Analysis of the pathogenesis in hypertophic cardiomyopathy by using zebrafish models.

• Project/Area Number: 25860589
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Kanazawa University
• Principal Investigator: Hodatsu Akihiko 金沢大学, 医学系, 協力研究員 (00623662)
• Co-Investigator(Renkei-kenkyūsha): SEGUCHI OSAMU 国立循環器病研究センター, 病院, 医師 (60570869)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: 肥大型心筋症 / ゼブラフィッシュ / 遺伝子変異

Outline of Final Research Achievements

MYBPC3 antisense morpholino oligonucleotide (MO) and MYBPC3 mRNA were injected in one cell stage zebrafish embryos to assess the functional consequences of the MYBPC3 mutations found in human hypertrophic cardiomyopathy patients. Wild type MYBPC3 mRNA, wild type and A745D mutant mRNA, or double mutant mRNA (A745D and R815Q mutants) were co-injected. They corresponds wild type, single mutation (heterozygote) and compound heterozygote, respectively. Ventricular dimension
and heart rate were similar between the MYBPC3 MO group and the MYBPC3 MO with WT mRNA group or the MYBPC3 MO with Ala745Asp mRNA and WT mRNA group, whereas ventricular dimension and heart rate were significantly increased in the MYBPC3 MO with Ala745Asp mRNA and Arg815Gln mRNA group compared with the MYBPC3 MO group.

Research Products

• [Journal Article] Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. (2016)
  • Author(s): Nomura A, Tada H, Teramoto R, Konno T, Hodatsu A, Won HH, Kathiresan S, Ino H, Fujino N, Yamagishi M, Hayashi K.
  • Journal Title: J Cardiol. Volume: 2 Issue: 2 Pages: 133-9
  • DOI: 10.1016/j.jjcc.2015.09.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation. (2015)
  • Author(s): Hayashi K, Konno T, Tada H, Tani S, Liu L, Fujino N, Nohara A, Hodatsu A, Tsuda T, Tanaka Y, Kawashiri MA, Ino H, Makita N, Yamagishi M.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: 8 Issue: 5 Pages: 1095-1104
  • DOI: 10.1161/circep.114.002519
  • Peer Reviewed / Open Access
• [Journal Article] Electrocardiographic QRS Fragmentation as a Marker for Myocardial Fibrosis in Hypertrophic Cardiomyopathy. (2015)
  • Author(s): Konno T, Hayashi K, Fujino N, Oka R, Nomura A, Nagata Y, Hodatsu A, Sakata K, Furusho H, Takamura M, Nakamura H, Kawashiri MA, Yamagishi M.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 26 Issue: 10 Pages: 1081-1087
  • DOI: 10.1111/jce.12742
  • Peer Reviewed / Open Access
• [Journal Article] Right ventricular hypertrophy is associated with cardiovascular events in hypertrophic cardiomyopathy: evidence from study with magnetic resonance imaging. (2015)
  • Author(s): Nagata Y, Konno T, Fujino N, Hodatsu A, Nomura A, Hayashi K, Nakamura H, Kawashiri MA, Yamagishi M.
  • Journal Title: Can J Cardiol. Volume: 31 Issue: 6 Pages: 702-708
  • DOI: 10.1016/j.cjca.2014.12.036
  • Peer Reviewed / Open Access
• [Journal Article] Increased extent of myocardial fibrosis in genotyped hypertrophic cardiomyopathy with ventricular tachyarrhythmias. (2014)
  • Author(s): Fujita T, Konno T, Yokawa J, Masuta E, Nagata Y, Fujino N, Funada A, Hodatsu A, Kawashiri MA, Yamagishi M, Hayashi K.
  • Journal Title: J Cardiol. Volume: in press Issue: 1 Pages: 63-68
  • DOI: 10.1016/j.jjcc.2014.10.002
  • Peer Reviewed / Open Access
• [Journal Article] Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models. (2014)
  • Author(s): Hodatsu A, Konno T, Hayashi K, Funada A, Fujita T, Nagata Y, Fujino N, Kawashiri MA, Yamagishi M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 307 Issue: 11 Pages: 1594-604
  • DOI: 10.1152/ajpheart.00637.2013
  • Peer Reviewed
• [Presentation] Impact of Mutation Dosage on Phenotypes in Hypertrophic Cardiomyopathywith MYBPC3 Mutations; Evidence from Zebrafish Models. (2015)
  • Author(s): Akihiko Hodatsu, Tetsuo Konno, Kenshi Hayashi, Yoji Nagata, Ryota Teramoto, Noboru Fujino, Masa-aki Kawashiri, Masakazu Yamagishi
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] ミオシン結合タンパクC複合ヘテロ接合性変異によ る肥大型心筋症の重症表現型～臨床例・ゼブラフィッシュ を用いた検討～ (2015)
  • Author(s): 宝達 明彦, 田中 仁啓, 永田 庸二, 寺本 了太, 津田 豊暢, 今野 哲雄, 林 研至, 川尻 剛照, 藤野 陽, 山岸 正和
  • Organizer: 第112回日本内科学会講演会
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10 – 2015-04-12
• [Presentation] 第112回日本内科学会講演会 (2015)
  • Author(s): 宝達 明彦, 田中 仁啓, 永田 庸二, 寺本 了太, 津田 豊暢, 今野 哲雄, 林 研至, 川尻 剛照, 藤野 陽, 山岸 正和
  • Organizer: ミオシン結合タンパクC複合ヘテロ接合性変異によ る肥大型心筋症の重症表現型～臨床例・ゼブラフィッシュ を用いた検討～
  • Place of Presentation: 京都
  • Year and Date: 2015-04-10
• [Presentation] Impact of Compound Heterozygosity on Phenotypes of hypertrophic cardiomyopathy with MYBPC3 mutasions; Evidence from zebrafish models. (2015)
  • Author(s): Akihiko Hodatsu, Tetsuo Konno, Kenshi Hayashi, Ryota Teramoto, Yoji Nagata, Noboru Fujino, Masa-aki Kawashiri, Masakazu Yamagishi
  • Organizer: American College of Cardiology 64th Annual Scientific Session
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-03-14 – 2015-03-16
• [Presentation] A founder mutation of the myosin binding protein-C gene in hypertrophic cardiomyopathy and adverse outcomes with compound heterozygosity (2014)
  • Author(s): Akihiko Hodatsu, Tetsuo Konno, Kenshi Hayashi, Takashi Fujita, Yoji Nagata, Noboru Fujino, Masa-aki Kawashiri, Masakazu Yamagishi
  • Organizer: European society of Cardiology Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03