Elucidation of novel pathophysiology underlysing lethal arrhythmia due to mutations in cardiac ion transporters

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15H04823
• Research Institution: Nagasaki University
• Principal Investigator: 蒔田 直昌 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00312356)
• Co-Investigator(Kenkyū-buntansha): 吉浦 孝一郎 長崎大学, 原爆後障害医療研究所, 教授 (00304931) ; 牧山 武 京都大学, 医学研究科, 助教 (30528302) ; 渡邊 泰秀 浜松医科大学, 医学部, 教授 (50305380)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: Na/Ca交換体 / 心室細動 / カルモジュリン

Outline of Annual Research Achievements

原因不明の致死性不整脈の病態として、細胞内Ca制御に係わるイオン輸送体に着目し、網羅的遺伝子解析と変異イオン輸送体機能解析を通じて、心臓突然死の予知予防への応用を目指す。初年度、致死性不整脈蘇生例15人に対して行った全エクソン解析・ターゲットエクソン解析から種々の遺伝子変異を同定したが、本年度は、カルモジュリン（CALM2）とNa-Ca交換体(NCX1;SLC8A1)に着目し機能解析を行った。
CALM2-N98Sは12歳のQT延長症候群患者に認められたde novo変異だが、患者末梢血からiPS心筋細胞を作成し、活動電位の延長を認め、その原因がCalmodulinの変異がL型CaチャネルのCa誘発性不活性化を傷害することであることを明らかにした。さらにCRISPR/cas9ゲノム編集技術でiPSの変異アレルを特異的に破壊することで活動電位持続時間が回復することを明らかにした(Yamamoto, Makita et al, Hum Mol Genet, 2017)。
特発性心室細動の遺伝子解析についてフランスINSERMと共同研究を行い、7個のSLC8A1(NCX1)変異を同定した。これらの変異は、細胞発現系を用いた解析で、45Ca取り込み能とNa/Ca交換電流の低下を認めた。さらに、O’Hara-Rudyヒト心室筋モデルと姫野らのヒト心室筋モデル(HuVEC)という２種類のモデルを用いてシミュレーションを行ったところ、活動電位の短縮と細胞内Ca濃度の上昇を認めた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

CALM2の論文は、CRISPR/Cas9を用いた新たな遺伝子治療に結び付く極めてimpactの高い研究である(Yamamoto, Makita et al , Hum Mol Genet, 2017)。NCX1に関する研究はほぼデータがそろっているが、現在変異タンパクの細胞内局在を示すin vitro実験を行っている。

Strategy for Future Research Activity

今後NCX1の細胞外ドメインを認識する抗体を用いて、変異NCX1タンパクの細胞内発現部位を、生きた細胞で映像化し、さらに電気生理学特性をパッチクランプで解析し論文化する予定である

Research Products

• [Journal Article] Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Sasaki K, Wuriyanghai Y, Hayano M, Nishiuchi S, Kohjitani H, Hirose S, Chen J, Yokoi F, Ishikawa T, Ohno S, Chonabayashi K, Motomura H, Yoshida Y, Horie M, Makita N, Kimura T
  • Journal Title: Hum Mol Genet Volume: 26 Pages: 1670-1677.
  • DOI: 10.1093/hmg/ddx073
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry (2017)
  • Author(s): Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Kusano K, Kamakura S, Yasuda S, Ogawa H, Miyamoto Y, Kapplinger JD, Ackerman MJ, Shimizu W
  • Journal Title: Circulation Volume: 135 Pages: 2255-2270.
  • DOI: 10.1161/CIRCULATIONAHA.117.027983
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel de novo calmodulin mutation in a 6-year-old boy who experienced an aborted cardiac arrest (2017)
  • Author(s): Takahashi K, Ishikawa T, Makita N, Takefuta K, Nabeshima T, Nakayashiro M
  • Journal Title: HeartRhythm Case Reports Volume: 3 Pages: 69-72.
  • DOI: 10.1016/j.hrcr.2016.09.004
  • Peer Reviewed / Open Access
• [Journal Article] Progressive atrial conduction system defects associated with bone malformation caused by a connexin45 mutation (2017)
  • Author(s): Seki A, Ishikawa T, Daumy X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau A, Thollet A, Fouchard S, Bonnaud S, Parent P, Shibata Y, Perrin JP, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura KI, Redon R, Schott JJ, Makita N
  • Journal Title: J Am Coll Cardiol Volume: 70 Pages: 58-70.
  • DOI: 10.1016/j.jacc.2017.05.039
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death (2017)
  • Author(s): Oshima Y, Yamamoto T, Ishikawa T, Mishima H, Matsusue A, Umehara T, Murase T, Abe Y, Kubo SI, Yoshiura KI, Makita N, Ikematsu K
  • Journal Title: J Hum Genet Volume: 62 Pages: 989-995.
  • DOI: 10.1038/jhg.2017.79
  • Peer Reviewed
• [Journal Article] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers (2017)
  • Author(s): Nishiuchi S, Makita N. et al
  • Journal Title: Circ Cardiovasc Genet Volume: 10 Pages: e001603.
  • DOI: 10.1161/CIRCGENETICS.116.001603
  • Peer Reviewed
• [Journal Article] Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes (2017)
  • Author(s): Kuroda Y, Yuasa S, Watanabe Y, Ito S, Egashira T, Seki T, Hattori T, Ohno S, Kodaira M, Suzuki T, Hashimoto H, Okata S, Tanaka A, Aizawa Y, Murata M, Aiba T, Makita N, Furukawa T, Shimizu W, Kodama I, Ogawa S, Kokubun N, Horigome H, Horie M, Kamiya K, Fukuda K
  • Journal Title: Biochemistry and Biophysics Reports Volume: 9 Pages: 245-256.
  • DOI: 10.1016/j.bbrep.2017.01.002
  • Peer Reviewed / Open Access
• [Journal Article] Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction (2017)
  • Author(s): Ishikawa T, Ohno S, Murakami T, Yoshida K, Mishima H, Fukuoka T, Kimoto H, Sakamoto R, Ohkusa T, Aiba T, Nogami A, Sumitomo N, Shimizu W, Yoshiura KI, Horigome H, Horie M, Makita N
  • Journal Title: Heart Rhythm Volume: 14 Pages: 717-724.
  • DOI: 10.1016/j.hrthm.2017.01.020
  • Peer Reviewed
• [Journal Article] Letter to the Editor (2017)
  • Author(s): Ishikawa T, Makita N, Aoki H, Saida Y
  • Journal Title: J Vet Intern Med Volume: 31 Pages: 967-968.
  • DOI: 10.1111/jvim.14781
  • Peer Reviewed
• [Journal Article] The Phenotypic Spectrum of a Mutation?Hotspot Responsible for the?Short QT Syndrome (2017)
  • Author(s): Hu D, Li Y, Zhang J, Pfeiffer R, Gollob MH, Healey J, Harrell DT, Makita N, Abe H, Sun Y, Guo J, Zhang L, Yan G, Mah D, Walsh EP, Leopold HB, Giustetto C, Gaita F, Zienciuk-Krajka A, Mazzanti A, Priori SG, Antzelevitch C, Barajas-Martinez H
  • Journal Title: JACC: Clinical Electrophysiology Volume: 3 Pages: 727-743.
  • DOI: 10.1016/j.jacep.2016.11.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes (2016)
  • Author(s): Yagihara N, Makita N et al
  • Journal Title: J Am Heart Assoc Volume: 5 Pages: e003644.
  • DOI: 10.1161/JAHA.116.003644
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Embryonic type Na+ channel beta-subunit, SCN3B masks the disease phenotype of Brugada syndrome (2016)
  • Author(s): Okata S, Yuasa S, Suzuki T, Ito S, Makita N, Yoshida T, Li M, Kurokawa J, Seki T, Egashira T, Aizawa Y, Kodaira M, Motoda C, Yozu G, Shimojima M, Hayashiji N, Hashimoto H, Kuroda Y, Tanaka A, Murata M, Aiba T, Shimizu W, Horie M, Kamiya K, Furukawa T, Fukuda K
  • Journal Title: Sci Rep Volume: 6 Pages: 34198.
  • DOI: 10.1038/srep34198
  • Peer Reviewed
• [Journal Article] Reply: Search for Evidence-Based Medicine for Brugada Syndrome: The Complex Network of the Brugada Syndrome (2016)
  • Author(s): Nademanee K, Raju H, De Noronha S, Papadakis M, Robinson L, Rothery S, Makita N, Kowase S, Boonmee N, Vitayakritsirikul V, Ratanarapee S, Sharma S, van der Wal AC, Christiansen M, Tan HL, Wilde AA, Nogami A, Sheppard MN, Veerakul G, Behr ER
  • Journal Title: J Am Coll Cardiol Volume: 67 Pages: 1658-1659.
  • DOI: 10.1016/j.jacc.2016.01.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inherited bradyarrhythmia: A diverse genetic background (2016)
  • Author(s): Ishikawa T, Tsuji Y, Makita N
  • Journal Title: J Arrhythm Volume: 32 Pages: 352-358.
  • DOI: 10.1016/j.joa.2015.09.009
  • Peer Reviewed / Open Access
• [Journal Article] Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I (2016)
  • Author(s): Daumy X, Amarouch MY, Lindenbaum P, Bonnaud S, Charpentier E, Bianchi B, Nafzger S, Baron E, Fouchard S, Thollet A, Kyndt F, Barc J, Le Scouarnec S, Makita N, Le Marec H, Dina C, Gourraud JB, Probst V, Abriel H, Redon R, Schott JJ
  • Journal Title: Int J Cardiol Volume: 207 Pages: 349-358.
  • DOI: 10.1016/j.ijcard.2016.01.052
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Mutations in Desmin Gene Uncover Phenotypic Overlap between Progressive Cardiac Conduction Defect with Muscular Dystrophy and Cardiomyopathy (2017)
  • Author(s): 木本浩貴, 石川泰輔, 町田紘子, 森田宏, 住友直方, 中村一文, 伊藤浩, バーク・ジュリアン, ショット・ジョンジャック, 蒔田直昌.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Calmodulin Mutations Responsible for Long QT Syndrome and Functional Rescue using a CRISPR/Cas9 System (2017)
  • Author(s): 蒔田直昌.
  • Organizer: 第94回日本生理学会大会
  • Invited
• [Presentation] ブルガダ症候群の予後予測を目指す変異心筋Naチャネルの機能解析 (2017)
  • Author(s): 下河舞子, 木本浩貴, 石川泰輔, 蒔田直昌.
  • Organizer: 第68回西日本生理学会
• [Presentation] lL-cis-Diltiazem Ameliorates Impaired Calcium Channel Inactivation in a Patient-Specific Stem Cell Model of Long-QT Syndrome with a Calmodulin Mutation (2017)
  • Author(s): Yokoi F, Makiyama T, Harita T, Yamamoto Y, Hayano M, Nishiuchi S, Kohjitani H, Wuriyanghai Y, Hirose S, Toyoda F, Yoshida Y, Makita N, Horie M, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Sasaki K, Wuriyanghai Y, Nishiuchi S, Kohjitani H, Hirose S, Ishikawa T, Motomura H, Ohno S, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] CALM2-D134H Mutation Associated With Long-QT Syndrome Delayed Inactivation of L-type Ca2+ Currents in Human iPS Cells Derived Cardiomyocytes. (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Yokoi F, Ishikawa T, Ohno S, Chonabayashi K, Suda K, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: American Heart Association Annual Scientific Session 2017
  • Int'l Joint Research
• [Presentation] CALM2-D134H Mutation Associated with Long-QT Syndrome Prevents Inactivation of L-type Ca2+ Currents in Human iPS Cell Derived Cardiomyocytes. (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Yokoi F, Ishikawa T, Ohno S, Chinabayashi K, Suda K, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Genotype-Phenotype Correlation of SCN5A Mutations for the Clinical and Electrocardiographic Characteristics of Probands with Brugada Syndrome: A Japanese Multicenter Registry (2017)
  • Author(s): Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Fukushima-Kusano K, Kamakura S, Yasuda S, Ogawa H, Y. M, Kapplinger J, Ackerman M, Shimizu W.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers (2017)
  • Author(s): Nishiuchi S, Makiyama T, Aiba T, Nakajima K, Ishikawa T, Murakoshi N, Watanabe H, Ohno S, Doi T, Shizuta S, Minamino T, Saito Y, Oginosawa Y, Nogami A, Aonuma K, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Sosiety Scientific Session
  • Int'l Joint Research
• [Presentation] Genetic-based risk stratification for cardiac disorders in LMNA mutation carriers (2017)
  • Author(s): Nishiuchi S, Aiba T, Nakajima K, Hirose S, Kohjitani H, Yamamoto Y, Harita T, Hayano M, Sasaki K, Ishikawa T, Onoue K, Saito Y, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers in Japan (2017)
  • Author(s): Nishiuchi S, Aiba T, Makiyama T, Nakajima K, Yagihara N, Ishikawa T, Onoue K, Murakoshi N, Watanabe I, Ohkubo K, Watanabe H, Ohno S, Doi T, Shizuta S, Minamino T, Saito Y, Oginosawa Y, Nogami A, Aonuma K, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: American Heart Association Annual Scientific Session 2017
  • Int'l Joint Research
• [Presentation] De novo and Familial Connexin45 Mutant R75H Causes Progressive Atrioventricular Block Associated with Craniofacial and Dentodigital Dysmorphisms (2017)
  • Author(s): Makita N, Seki A, Ishikawa T, Dawmy X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau A, Aurelie T, Swanny F, St?phanie B, Parent P, Shibata Y, Perrin JJ, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura K, Redon R, Schott J, J.
  • Organizer: Printemps de la Cardiologie Recherche Fondamentale et Clinique
  • Int'l Joint Research / Invited
• [Presentation] Brugada Syndrome: Basic and Clinical Updates, Advancement of Basic Research (2017)
  • Author(s): Makita N.
  • Organizer: 13th Annual Congress European Cardiac Arrhythmia Society
  • Int'l Joint Research / Invited
• [Presentation] Genetic Mutation of Brugada Syndrome (2017)
  • Author(s): Makita N.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Genetic and Biophysical Basis of Calmodulinopathy, and Functional Rescue by Genome-Editing in Patient-Derived iPS Cardiomyocytes (2017)
  • Author(s): Makita N.
  • Organizer: 20th International Symposium on Calcium Binding Proteins and Calcium Function in Health and Disease
  • Int'l Joint Research / Invited
• [Presentation] Multinational genome-wide association study in long QT syndrome identifies a role for common genetic variation in disease susceptibility and points to a polygenic architecture in mutation-negative cases (2017)
  • Author(s): Lahrouchi N, Makita N, et al.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Mutation in L-type Calcium Channel Cav1.3 (CACNA1D) Underlying a Consanguineous Family Associated with Congenital AV Block and Deaf-Blindness (2017)
  • Author(s): Kimoto H, Ishikawa T, Mishima H, Hasdemir C, Yoshiura K, Makita N.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Sick sinus syndrome caused by HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular non-compaction (2017)
  • Author(s): Ishikawa T, Ohno S, Murakami T, Yoshida K, Fukuoka T, Mishima H, Kimoto H, Aiba T, Nogami A, Sumitomo N, Shimizu W, Horigome H, Yoshiura KI, Horie M, Makita N.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Genetics of Familial Atrial Fibrillation (2017)
  • Author(s): Ishikawa T, Makita N.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Progressive Cardiac Conduction Defect and Sick Sinus Syndrome as Sodium Channelopathy (2017)
  • Author(s): Ishikawa T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Mutation Spot-sensitive Clinical Features and Risk of Life-threatening Arrhythmia in Long QT Syndrome Type 1 in Japan (2017)
  • Author(s): Aiba T, Makimoto H, Yagihara N, Watanabe H, Ohno S, Hayashi K, Sumitomo N, Yoshinaga M, Morita H, Miyamoto Y, Makita N, Horie M, Yasuda S, Kusano K, Shimizu W.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] 歯牙骨格形成異常を合併する洞不全症候群に固定されたコネキシン45遺伝子変異と機能異常 (2016)
  • Author(s): 木本浩貴, 石川泰輔, 西井明子, 斎藤加代子, 三嶋博之, 大槻早紀, 辻幸臣, 吉浦孝一郎, 萩原誠久, 蒔田直昌.
  • Organizer: 第67回西日本生理学会
• [Presentation] Naチャネル遺伝子のバリエーションと致死性不整脈の罹患性との関連 (2016)
  • Author(s): 蒔田直昌, 石川泰輔.
  • Organizer: 第93回日本生理学会大会
• [Presentation] 心臓刺激伝導系と心室の電気的興奮現象のマルチスケールシミュレーション研究 (2016)
  • Author(s): 稲田慎, ハーレルダニエル, 原口亮, 芦原貴司, 相庭武司, 山下富義, 柴田仁太郎, 池田隆徳, 三井和幸, 蒔田直昌, 本荘晴朗, ボエットマーク, 中沢一雄.
  • Organizer: 第93回日本生理学会大会
• [Presentation] ECG Screening of 1-month-old Infants May Prevent Out-of-hospital Cardiac Arrest in Infancy (2016)
  • Author(s): Yoshinaga M, Ohno S, Ushinohama H, Sato S, Miyamoto T, Tauchi N, Horigome H, Sumitomo N, Shiraishi H, Ichida F, Hata T, Nomura Y, Horie M, Makita N, Nagashima M.
  • Organizer: American Heat Association Scientific Meeting 2016
  • Int'l Joint Research
• [Presentation] Modeling of long-QT syndrome associated with a calmodulin mutation using human induced pluripotent stem cells (2016)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Sasaki K, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Cheng J, Ishikawa T, Ohno S, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Utility of QT dynamics for identyfying genetic testing candidates in children with borderline QT interval prolongation (2016)
  • Author(s): Takahashi K, Makita N, Shimizu W.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Novel de novo Calmodulin Mutation in a Pre-school boy Experiencing Aborted Cardiac Arrest (2016)
  • Author(s): Takahashi K, Makita N.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Conditional knockout mice recapitulated two families with congenital AV block and sick sinus syndrome with a novel connexin 45 mutation. (2016)
  • Author(s): Nishii A, Ishikawa T, Daumy X, Urano M, Saito K, Baruteau A, Nishii K, Shibata Y, Kobayashi Y, Redon R, Schott JJ, Probst V, Hagiwara N, Makita N.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Catheter Ablation of Brugada Syndrome：Further Evidence of Conduction Delay in the Right Ventricular Subepicardium as Mechanism of Brugada ECG and Ventricular Fibrillation (2016)
  • Author(s): Nakagawa H, Sakamoto Y, Yamashiro K, Takagi M, Kusano K, Noda T, Yamazaki M, Honjo H, Makita N, Tsuchiya T, Hoogeudiik MG, Nademanee K.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Common genetic variants at SCN5A, SCN10A, and HEY2 are associated with cardiac conduction disturbance in patients with Brugada syndrome (2016)
  • Author(s): Murakoshi N, Xu D, Nogami A, Makita N, Sekiguchi Y, Kurosaki K, Kowase S, Naruse Y, Aonuma K.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Overview of Genes Related to Cardiac Conduction (2016)
  • Author(s): Makita N.
  • Organizer: Korean Heart Rhythm Society 8th Annual Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Genetic Background of Inherited Bradyarrhythmia (2016)
  • Author(s): Makita N.
  • Organizer: Korean Heart Rhythm Society 8th Annual Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Dose-Sensitive Relationship of an SCN10A Pore Mutation and Enhancer SNPs Identified in a Brugada Syndrome Family with Different Expressivity (2016)
  • Author(s): Ishikawa T, Ohkubo K, Yamaguchi R, Harrell DT, Tsuji Y, Watanabe I, Makita N.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Broader Genetic Spectrum of Familial Atrial Arrhythmias Involving Rare Variations in the Common Arrhythmia-Susceptible Genes (2016)
  • Author(s): Ishikawa T, Mishima H, Ohno S, Harrell DT, Tsuji Y, Yoshiura K, Horie M, Makita N.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Selective therapeutic targeting of ion channel rare variants predisposing to lone atrial fibrillation (2016)
  • Author(s): Hayashi K, Fujino N, Tsuda T, Tanaka Y, Ino H, Makita N, Yamagishi M.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] International Calmodulinopathy Registry (ICaMR) (2016)
  • Author(s): Crotti L, Makita N.
  • Organizer: American Heart Association's Scientific Sessions
  • Int'l Joint Research