Cardiac Myosin Light Chain Kinase Mutation as a Cause of Cardiomyopathies

• Project/Area Number: 24790748
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: KONNO Tetsuo 金沢大学, 医学系, 助教 (50377389)
• Co-Investigator(Renkei-kenkyūsha): KITAKAZE Masafumi 独立行政法人国立循環器病研究センター, 臨床研究開発部, 部長 (20294069) ; TAKASHIMA Seiji 大阪大学, 大学院生命機能研究科, 教授 (90379272) ; YAMAZAKI Satoru 独立行政法人国立循環器病研究センター, 細胞生物学部細胞形態研究室, 室長 (70348796) ; SEGUCHI Osamu 独立行政法人国立循環器病研究センター, 病院移植部, 研究員 (60570869)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: genetics / cardiomyopathy / heart failure / 心不全 / 心筋症 / ゼブラフィッシュ

Outline of Final Research Achievements

Recently, cardiac myosin light chain kinase (cMLCK) was cloned from the myocardia of patients with heart failure, although it is unknown whether mutations in cMLCK gene (MYLK3) causes cardiomyopathies. We identified a missense and deletion variant in hypertrophic cardiomyopathy (HCM) and in dilated cardiomyopathy (DCM), respectively. In vitro kinase assay demonstrated enhanced kinase activity in the missense mutant protein, while diminished activity in deletion mutant protein. Whole exome sequencing showed absence of known DCM causing mutations in pedigrees harboring the mutation. These findings suggest that enhanced cMLCK activity may cause HCM, while declined cMLCK activity may cause DCM. Our data will provide the new insights into mechanisms responsible for cardiomyopathies.

Research Products

• [Journal Article] Right Ventricular Hypertrophy is Associated With Cardiovascular Events in Hypertrophic Cardiomyopathy: Evidence From Study With Magnetic Resonance (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: in press
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Journal Article] High sensitivity of late gadolinium enhancement for predicting microscopic myocardial scarring in biopsied specimens in hypertrophic cardiomyopathy. (2014)
  • Author(s): Konno T，Hayashi K，Fujino N，Nagata Y，Hodatsu A，Masuta E，Sakata K，Nakamura H，Kawashiri M，Yamagishi M.
  • Journal Title: PLoS One. Volume: 9 Issue: 7 Pages: e101465-e101465
  • DOI: 10.1371/journal.pone.0101465
  • NAID: 120006460361
  • Peer Reviewed / Open Access
• [Journal Article] Fragmented QRS Predicts Heart Failure Progression in Patients With Hypertrophic Cardiomyopathy (2014)
  • Author(s): Nomura A, Konno T, Fujita T, Tanaka Y, Nagata Y, Tsuda T, Hodatsu A, Sakata K, Nakamura H, Kawashiri MA, Fujino N, Yamagishi M, Hayashi K.
  • Journal Title: Circulation Journal Volume: 79 Issue: 1 Pages: 136-143
  • DOI: 10.1253/circj.CJ-14-0822
  • NAID: 130004704014
  • ISSN: 1346-9843, 1347-4820
  • 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
• [Journal Article] Left ventricular apical aneurysm and systolic dysfunction in hypertrophic cardiomyopathy. (2014)
  • Author(s): Fujino N, Konno T, Yamagishi M, Hayashi K.
  • Journal Title: J Cardiol Volume: 64 Issue: 4 Pages: 253-5
  • DOI: 10.1016/j.jjcc.2014.04.009
  • Peer Reviewed / Open Access
• [Journal Article] Erdheim-Chester disease involving the brain and the heart. (2014)
  • Author(s): Kawashiri MA, Ishibashi-Ueda H, Funada A, Yoshimuta T, Konno T, Hayashi K, Yamagishi M.
  • Journal Title: J Am Coll Cardiol. Volume: 25 Issue: 11 Pages: 1121-1121
  • DOI: 10.1016/j.jacc.2013.11.047
  • Peer Reviewed
• [Journal Article] Current perspectives in genetic cardiovascular disorders: from basic to clinical aspects (2014)
  • Author(s): Kawashiri MA, Hayashi K, Konno T, Fujino N, Ino H, Yamagishi M.
  • Journal Title: Heart Vessels Volume: 29 Issue: 2 Pages: 129-41
  • DOI: 10.1007/s00380-013-0391-5
  • Peer Reviewed
• [Journal Article] Sarcomere Gene Mutations Are Associated With Increased Cardiovascular Events in Left Ventricular Hypertrophy : Results From Multicenter Registration in Japan. (2013)
  • Author(s): Fujita T, Komuro I (18人中13番目）
  • Journal Title: JACC Heart Fail Volume: 6 Issue: 6 Pages: 459-466
  • DOI: 10.1016/j.jchf.2013.08.007
  • Peer Reviewed
• [Journal Article] A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome (2013)
  • Author(s): Kurata Y
  • Journal Title: Heart Rhythm Volume: 10 Issue: 1 Pages: 61-7
  • DOI: 10.1016/j.hrthm.2012.09.053
  • Peer Reviewed
• [Journal Article] Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia (2012)
  • Author(s): Tada H
  • Journal Title: Eur J Clin Invest Volume: 42 Issue: 10 Pages: 1094-1099
  • DOI: 10.1111/j.1365-2362.2012.02700.x
  • Peer Reviewed
• [Journal Article] Stress-induced takotsubo cardiomyopathy complicated with wall rupture and thrombus formation. (2012)
  • Author(s): Yoshida S, Miwa K, Matsubara T, Yasuda T, Inoue M, Teramoto R, Okada H, Kanaya H, Hayashi K, Konno T, et al.
  • Journal Title: Int J Cardiol. Volume: 161(1) Issue: 1 Pages: e18-e20
  • DOI: 10.1016/j.ijcard.2012.03.152
  • Peer Reviewed
• [Presentation] Compound heterozygosity affects phenotypes in hypertrophic cardiomyopathy with MYBPC3 mutations: evidence from zebrafish models (2015)
  • Author(s): Hodatsu A, Konno T, Hayashi K, Nagata Y, Teramoto R, Fujino N, Kawashiri MA, Yamagishi M.
  • Organizer: American College of Cardiology Scientific Sessions
  • Place of Presentation: San Diego Convention Center, San Diego, U.S.A.
  • Year and Date: 2015-03-16
• [Presentation] Electrocardiographic QRS Fragmentation as a Marker for Myocardial Scarring in Hypertrophic Cardiomyopathy (2014)
  • Author(s): Konno T, Hayashi K, Fujino N, Nagata Y, Hodatsu A, Masuta E, Sakata K, Nakamura H, Kawashiri MA, Yamagishi M.
  • Organizer: European Sciety of Cardiology, Annual congress
  • Place of Presentation: Gran Via, Valcerona, Spain
  • Year and Date: 2014-09-02
• [Presentation] 心不全の治療過程で出現する腎機能悪化：腎うっ血の関与を中心にトルバプタン使用の現状を含めて (2014)
  • Author(s): 今野哲雄
  • Organizer: 日本循環器学会北陸地方会
  • Place of Presentation: 金沢大学医学部, 金沢
  • Year and Date: 2014-07-06
  • Invited
• [Presentation] Fragmented QRS Predicts Cardiac Events in Hypertrophic Cardiomyopathy. (2014)
  • Author(s): Nomura A, Konno T, Fujita T, Tanakk Y, Yoshida S, Hayashi K, Sakata K, Kawashiri MA, Fujino N, Yamagishi M.
  • Organizer: Scientific Sessions, Amecican College of Cardiology
  • Place of Presentation: Washington, DC, U.S.A.
• [Presentation] Progression of Coronary Plaque Burden In Patients with Familial Hypercholesterolaemia: Assessment with Coronary CT. (2013)
  • Author(s): Tada H, Kawashiri MA, Nakanishi C, Konno T, Sakata K, Hayashi K, Yoshimuta T, Nohara A, Inazu A, Mabuchi H, Yamagishi M.
  • Organizer: American Heart Associations, Scientific Sessions
  • Place of Presentation: Dallas, U.S.A.
• [Presentation] Clinical Impact of Heterozygous Carrier of ATP-binding Cassette Sub-family G Member 5 Gene on Asymptomatic Normolipidemic Patients: Evidence from Familial Gene Analysis. (2013)
  • Author(s): Tada H, Kawashiri MA, Nakanishi C, Konno T, Sakata K, Hayashi K, Yoshimuta T, Nohara A, Inazu A, Mabuchi H, Yamagishi M.
  • Organizer: American Heart Associations, Scientific Sessions
  • Place of Presentation: Dallas, U.S.A.
• [Presentation] Impact of New LQTS Diagnostic Criteria on Detection of Long QT Syndrome with Carrying Gene Mutations. (2013)
  • Author(s): Hayashi K, Fujino N, Konno T, Tsuda T, Imi Y, Saito T, Ohta K, Ino H, Kawashiri MA, Yamagishi M.
  • Organizer: American Heart Associations, Scientific Sessions
  • Place of Presentation: Dallas, U.S.A.
• [Presentation] Electrocardiographic QRS Fragmentation as a Marker for Myocardial Scarring in Hypertrophic Cardiomyopathy (2013)
  • Author(s): Konno T, Hayashi K, Fujino N, et al.
  • Organizer: 日本循環器学会学術集会総会
  • Place of Presentation: 横浜