searched for CACNA1C gene mutations. As a result, CACNA1C mutations were identified in 17 probands, including 3 probands with classical Timothy syndrome.
As a result of analyzing the clinical and electrocardiographic characteristics in these LQT8 patients, the cases with late-appearance T wave showed severe clinical phenotypes at a high rate. It was suggested that the larger of calcium current by mutation lead to the late-appearance T wave changes. We made a paper comparing this feature with LQT3, which exhibits similar ECG changes (currently being submitted to the peer review journal).

Academic Significance and Societal Importance of the Research Achievements

まず従来は非常に稀で重篤な臨床像を呈すると考えられてきたLQT8の同定率がLQT3に匹敵するほど高く、心電図異常以外の症状を呈さない軽症例も存在することが明らかとなり、実臨床にてLQT患者の診療にあたる上で重要な事実となった。またこれらLQT8患者の心電図学的特徴とイオンチャネルの機能変化・臨床像の重症度を紐づけることで、LQT8患者の中でもハイリスク群に属する患者を予測することができ、治療や安全管理の上で非常に役立つと考えられる。

Research Products

• [Journal Article] Novel intracellular transport-refractory mutations in KCNH2 identified in patients with symptomatic long QT syndrome (2018)
  • Author(s): Fukumoto Daisuke、Ding Wei-Guang、Wada Yuko、Fujii Yusuke、Ichikawa Mari、Takayama Koichiro、Fukuyama Megumi、Kato Koichi、Itoh Hideki、Makiyama Takeru、Omatsu-Kanbe Mariko、Matsuura Hiroshi、Horie Minoru、Ohno Seiko
  • Journal Title: Journal of Cardiology Volume: 71 Issue: 4 Pages: 401-408
  • DOI: 10.1016/j.jjcc.2017.10.004
  • Peer Reviewed
• [Presentation] Usefulness of Genetic Screening for Long QT syndrome in the School-Based Electrocardiographic Screening Programs (2019)
  • Author(s): 福山 恵, 大野 聖子, 小澤 淳一, 髙山 幸一郎, 加藤 浩一, 伊藤 英樹, 青木 寿明, 牧山 武, 堀江 稔
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Excessive Ca2+ Release from Ryanodine Receptors Underlying a RyR2 Mutation Associated with Catecholaminergic Polymorphic Ventricular Tachycardia (2019)
  • Author(s): 伊藤 英樹, 村山 尚, 呉林 なごみ, 大野 聖子, 藤居 祐介, 加藤 浩一, 福山 恵, 髙山 幸一郎, 渡邉 昌也, 安斉 俊久, 堀江 稔
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] An NGS-based genotyping in LQTS; minor genes are no longer minor (2019)
  • Author(s): Seiko Ohno, Junichi Ozawa, Megumi Fukuyama, Takeru Makiyama, Minoru Horie
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Ebstein病に左室緻密化障害を合併した心室頻拍の一例 (2019)
  • Author(s): 西川拓磨, 小澤友哉, 奥谷雄介, 藤居祐介, 加藤浩一, 福山 恵, 芦原貴司, 山本 孝
  • Organizer: 第126回日本循環器学会近畿地方会
• [Presentation] Consideration of CACNA1C variants in Long QT Syndrome (2018)
  • Author(s): Megumi Fukuyama, Seiko Ohno, Minoru Horie
  • Organizer: 第65回日本不整脈心電学会学術大会
• [Presentation] How to Confirm the Pathogenicity of Gene Variants in Inherited Primary Arrhythmia Syndrome. (2018)
  • Author(s): Fukuyama M, Ohno S, Takayama K, Ichikawa M, Fukumoto D, Horie M.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Novel RYR2 mutations causative for long QT syndromes. (2017)
  • Author(s): Fukuyama M, Ohno S, Takayama K, Ichikawa M, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] SCN10A Mutations Related with Bradycardia and Conduction Block in Young Patients. (2017)
  • Author(s): Aoki H, Ohno S, Fukuyama M, Yoshinaga M, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] Double mutations in RYR2 cause severe phenotype of catecholaminergic polymorphic ventricular tachycardia (2017)
  • Author(s): Takayama K, Ohno S, Fukumoto D, Wada Y, Ichikawa M, Fukuyama M, Itoh H, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] Novel intracellular transport-refractory mutations in KCNH2 identified in symptomatic long QT syndrome patients (2017)
  • Author(s): Fukumoto D, Ohno S, Wada Y, Fujii Y, Ichikawa M, Takayama K, Fukuyama M, Makiyama T, Itoh H, Ding WG, Matsuura H, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] Identification of copy number variations by next generation sequencer in patients with inherited primary arrhythmia syndromes. (2017)
  • Author(s): Ichikawa M, Ohno S, Fukumoto D, Takayama K, Wada Y, Fukuyama M, Makiyama T, Itoh H, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] High frequency of CACNA1C mutations among genotyped LQTS patients (2017)
  • Author(s): Ohno S, Ozawa J, Fukuyama M, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] Novel RYR2 Mutations Causative for Long QT Syndromes. (2017)
  • Author(s): Fukuyama M, Ohno S, Takayama K, Ichikawa M, Fukumoto D, Horie M.
  • Organizer: APHRS2017
  • Int'l Joint Research
• [Presentation] Next-Generation Sequencing Is One of the Promising Ways for Identifying Copy Number Variations in Patients with Inherited Primary Arrhythmia Syndromes. (2017)
  • Author(s): Ichikawa M, Ohno S, Fukumoto D, Takayama K, Wada Y, Fukuyama M, Makiyama T, Itoh H, Horie M.
  • Organizer: APHRS2017
  • Int'l Joint Research
• [Presentation] Novel N-Terminal KCNH2 Mutations Identified in Symptomatic Long QT Syndrome Patients. (2017)
  • Author(s): Fukumoto D, Ohno S, Wada Y, Fujii Y, Ichikawa M, Takayama K, Fukuyama M, Itoh H, Ding WG, Matsuura H, Horie M.
  • Organizer: APHRS2017
  • Int'l Joint Research