The research project about the association between SNTA variant and Early depolarisation syndrome

• Project/Area Number: 20K17113
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kato Koichi 滋賀医科大学, 医学部, 助教 (70736983)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Brugada症候群 / SNTA1 / SCN5A / 遺伝性QT延長症候群 / CALM3 / カルモジュリン / 遺伝性不整脈 / QT延長症候群 / ブルガダ症候群 / 心臓イオンチャネル / 心臓ナトリウム電流 / 機能喪失型変異 / 早期再分極症候群 / 心臓突然死

Outline of Research at the Start

働き盛りの成人が不整脈で突然死する早期再分極症候群（Early Repolarization Syndrome: ERS）の原因は、未だよくわかっていない。心臓ナトリウム(Na)チャネル遺伝子SCN5Aの異常によるNa電流の低下が重要視されているが、SCN5A変異が見つかるケースはERS全体で２割以下で、他の原因遺伝子検索が続いている。ジストロフィン関連タンパクのα-1-Syntrophinは、Naチャネルと結合してその調整を行う。今回我々は、ERSやそれと類似した病型を取る３家系に、3種類のSNTA1遺伝子異常を同定した。これらの変異がどのようにERSを引き起こしたのかを明らかにすることが本研究の目的である。

Outline of Final Research Achievements

In this study, we first analysed the functional effect of SNTA1 genetic variant found in a family with Brugada syndrome. However, in an over expression system using HEK293 cells, the variant's effect was fairly small. Thus, we allocated a part of our resources to another variant in another channel interacting protein "calmodulin". By functional analyses, we found the detected variant affected not only ICaL, but also IKs, which possibly produced relatively milder phenotype of the affected family members.

Academic Significance and Societal Importance of the Research Achievements

本研究を通して、遺伝性不整脈の原因としてチャネル遺伝子そのものの異常だけでなく、チャネル結合蛋白の遺伝子異常が、疾患の表現型に与える影響というものへの理解がまた一つ深まったといえる。
現状保険適応となっている遺伝性不整脈の遺伝子検査では、チャネル結合蛋白遺伝子の配列を読むことまでは可能だが、その配列異常（遺伝子異常）が実際に検査を受けた患者さんの病態と本当に関係があるのか、あるとすればどのような重症度で、どのような臨床症状を引き起こすのか、などまできちんと評価できる検査機関はない。本研究の成果がそのような臨床での遺伝子検査の結果解釈の一助となれば良いと考えている。

Research Products

• [Journal Article] Novel Calmodulin Variant p.E46K Associated With Severe Catecholaminergic Polymorphic Ventricular Tachycardia Produces Robust Arrhythmogenicity in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. (2023)
  • Author(s): Gao J, Makiyama T, Yamamoto Y, Kobayashi T, Aoki H, Maurissen TL, Wuriyanghai Y, Kashiwa A, Imamura T, Aizawa T, Huang H, Kohjitani H, Nishikawa M, Chonabayashi K, Fukuyama M, Manabe H, Nakau K, Wada T, Kato K, Toyoda F, Yoshida Y, Makita N, Woltjen K, Ohno S, Kurebayashi N, Murayama T, Sakurai T, Horie M, Kimura T.
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 16 Issue: 3 Pages: 9999-9999
  • DOI: 10.1161/circep.122.011387
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-missense variants of <i>KCNH2</i> show better outcomes in type 2 long QT syndrome (2023)
  • Author(s): Aizawa Takanori、Wada Yuko、Hasegawa Kanae、Huang Hai、Imamura Tomohiko、Gao Jingshan、Kashiwa Asami、Kohjitani Hirohiko、Fukuyama Megumi、Kato Koichi、Kato Eri Toda、Hisamatsu Takashi、Ohno Seiko、Makiyama Takeru、Kimura Takeshi、Horie Minoru
  • Journal Title: EP Europace Volume: 25 Issue: 4 Pages: 1491-1499
  • DOI: 10.1093/europace/euac269
• [Journal Article] Successful Management of a Young Athlete with Type 2 Long QT Syndrome by Genotype-specific Risk Stratification and Bridging Therapy with a Wearable Cardioverter Defibrillator (2022)
  • Author(s): Kojima Katsumi、Kato Koichi、Fujii Yusuke、Okuyama Yusuke、Ohno Seiko、Ozawa Tomoya、Horie Minoru、Nakagawa Yoshihisa
  • Journal Title: Internal Medicine Volume: 61 Issue: 8 Pages: 1179-1182
  • DOI: 10.2169/internalmedicine.8093-21
  • NAID: 130008150341
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-04-15
• [Journal Article] Case report: Vascular graft infection due to Aspergillus species presenting with recurrent vascular occlusion (2022)
  • Author(s): Tano Ayami、Kato Koichi、Seike Yoshimasa、Matsuda Hitoshi、Suzue Takashi、Kaneko Yoshihiro、Kodama Misato、Sawayama Yuichi、Miyamoto Akashi、Yagi Noriaki、Nakagawa Yoshihisa
  • Journal Title: BMC Cardiovascular Disorders Volume: 22 Issue: 1 Pages: 02571-73
  • DOI: 10.1186/s12872-022-02571-3
  • Peer Reviewed / Open Access
• [Journal Article] Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family (2022)
  • Author(s): Kato Koichi、Isbell Holly M.、Fressart Veronique、Denjoy Isabelle、Debbiche Amal、Itoh Hideki、Poinsot Jacques、George Alfred L.、Coulombe Alain、Shea Madeline A.、Guicheney Pascale
  • Journal Title: Circulation: Arrhythmia and Electrophysiology Volume: 15 Issue: 3
  • DOI: 10.1161/circep.121.010572
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] School-based routine screenings of electrocardiograms for the diagnosis of long QT syndrome (2022)
  • Author(s): Fukuyama Megumi、Horie Minoru、Aoki Hisaaki、Ozawa Junichi、Kato Koichi、Sawayama Yuichi、Tanaka-Mizuno Sachiko、Makiyama Takeru、Yoshinaga Masao、Nakagawa Yoshihisa、Ohno Seiko
  • Journal Title: EP Europace Volume: - Issue: 9 Pages: 1496-1503
  • DOI: 10.1093/europace/euab320
  • Peer Reviewed
• [Journal Article] An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia (2022)
  • Author(s): Peltenburg, P. J. Kallas, D. Bos, J. M. Lieve, K. V. V. Franciosi, S. Roston, T. M. Denjoy, I. Sorensen, K. B. Ohno, S. Shimizu, W. Horie, M. Leenhardt, A. Ackerman, M. J. Sanatani, S. van der Werf, C. Wilde, A. A. M.
  • Journal Title: Circulation Volume: 145 Issue: 5 Pages: 333-344
  • DOI: 10.1161/circulationaha.121.056018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome (2021)
  • Author(s): Hirose Sayako、Murayama Takashi、Tetsuo Naoyuki、Hoshiai Minako、Kise Hiroaki、Yoshinaga Masao、Aoki Hisaaki、Fukuyama Megumi、Wuriyanghai Yimin、Wada Yuko、Kato Koichi、Makiyama Takeru、Kimura Takeshi、Sakurai Takashi、Horie Minoru、Kurebayashi Nagomi、Ohno Seiko
  • Journal Title: EP Europace Volume: 24 Issue: 3 Pages: 497-510
  • DOI: 10.1093/europace/euab250
  • Peer Reviewed / Open Access
• [Presentation] Correction of cryptic donor site splicing by antisense oligo nucleotides in a case of Brugada syndrome. (2023)
  • Author(s): Hideyuki Jinzai1, Koichi Kato1, Takeru Makiyama2, Yuichi Sawayama1, Seiko Ohno4, Yoshihisa Nakagawa1, Minoru Horie1
  • Organizer: 2023 日本循環器学会
• [Presentation] Compound heterozygous SCN5A variants caused severe bradyarrhythmia via complex channel-channel interaction. (2023)
  • Author(s): Ayami Tano1), Koichi Kato2), Hideyuki Jinzai2), Daisuke Fukumoto2), Toru Kubo 3), Seiko Ohno4), Yoshihisa Nakagawa2), Minoru Horie2)
  • Organizer: 2023 日本循環器学会
• [Presentation] Haploinsufficient Variant of KCNH2 Cause Better Arrhythmia Outcome in Patients with Type 2 Long QT Syndrome (2022)
  • Author(s): Aizawa Takanori , Wada Yuko , Makiyama Takeru , Huang Hai , Imamura Tomohiko , Gao Jingshan , Kashiwa Asami , Kohjitani Hirohiko , Kato Koichi , Ohno Seiko , Kimura Takeshi , Horie Minoru
  • Organizer: 日本循環器学会
• [Presentation] Correction of SCN5A splicing error of Brugada syndrome patient by antisense oligo nucleotides (2022)
  • Author(s): Koichi Kato1, Hideyuki Jinzai1, Takeru Makiyama2, Yuichi Sawayama1, Ryotaro Kida1, Ryo Kurosawa3, Masahiko Ajiro3, Seiko Ohno4, Yoshihisa Nakagawa1, Minoru Horie1
  • Organizer: Asia Pacific Heart Rhythm Society 2022
  • Int'l Joint Research
• [Presentation] Mutant Nav1.5 with dominant-negative effect does not correspond to the severe phenotype (2022)
  • Author(s): Ayami Tano1), Koichi Kato2), Hideyuki Jinzai2), Daisuke Fukumoto2), Seiko Ohno3), Yoshihisa Nakagawa2), Minoru Horie2)
  • Organizer: Asia Pacific Heart Rhythm Society 2022
  • Int'l Joint Research
• [Presentation] Genetic Analysis for Inherited Primary Arrhythmia Syndrome Speaker (2022)
  • Author(s): Koichi Kato 1、Co-author：Megumi Fukuyama 1、Co-author：Ayami Tano 1、Co-author：Keiko Sonoda 2、Co-author： Koichiro Takayama 2、Co-author：Dimitar P Zankov 2、Co-author：Minoru Horie 1、Co-author：Takeru Makiyama 3、Co- author：Yoshihisa Nakagawa 1、Co-author：Seiko Ohno 2
  • Organizer: 日本不整脈心電学会 2022
• [Presentation] LMNA missense mutation causes nonsense-mediated mRNA decay and severe dilated cardiomyopathy. (2021)
  • Author(s): Koichi Kato , Seiko Ohno , Keiko Sonoda , Takeru Makiyama , Tomoya Ozawa , Yoshihisa Nakagawa , Minoru Horie
  • Organizer: 日本不整脈心電学会
• [Presentation] A Synonymous SCN5A Variant p.E446E Causing Brugada Syndrome via Cryptic Donor Site Splicing (2021)
  • Author(s): Yuichi Sawayama、Koichi Kato、Masahiko Ajiro、 Ryo Kurosawa、Megumi Fukuyama、Seiko Ohno、 Yoshihisa Nakagawa、Minoru Horie
  • Organizer: 第85回日本循環器学会学術集会