Genetic analysis of molecular networks supporting cardiac T-tubules

2015 Fiscal Year Final Research Report

• Project/Area Number: 25670171
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Sakamoto Eiji 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (40291067)
• Co-Investigator(Renkei-kenkyūsha): ONO Kageyoshi 帝京大学, 薬学部, 教授 (40177259)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 心筋細胞 / T管 / 心臓病

Outline of Final Research Achievements

We aimed to genetically elucidate the molecular basis of cardiac T-tubules. For this purpose, we used unique spontaneous mutant hamster of TO-2 manifesting severe dilated cardiomyopathy (CM). It derives from BIO14.6 and both strains share the chromosomal deletion to lack delta-sarcoglycan, a member of dystrophin-associated proteins. A series of morphological, biochemical and molecular biological studies led us to find that TO-2 has an additional genetic mutation in desmin, an intermediate filament protein connecting with dystrophin. We further elucidated that this desmin Ala191Thr point mutation weakened the filament formation of desmin protein, leading to fragility of myofibrils and T-tubules. These facts showed that the T-tubular disruption leading to severe CM in TO-2 is caused by mutations of two closely related proteins, delta-sarcoglycan and desmin. The results of this study laid the foundation of further analysis for the whole molecular network supporting cardiac T-tubules.

Free Research Field

分子医学