Strategy for regulation of cardiac functional defects due to the abnormality in molecular distribution caused by gene mutations

2014 Fiscal Year Final Research Report

• Project/Area Number: 25670172
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KIMURA Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 遺伝学 / 遺伝子 / ゲノム / 循環器・高血圧

Outline of Final Research Achievements

We investigated functional impacts of disease-associated mutations in the molecular pathogenesis of cardiac muscle diseases, cardiomyopathy and arrhythmia. Three cardiomyopathy-associated CARP mutations caused fundamentally different functional impairments, although they commonly increased binding to titin. Two titin mutations increased binding ability to MURF1 and induced ubiquitination of titin. LMNA and FHOD3 mutations impaired the regulation of SRF-dependent gene expression via different mechanisms, i.e. androgen receptor-coupled nuclear translocation of SRF and actin dynamics-dependent SRF activation, respectively. We tried to find chemical compounds to restore the arrhythmia-causing functional defects of Kv1.7 and Nav1.5 and obtained about 50 candidate compounds. We found novel arrhythmia-associated mutations in CALM2 and MYH6 and revealed the functional alterations caused by the mutations, which were not directly associated with channel molecules.

Free Research Field

人類遺伝学