Genetic analysis and pathological role in ventricular noncompaction associated with fatal arrhythmia

• Project/Area Number: 15K09685
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: University of Toyama
• Principal Investigator: Ichida Fukiko 富山大学, 事務局, 学長補佐 (30223100)
• Co-Investigator(Kenkyū-buntansha): 西田 尚樹 富山大学, 大学院医学薬学研究部(医学), 教授 (10315088) ; 木下 耕史 富山大学, 大学院医学薬学研究部(医学), 助教 (10585920) ; 畑 由紀子 富山大学, 大学院医学薬学研究部(医学), 准教授 (30311674) ; 小澤 綾佳 富山大学, 附属病院, 診療助手 (40596540) ; 廣野 恵一 富山大学, 附属病院, 助教 (80456384) ; 高崎 麻美 富山大学, 大学病院, その他 (80749739)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 心筋緻密化障害 / 遺伝子変異 / サルコメア遺伝子 / iPS細胞 / 次世代シーケンサー / 致死性不整脈 / 心筋細胞 / 突然死 / 遺伝子解析 / i PS細胞 / 機能解析

Outline of Final Research Achievements

We targeted and sequenced 80 genes related to cardiomyopathy in 102 LVNC patients using NGS. We identified variants in a significant proportion of cases (30%), which were associated with poor prognosis, and independent risk factor for adverse events including heart transplantation and sudden death. To elucidate the pathological role, we developed and studied human induced pluripotent stem cells (hiPSCs) from a patient carrying a TPM1 p.Arg178His mutation, who underwent heart transplantation. These cells displayed pathological changes, with mislocalization of tropomyosin 1, causing disruption of the sarcomere structure in cardiomyocytes, and impaired calcium handling. Sarcomere genes are implicated as genetic triggers in the development of LVNC and fatal arrhythmia, regulating the expression of numerous genes involved in heart development, or modifying the severity of disease.

Research Products

• [Journal Article] Barth syndrome: Different approaches to diagnosis (2018)
  • Author(s): Imai-Okazaki A, Kishita Y, Kohda M, Yatsuka Y, Hirata T, Mizuno Y, Harashima H, Hirono K, Ichida F, Noguchi A, Yoshida M, Tokorodani C, Nishiuchi R, Takeda A, Nakaya A, Sakata Y, Murayama K, Ohtake A, & Okazaki Y
  • Journal Title: Journal of Pediatrics Volume: 193 Pages: 256-260
  • DOI: 10.1016/j.jpeds.2017.09.075
  • Peer Reviewed / Open Access
• [Journal Article] Survival in Young Patients With Noncompaction May Not Only Depend on Cardiac But Also on Neuromuscular Comorbidity ― Reply ― (2017)
  • Author(s): Wang Ce、Yu Xianyi、Ichida Fukiko
  • Journal Title: Circulation Journal Volume: 81 Issue: 8 Pages: 1239
  • DOI: 10.1253/circj.CJ-17-0544
  • NAID: 130005859010
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Endothelin-1 may play an important role in the Fontan circulation (2017)
  • Author(s): Aoki Masaya、Hirono Keiichi、Higuma Tomonori、Suzuki Yoko、Nakayama Kazuhiko、Ichida Fukiko、Origasa Hideki、Nishida Naoki、Imura Johji、Emoto Noriaki、Yoshimura Naoki
  • Journal Title: Interactive CardioVascular and Thoracic Surgery Volume: 26 Issue: 3 Pages: 480-486
  • DOI: 10.1093/icvts/ivx378
  • Peer Reviewed
• [Journal Article] A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. (2017)
  • Author(s): Wang C, Hata Y, Hirono K, Takasaki A, Ozawa SW, Nakaoka H, Saito K, Miyao N, Okabe M, Ibuki K, Nishida N, Origasa H, Yu X, Bowles NE, Ichida F; for LVNC Study Collaborators.
  • Journal Title: J Am Heart Assoc. Volume: 6 Issue: 9
  • DOI: 10.1161/jaha.117.006210
  • NAID: 120006772542
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Guidelines for Therapeutic Drug Monitoring of Cardiovascular Drugs Clinical Use of Blood Drug Concentration Monitoring (JCS 2015) ― Digest Version ― (2017)
  • Author(s): Aonuma K, Horie M, et al.
  • Journal Title: Circulation Journal Volume: 81 Issue: 4 Pages: 581-612
  • DOI: 10.1253/circj.CJ-66-0138
  • NAID: 130005475851
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Overview of the 81^st Annual Scientific Meeting of the Japanese Circulation Society ― Cardiovascular Medicine for the Next Generation ― (2017)
  • Author(s): Fujino Noboru、Yoshimuta Tsuyoshi、Ichida Fukiko、Kinugawa Koichiro、Usuda Kazuo、Kitayama Michihiko、Ino Hidekazu、Kawashiri Masa-aki、Tada Hiroshi、Mizuno Sumio、Hayashi Kenshi、Takemura Hirofumi、Yamagishi Masakazu、on behalf of all the members of the Japanese Circulation Society in Hokuriku District
  • Journal Title: Circulation Journal Volume: 81 Issue: 9 Pages: 1261-1267
  • DOI: 10.1253/circj.CJ-17-0706
  • NAID: 130006003909
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Low risk of treatment resistance in Down syndrome with Kawasaki disease (2017)
  • Author(s): Takatsuki Shinichi、Ogata Shohei、Ishii Masahiro、Yokozawa Masato、Ono Masae、Fujiwara Masako、Ida Hiroyuki、Motomura Hideki、Moriuchi Hiroyuki、Taketazu Mio、Kawamura Yoichi、Kawano Tatsuya、Izumi Tatsuro、Shiono Junko、Tsuchiya Shiro、Tsuchiya Keiji、Goushi Terufumi、Ichida Fukiko、Saji Tsutomu
  • Journal Title: Pediatrics International Volume: 59 Issue: 12 Pages: 1236-1239
  • DOI: 10.1111/ped.13429
  • Peer Reviewed
• [Journal Article] Pulmonary vascular disease in a failed Fontan patient with Down’s syndrome (2017)
  • Author(s): Aoki Masaya、Hirono Keiichi、Higuma Tomonori、Suzuki Yoko、Nakayama Kazuhiko、Yamashita Akio、Fukahara Kazuaki、Ichida Fukiko、Emoto Noriaki、Yoshimura Naoki
  • Journal Title: General Thoracic and Cardiovascular Surgery Volume: 66 Issue: 5 Pages: 299-302
  • DOI: 10.1007/s11748-017-0809-6
  • Peer Reviewed
• [Journal Article] Latent pathogenicity of the G38S polymorphism of KCNE1 K+ channel modulator. (2017)
  • Author(s): 2)Yamaguchi Y, Mizumaki K, Hata Y, Sakamoto T, Nakatani Y, Kataoka N, Ichida F, Inoue H, Nishida N.
  • Journal Title: Heart Vessels Volume: 32 Issue: 2 Pages: 186-192
  • DOI: 10.1007/s00380-016-0859-1
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Long-Term Prognosis of Patients With Left Ventricular Noncompaction ― Comparison Between Infantile and Juvenile Types ― (2017)
  • Author(s): Wang, Ce; Takasaki, Asami; Ozawa, Sayaka; Nakaoka, Hideyuki; Okabe, Mako; Miyao, Nariaki; Saito, Kazuyoshi; Ibuki, Keijiro; Hirono, Keiichi; Yoshimura, Naoki; Yu, Xian; Ichida, Fukiko
  • Journal Title: Circulation Journal Volume: 81 Issue: 5 Pages: 694-700
  • DOI: 10.1253/circj.CJ-16-1114
  • NAID: 130005612070
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy (2017)
  • Author(s): Ayako Chida; Kei Inai; Hiroki Sato; Eriko Shimada; Tsutomu Nishizawa; Mitsuyo Shimada; Michiko Furutani; Yoshiyuki Furutani; Yoichi Kawamura; Masaya Sugimoto; Jun Ishihara; Masako Fujiwara; Takashi Soga; Masatoshi Kawana; Fukiko Ichida;
  • Journal Title: Heart Vessels Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum Tenascin-C as a Novel Predictor for Risk of Coronary Artery Lesion and (2016)
  • Author(s): Okuma Y, Suda K, Nakaoka H, Katsube Y, Mitani Y, Yoshikane Y, Ichida F,
  • Journal Title: Circ J. Volume: 80 Pages: 2376-2381
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical Features of Acute and Fulminant Myocarditis in (2016)
  • Author(s): Matsuura H, Ichida F, Saji T, Ogawa S, Waki K, Kaneko M, Tahara M, Soga T, Ono
  • Journal Title: Circ J. Volume: 80 Pages: 2362-2368
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] iPSC-derived cardiomyocytes reveal abnormal TGF-β (2016)
  • Author(s): Kodo K, Ong SG, Jahanbani F, Termglinchan V, Hirono K, InanlooRahatloo K,
  • Journal Title: Nat Cell Biol. Volume: 18 Issue: 10 Pages: 1031-42
  • DOI: 10.1038/ncb3411
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A novel MYH7 gene mutation in a fetus with left ventricular noncompaction. (2015)
  • Author(s): Nomura Y, Momoi N, Hirono K, Hata Y, Takasaki A, Nishida N, Ichida F.
  • Journal Title: Can J Cardiol. Volume: 1 Issue: 1 Pages: 1-3
  • DOI: 10.1016/j.cjca.2014.11.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evaluation of Right Ventricular Function Using Single Beat Three-dimensional Echocardiography in Neonate (2015)
  • Author(s): 4)Kazuhiro Watanabe, Ikuo Hashimoto, Keijiro Ibuki, Mako Okabe, Hisashi Kaneda, Ichida Fukiko.
  • Journal Title: Pediatric Cardiology Volume: 36 Issue: 5 Pages: 198-24
  • DOI: 10.1007/s00246-015-1095-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel ACTC1 gene mutation in a young boy with left ventricular noncompaction and arrhythmias. (2015)
  • Author(s): Yoshida Y, Keiichi Hirono, Kae Nakamura, Tsugutoshi Suzuki, Yukiko Hata, Naoki Nishida
  • Journal Title: Heart Rhythm Case Report Volume: 1 Issue: 1 Pages: 0-0
  • DOI: 10.1016/j.hrcr.2015.11.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Early Neurodevelopmental Outcomes after Cardiac Surgery in Infancy: A Multi-center Retrospective Analysis of 1,718 Patients. (2015)
  • Author(s): Gaynor W, Christian Stopp, David Wypij, Dean B. Andropoulos, Joseph Atallah, John Beca, Kim Duncan, Nancy S, Fukiko Ichida,et al.
  • Journal Title: Pediatrics Volume: 135 Issue: 5 Pages: 816-25
  • DOI: 10.1542/peds.2014-3825
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil <i>N</i>-Demethylation and Tadalafil Demethylenation (2015)
  • Author(s): Takahiro R, Nakamura S, Kohno H, Yoshimura N, Nakamura T, Ozawa S, Hirono K, Ichida F, and Taguchi M.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 38 Issue: 1 Pages: 58-65
  • DOI: 10.1248/bpb.b14-00566
  • NAID: 130004872227
  • ISSN: 0918-6158, 1347-5215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Invited Lecture The Zebras in Pediatric Cardiology. A National Registry of Rare Cardiac Disease in Children (2017)
  • Author(s): Fukiko Ichida
  • Organizer: The 51th Annual Meeting of AEPC
  • Place of Presentation: リヨン
  • Year and Date: 2017-03-30
  • Int'l Joint Research / Invited
• [Presentation] 心筋緻密化障害の臨床～～症例報告から遺伝子解析まで20年間の研究から見えたもの (2017)
  • Author(s): 市田蕗子
  • Organizer: 第319回日本小児科学会北陸地方会
  • Place of Presentation: 富山
  • Year and Date: 2017-03-12
  • Invited
• [Presentation] 心筋緻密化障害の臨床～～症例報告から遺伝子解析まで20年間の研究から見えたもの～ (2017)
  • Author(s): 市田蕗子
  • Organizer: 第319回日本小児科学会北陸地方会
  • Invited
• [Presentation] The Zebras in Pediatric Cardiology. A National Registry of Rare Cardiac Disease in Children (2017)
  • Author(s): Fukiko Ichida
  • Organizer: The 51th Annual Meeting of AEPC
  • Int'l Joint Research / Invited
• [Presentation] 心筋緻密化障害の分子遺伝医学 (2017)
  • Author(s): 市田蕗子
  • Organizer: 第120回日本小児科学会
  • Invited
• [Presentation] 心筋緻密化障害の臨床～20年間の研究から見えたもの (2017)
  • Author(s): 市田蕗子
  • Organizer: 第9回郡山セミナー
• [Presentation] Clinical features of left ventricular noncompaction: long-term clinical course and genetic background (2016)
  • Author(s): 31)Fukiko Ichida
  • Organizer: The 6th APPCS
  • Place of Presentation: Shanghai
  • Year and Date: 2016-10-22
  • Int'l Joint Research / Invited
• [Presentation] 心筋緻密化障害 (2016)
  • Author(s): 市田蕗子
  • Organizer: 第15回日本心臓血管発生研究会
  • Place of Presentation: 大坂
  • Year and Date: 2016-10-14
  • Invited
• [Presentation] 心筋緻密化障害の臨床～20年間の研究から見えたもの (2016)
  • Author(s): 市田蕗子
  • Organizer: 第9回郡山セミナー
  • Place of Presentation: 郡山
  • Year and Date: 2016-04-23
  • Invited
• [Presentation] Clinical Features and Prognosis of Patients with Left Ventricular Noncompaction Cardiomyopathy: A Comparison between Infantile and Juvenile Types. (2015)
  • Author(s): Asami Takasaki, Sayaka Ozawa, Nariaki Miyao, Hideyuki Nakaoka, Keijiro Ibuki, Keiichi Hirono, Naoki Yoshimura, Fukiko Ichida.
  • Organizer: The 88th Scientific sessions of AHA 2015
  • Place of Presentation: Florida
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] 胎児期・新生児期発症の左室心筋緻密化障害における臨床遺伝学的検討 (2015)
  • Author(s): 廣野 恵一, 畑 由紀子, 宮尾 成明, 仲岡 英幸, 高崎 麻美, 伊吹 圭二郎, 小澤 綾佳, 西田 尚樹, 市田 蕗子.
  • Organizer: 第51回日本小児循環器学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-16
• [Presentation] TAZ遺伝子変異を伴う左室心筋緻密化障害における臨床遺伝学的検討. (2015)
  • Author(s): 11)廣野恵一、畑由紀子、宮尾成明、高崎麻美、仲岡英幸、伊吹圭二郎、小澤綾佳、西田尚樹、市田蕗子.
  • Organizer: 第1回日本心筋症研究会、
  • Place of Presentation: 東京
  • Year and Date: 2015-07-04
• [Presentation] 若年性左室心筋緻密化障害におけるサルコメア遺伝子異常とその臨床的意義. (2015)
  • Author(s): 12)高崎麻美、廣野恵一、畑由紀子、仲岡英幸、伊吹圭二郎、小澤綾佳、西田尚樹、芳村直樹、関根道和、市田蕗子
  • Organizer: 第1回日本心筋症研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-04
• [Presentation] Sarcomere gene mutations in the patients with left ventricular noncompaction (2015)
  • Author(s): 10)Keiichi Hirono, Asami Takasaki, Yukiko Hata, Hideyuki Nakaoka, Keijiro Ibuki, Sayaka Ozawa, Michikazu Sekine, Naoki Yoshimura, Naoki Nishida, and Fukiko Ichida
  • Organizer: 第79回日本循環器学会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-25
• [Book] 今日の治療指針-2017年版 (2017)
  • Author(s): 市田蕗子
  • Total Pages: 3
  • Publisher: 医学書院
• [Book] ガイドラインと最新文献で学ぶ小児科学レビュー2016-17 (2017)
  • Author(s): 廣野恵一、市田蕗子
  • Total Pages: 5
  • Publisher: 総合医学社
• [Book] 『Kawasaki Disease: Current Understanding of Mechanism and Evidence-based Treatment』 (2016)
  • Author(s): 1)Keiichi Hirono, Fukiko Ichida
  • Total Pages: 6
  • Publisher: Springer
• [Book] Neurodevelopmental Outcomes in Children with Congenital Heart Disease. How Humans Evolved Supersize Brains (2016)
  • Author(s): 2)Akiko Hiraiwa, Keijiro Ibuki, Kazuhiro Watanabe, Mie Matsui,Naoki Yoshimura, Fukiko Ichida.
  • Total Pages: 8
  • Publisher: Ichiryusyobou
• [Book] 心筋緻密化障害『心エコーハンドブック 心不全』 (2016)
  • Author(s): 小澤綾佳、市田蕗子
  • Total Pages: 8
  • Publisher: 金芳堂
• [Book] 心筋疾患『ガイドラインと最新文献で学ぶ小児科学レビュー2016-17』 (2016)
  • Author(s): 廣野恵一、市田蕗子
  • Total Pages: 3
  • Publisher: 総合医学社
• [Book] 『診断モダリティとしての心筋病理：心筋緻密化障害』 (2016)
  • Author(s): 7)廣野恵一、市田蕗子
  • Total Pages: 3
  • Publisher: 南江堂
• [Book] 今日の診断指針（第7版） (2015)
  • Author(s): 市田蕗子
  • Publisher: 医学書院
• [Book] 『今日の小児治療指針 第16版』 (2015)
  • Author(s): 市田蕗子
  • Publisher: 医学書院
• [Book] 『Annual review循環器2015』 (2015)
  • Author(s): 伊吹圭一郎、市田蕗子
  • Publisher: 中外医学社
• [Book] 『ネルソン小児科学 原著第19版』 (2015)
  • Author(s): 市田蕗子
  • Publisher: エルゼビア・ジャパン
• [Book] 『成人先天性心疾患パーフェクトガイド』 (2015)
  • Author(s): 市田蕗子
  • Publisher: 文光堂