Genetic and functional basis of cardiac ion channelopathy

2014 Fiscal Year Final Research Report

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 22136007
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Nagasaki University
• Principal Investigator: MAKITA Naomasa 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00312356)
• Co-Investigator(Kenkyū-buntansha): MAEMURA Koji 長崎大学, 医歯薬学総合研究科(医学系), 教授 (90282649) ; TSUJI Yukiomi 長崎大学, 医歯薬学総合研究科(医学系), 講師 (60432217)
• Co-Investigator(Renkei-kenkyūsha): ISHIKAWA Taisuke 長崎大学, 医歯薬学総合研究科(医学系), 助教 (60708692)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 洞不全症候群 / MYH6 / ミオシン重鎖 / 遺伝性不整脈

Outline of Final Research Achievements

Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. We identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C (MyBP-C) in one patient. Co-immunoprecipitation analysis revealed sarcomere impairments. The HL-1 stably expressing delE933 showed slower conduction velocity on than wild-type. Furthermore, targeted knock-down of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by co-expressed wild-typeα-MHC but not by delE933. The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial SSS

Free Research Field

循環器内科学