Genetic background of sudden cardiac death in forensic autopsy cases.

• Project/Area Number: 24590852
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Legal medicine
• Research Institution: University of Toyama
• Principal Investigator: HATA Yukiko 富山大学, 大学院医学薬学研究部(医学), 助教 (30311674)
• Co-Investigator(Kenkyū-buntansha): NISHIDA Naoki 富山大学, 大学院医学薬学研究部(医学), 教授 (10315088) ; KINOSHITA Koshi 富山大学, 大学院医学薬学研究部(医学), 助教 (10585920) ; MORI Hisashi 富山大学, 大学院医学薬学研究部(医学), 教授 (00239617)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 心臓突然死 / チャネル異常症 / 心筋症 / 法医剖検例 / 致死性不整脈遺伝子 / 法医剖検 / イオンチャネル / 心臓性突然死 / イオンチャンネル / 遺伝子変異解析 / １塩基多型

Outline of Final Research Achievements

The adequate assessment of the causes of sudden cardiac death (SCD) is importance. An arrhythmia-related gene analysis may potentially provide a pathogenic basis for SCD and establish cause and manner of death.
In this molecular analysis for SCD cases, over one-third of subjects had arrhythmia-related gene variant. This suggests that arrhythmia mutations and/or susceptibility polymorphisms identified in the present study might represent risk factors for arrhythmias in subjects and involved in part of the pathogenesis of SCD. Furthermore, we identified a novel hERG frameshift mutation in a patient who died from SCD. The mutation decreased the number of functional channels presumably by impairing the post-transcriptional processing of the mutant product. This decrease may explain, at least in part, the cause of SCD.
Our findings provide deeper insight into the current understanding of the contribution of variants of the arrhythmia-related genes among subjects with SCD.

Research Products

• [Journal Article] A590T mutation in KCNQ1 C-terminal helix D decreases IKs channel trafficking and function but not Yotiao interaction. (2014)
  • Author(s): Kinoshita K, Komatsu T, Nishide K, Hata Y, Hisajima N, Takahashi H, Kimoto K, Aonuma K, Tushima E, Tabata T, Yoshida T, Mori H, Nishida K, Yamaguchi Y, Ichida F, Fukurotani K, Inoue H, Nishida N.
  • Journal Title: J Mol Cell Cardiol Volume: 72 Pages: 273-280
  • DOI: 10.1016/j.yjmcc.2014.03.019
  • Peer Reviewed / Open Access
• [Journal Article] High takeoff of the left main coronary artery at autopsy after sudden unexpected death in a male. (2014)
  • Author(s): Nishida N, Hata Y, Kinoshita K.
  • Journal Title: Pathology Volume: 46 Issue: 4 Pages: 361-364
  • DOI: 10.1097/pat.0000000000000099
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Modification of KCNH2-encoded cardiac potassium channels by KCNE1 polymorphism. (2014)
  • Author(s): Tabata T, Yamaguchi Y, Hata Y, Ichida F, Mori H.
  • Journal Title: Circ J Volume: 78 Pages: 2331-2331
• [Journal Article] Familial Ebstein's anomaly, left ventricular noncompaction, and ventricular septal defect associated with an MYH7 mutation. (2014)
  • Author(s): Hirono K, Hata Y, Ibuki K, Yoshimura N.
  • Journal Title: J Thorac Cardiovasc Surg Volume: 148 Issue: 5 Pages: 223-226
  • DOI: 10.1016/j.jtcvs.2014.08.049
  • Peer Reviewed
• [Journal Article] Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death (2014)
  • Author(s): Yukiko Hata, Hisashi Mori, Ayumi Tanaka, Yosuke Fujita, Takeshi Shimomura, Toshihide Tabata, Koshi Kinoshita, Yoshiaki Yamaguchi, Fukiko Ichida, Yoshihiko Kominato, Noriaki Ikeda, Naoki Nishida
  • Journal Title: International Journal of Legal Medicine Volume: 128 Issue: 1 Pages: 105-115
  • DOI: 10.1007/s00414-013-0853-4
  • Peer Reviewed
• [Journal Article] Glycine/Serine Polymorphism at Position 38 Influences KCNE1 Subunit’s Modulatory Actions on Rapid and Slow Delayed Rectifier K⁺ Currents (2014)
  • Author(s): Yoshiaki Yamaguchi, Kohki Nishide, Mario Kato, Yukiko Hata, Koichi Mizumaki, Koshi Kinoshita, Yuki Nonobe, Toshihide Tabata, Tamotsu Sakamoto, Naoya Kataoka, Yosuke Nakatani, Fukiko Ichida, Hisashi Mori, Kenkichi Fukurotani, Hiroshi Inoue, MD, Naoki Nishida
  • Journal Title: Circulation Journal Volume: 78 Issue: 3 Pages: 610-618
  • DOI: 10.1253/circj.CJ-13-1126
  • NAID: 130003391006
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Characterization of a novel mutant KCNQ1 channel subunit lacking a large part of the C-terminal domain (2013)
  • Author(s): Katsuya Kimoto, Koshi Kinoshita, Tomoki Yokoyama, Yukiko Hata, Takuto Komatsu, Eikichi Tsushima, Kohki Nishide, Yoshiaki Yamaguchi, Koichi Mizumaki, Toshihide Tabata, Hiroshi Inoue, Naoki Nishida, Kenkichi Fukurotani
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 440 Issue: 2 Pages: 283-288
  • DOI: 10.1016/j.bbrc.2013.09.075
  • Peer Reviewed
• [Journal Article] 14-3-3ε gene variants in a Japanese patient with left ventricular noncompaction and hypoplasia of the corpus callosum. (2013)
  • Author(s): Chang B, Gorbea C, Lezin G, Li L, Shan L, Sakai N, Kogaki S, Otomo T, Okinaga T, Hamaoka A, Yu X, Hata Y, Nishida N, Yost HJ, Bowles NE, Brunelli L, Ichida F.
  • Journal Title: Gene Volume: 515 Issue: 1 Pages: 173-180
  • DOI: 10.1016/j.gene.2012.12.049
  • Peer Reviewed
• [Journal Article] A novel missense mutation causing a G487R substitution in the S2-S3 loop of human ether-a-go-go-related gene channel (2012)
  • Author(s): Kinoshita K, Yamaguchi Y, Nishide K, Kimoto K, Nonobe Y, Fujita A, Asano K, Tabata T, Mori H, Inoue H, Hata Y, Fukurotani K, Nishida N
  • Journal Title: J Cardiovasc Electrophysiol Volume: 23 Issue: 11 Pages: 1246-1253
  • DOI: 10.1111/j.1540-8167.2012.02383.x
  • Peer Reviewed
• [Journal Article] Surgical repair of left ventricular noncompaction in a patient with a novel mutation of the myosin heavy chain 7 gene. (2012)
  • Author(s): Uchiyama T., Yoshimura K., Kaneko K., Nemoto S., Ichida F., Hata Y., Nishida N.
  • Journal Title: Tohoku J Exp Med Volume: 228 Pages: 301-314
  • NAID: 10031135554
  • Peer Reviewed
• [Presentation] Sarcomere gene mutations in left ventricular noncompaction. (2014)
  • Author(s): Takasaki A, Hata Y, Hirono K, Nakaoka H, Ibuki K, Ozawa S, Yoshimura N, Nishida N, Ichida F.
  • Organizer: The 87th Scientific sessions of AHA 2014
  • Place of Presentation: Chicago
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 次世代シークエンサーを用いた心臓性突然死症例の遺伝子解析. (2014)
  • Author(s): 畑由紀子，木下耕史，西田尚樹
  • Organizer: 第36回日本法医学会学術中部地方集会
  • Place of Presentation: 愛知
  • Year and Date: 2014-10-18
• [Presentation] 家族歴による早期診断と遺伝子解析を行ないえたBarth症候群の乳児例. (2014)
  • Author(s): 趙麻未，鮎沢衛，加藤雅崇，渡邉拓史，小森暁子，阿部百合子，神保詩乃，神山浩，廣野恵一，市田蕗子，畑由紀子，西田尚樹．
  • Organizer: 第23回日本小児心筋疾患学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-11
• [Presentation] 胎児期に心不全を契機に発見されたMYH7遺伝子変異を有する左室心筋緻密化障害の一例． (2014)
  • Author(s): 廣野恵一，野村泰久，畑由紀子，仲岡英幸，伊吹圭二郎，小澤綾佳，桃井伸緒，西田尚樹，市田蕗子，足立雄一
  • Organizer: 第50回日本小児循環器学会
  • Place of Presentation: 岡山
  • Year and Date: 2014-07-03 – 2014-07-05
• [Presentation] Postmortem molecular analysis of long QT syndrome-associated genes for sudden cardiac death in 2 to 50 year olds. (2014)
  • Author(s): Hata Y, Kinoshita K, Yamaguchi Y, Hirono K, Ichida F, Nishida N.
  • Organizer: The 9th International Symposium on Advances in Legal Medicine
  • Place of Presentation: Fukuoka
  • Year and Date: 2014-06-16 – 2014-06-20
• [Presentation] A case of sudden cardiac death with a G487R mutation in the hERG channel. (2014)
  • Author(s): Kinoshita K, Nishide K, Kimoto K, Tabata T, Hata Y, Nishida N.
  • Organizer: The 9th International Symposium on Advances in Legal Medicine
  • Place of Presentation: Fukuoka
  • Year and Date: 2014-06-16 – 2014-06-20
• [Presentation] 新生児期に心不全にて発症しサルコメア遺伝子の二重変異異常を認めた左室心筋緻密化障害の一例. (2014)
  • Author(s): 廣野恵一，仲岡英幸，伊吹圭二郎，小澤綾佳，市田蕗子，畑由紀子，西田尚樹，小垣滋豊，福嶌教偉.
  • Organizer: 第311回日本小児科学会北陸地方会
  • Place of Presentation: 福井
  • Year and Date: 2014-06-08
• [Presentation] Functional Characterization of KCNQ1 Channel Subunit with an A590T Mutation. (2013)
  • Author(s): Kinoshita K, Komatsu T, Kimoto K, Nishide K, Tabata F, Ichda F, Yamaguchi Y, Nishida K, Inoue H, Hata Y, Nishida N
  • Organizer: Basic Cardiovascular Sciences 2013
  • Place of Presentation: Las Vegas
• [Presentation] Vanishing white matter disease (VWMD)の1剖検例 (2013)
  • Author(s): 畑由紀子、木下耕史、西田尚樹
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌
• [Presentation] 突然死した筋強直性ジストロフィー症の1剖検例 (2013)
  • Author(s): 畑由紀子、木下耕史、西田尚樹
  • Organizer: 第97次日本法医学会学術全国集会
  • Place of Presentation: 札幌
• [Presentation] Abnormal repolarization dynamics in Patients with G38S single nucleotide polymorphism of KCNE1 Gene. (2012)
  • Author(s): Yamaguchi Y., Mizumaki K., Nishida K., Iwamoto J., Nakatani Y., Kataoka N., Hata Y., Ichida F., Nishida N., Inoue H.
  • Organizer: Heart Rhythm Society
  • Place of Presentation: Boston USA
• [Presentation] 心臓性突然死症例において認められたHERG遺伝子の新規M579fs＋75Mフレームシフト変異の機能解析 (2012)
  • Author(s): 畑由紀子，森 寿，田中亜由美，田端俊英，下村岳司，藤田洋介，木下耕史，山口由明，水牧功一，井上 博，西田尚樹
  • Organizer: 第60回日本心臓病学会学術集会
  • Place of Presentation: 金沢
• [Presentation] 遺伝子検査でKCNE1遺伝子にD85N SNPを有するQT延長症候群例におけるQT/RR関係，T-Wave peak-to-end/RR関係の解析 (2012)
  • Author(s): 山口由明，水牧功一，西田邦洋，坂本 有，片岡直也，木下耕史，畑由紀子，市田蕗子，西田尚樹，井上 博
  • Organizer: 第29回日本心電学会学術集会
  • Place of Presentation: 千葉
• [Presentation] 左冠状動脈口のvery high take-offによる突然死と考えられた1例
  • Author(s): 西田尚樹、畑由紀子、木下耕史
  • Organizer: 日本循環器学会第142回東海・第127回北陸合同地方会
  • Place of Presentation: 金沢
• [Presentation] 法医剖検例における心臓性突然死の遺伝子検索
  • Author(s): 畑由紀子、木下耕史、西田尚樹
  • Organizer: 富山大学学術交流会
  • Place of Presentation: 富山
• [Book] 病理と臨床【法医と病理の相互理解】 法医解剖と病理 (2014)
  • Author(s): 西田尚樹, 畑由紀子
  • Publisher: 文光堂
• [Book] Medical Topics Series 不整脈2013. (2013)
  • Author(s): 相澤義房、網野真理、池田隆徳、上田明子、江頭徹、大草智子、河田宏、栗田隆史、源河朝広、清水渉、副島京子、高橋尚彦、夛田浩、中谷晴昭、西田尚樹、福田恵一、古川哲史、堀江稔、蒔田直昌、水牧功一、三田村秀雄、矢坂正弘、山下武志、吉岡公一郎
  • Publisher: メディカルレビュー社
• [Remarks] 富山大学大学院医学薬学研究部（医学系）法医学講座 研究業績
  • URL: http://www.med.u-toyama.ac.jp/legal/study.html