Mechanism of Inherited Arrhythmia Syndrome with SCN10A mutation

• Project/Area Number: 15K19375
• 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: HORIE Minoru ; OHNO Seiko
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 遺伝性不整脈症候群 / 遺伝子 / 心筋ナトリウムチャネル / SCN10A / Nav1.8 / 循環器 / 家族性不整脈症候群 / ブルガダ症候群 / SCN10A遺伝子

Outline of Final Research Achievements

I have investigated SCN10A polymorphisms in patients with inherited primary arrhythmia syndrome (IPAS), and their clinical characteristics.
1) Our SCN5A mutation carriers (except LQTS) with additional SCN10A SNPs were significantly symptomatic and more experience fatal arrhythmic attacks. Multiple genetic hits by SCN5A and SCN10A variants may result in a severer loss-of-function of voltage-gated sodium channels and thereby more malignant phenotypes. 2) We identified rare SCN10A variants in patients with IPAS, and half of them were suspected as deleterious using the prediction software. Most of patients with deleterious SNPs suffered from severe symptom. More than half of them experienced fatal arrhythmic attacks and 30% are deceased. Rare SNPs of SCN10A predicted as deleterious by prediction software might modify clinical severity of carriers.
I clarified these phenomena in our study.

Research Products

• [Journal Article] Phenotypic Variability of <i>ANK2</i> Mutations in Patients With Inherited Primary Arrhythmia Syndromes (2016)
  • Author(s): Ichikawa M, Horie M, et al.
  • Journal Title: Circulation Journal Volume: 80 Issue: 12 Pages: 2435-2442
  • DOI: 10.1253/circj.CJ-16-0486
  • NAID: 130005284992
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family (2016)
  • Author(s): Ichikawa M, Ohno S, Fujii Y, Ozawa J, Sonoda K, Fukuyama M, Kato K, Kimura H, Itoh H, Hayashi H, Horie M.
  • Journal Title: Internal Medicine Volume: 55 Issue: 3 Pages: 259-262
  • DOI: 10.2169/internalmedicine.55.6014
  • NAID: 130005122603
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel SCN10A variants associated with Brugada syndrome (2015)
  • Author(s): Fukuyama M, Ohno S, Makiyama T, Horie M.
  • Journal Title: Europace Volume: 0 Issue: 6 Pages: 0-0
  • DOI: 10.1093/europace/euv078
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Common Mutation of Long QT Syndrome Type 1 in Japan (2015)
  • Author(s): Itoh H, Dochi K, Shimizu W, Denjoy I, Ohno S, Aiba T, Kimura H, Kato K, Fukuyama M, Hasagawa K, Schulze-Bahr E, Guicheney P, Horie M.
  • Journal Title: Circulation Journal Volume: 79 Issue: 9 Pages: 2026-2030
  • DOI: 10.1253/circj.CJ-15-0342
  • NAID: 130005095315
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Rare Single Nucleotide Polymorphism of SCN10A in Patients with Inherited Primary Arrhythmia Syndromes (2017)
  • Author(s): Megumi Fukuyama, Seiko Ohno, Mari Ichikawa, Takeru Makiyama, Minoru Horie
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢、石川
  • Year and Date: 2017-03-17
• [Presentation] A Novel Transport Refractory Mutation in KCNH2 Identified in Symptomatic Long QT Syndrome Patients. (2017)
  • Author(s): Fukumoto D, Ohno S, Wada Y, Fujii Y, Ichikawa M, Fukuyama M, Itoh H, Matsuura H, Horie M
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢、石川
  • Year and Date: 2017-03-17
• [Presentation] High prevalence of late onset T in patients with long QT syndrome type 8. (2016)
  • Author(s): Ohno S, Junichi Ozawa, Megumi Fukuyama, Takeru Makiyama, Minoru Horie
  • Organizer: American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Various ANK2 mutations in patients with inherited primary arrhythmia syndromes. (2016)
  • Author(s): Ichikawa M, Aiba T, Ohno S, Shigemizu D, Ozawa J, Sonoda K, Fukuyama M, Itoh H, Miyamoto Y, Tsunoda T, Makiyama T, Tanaka T, Shimizu W, Horie M
  • Organizer: 9th APHRS Scientific Session.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] Rare Single Nucleotide Polymorphism of SCN10A in Patients with Inherited Primary Arrhythmia Syndromes (2016)
  • Author(s): Megumi Fukuyama, Seiko Ohno, Mari Ichikawa, Takeru Makiyama, Minoru Horie
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] A novel CACNA1C mutation identified in a patient with atypical Timothy syndrome exerts both loss- and gain-of-function effects on Cav1.2. (2016)
  • Author(s): Ozawa J, Ohno S, Toyoda F, Itoh H, Fukuyama M, Harita T, Makiyama T, Hiroshi Suzuki, Akihiko Saitoh, Matsuura H, Horie M
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] AKAP9 mutations identified in young patientswith idiopathic ventricular fibrillation or polymorphic ventricular tachycardia. (2015)
  • Author(s): Sonoda K, Ohno S, Ichikawa M, Fujii Y, Wang Q, Kato K, Fukuyama M, Ito H, Hayashi H, Horie M:
  • Organizer: ESC CONGRESS 2015
  • Place of Presentation: London, England
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] SCN10A polymorphisms are associated with the clinical severity of probands with sodium channelopathies. (2015)
  • Author(s): Fukuyama M, Ohno S, Ichikawa M, Makiyama T, Horie M
  • Organizer: Europace
  • Place of Presentation: Milan, Italy
  • Year and Date: 2015-06-21
  • Int'l Joint Research
• [Presentation] Arrhythmogenic ventricular cardiomyopathy with peculiar ventricular aneurysm and TMEM43 mutations. (2015)
  • Author(s): Ichikawa M, Ohno S, Fujii Y, Ozawa J, Sonoda K, Fukuyama M, Kato K, Itoh H,Horie M
  • Organizer: Europace
  • Place of Presentation: Milan, Italy
  • Year and Date: 2015-06-21
  • Int'l Joint Research
• [Presentation] desmosome gene mutations cause or modify the Brugada syndrome? (2015)
  • Author(s): Ohno S, Aizawa Y,Fukuyama M,Makiyama T,Kosaki K,Fukuda K,Horie M
  • Organizer: Heart Rhythm
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Book] 『循環器内科』第77巻4号345~352頁「特殊なQT延長：Andersen症候群・Timothy症候群」 (2015)
  • Author(s): 福山 恵
  • Total Pages: 8
  • Publisher: 科学評論社