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Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy |
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| Authors: | Vivek S. Peche Tad A. Holak Bhagyashri D. Burgute Kosmas Kosmas Sushant P. Kale F. Thomas Wunderlich Fatiha Elhamine Robert Stehle Gabriele Pfitzer Klaus Nohroudi Klaus Addicks Florian Stöckigt Jan W. Schrickel Julia Gallinger Michael Schleicher Angelika A. Noegel |
| Affiliation: | 1. Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany 2. Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany 5. Max-Planck-Institute of Biochemistry, 82152, Martinsried, Germany 6. Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Krakow, Poland 10. Department of Neurology, Southern Illinois University School of Medicine, Springfield, IL, USA 7. Max-Planck-Institute of Neurological Research, Cologne, Germany 3. Institute of Vegetative Physiology, University of Cologne, Cologne, Germany 4. Institute of Anatomy I, University of Cologne, Cologne, Germany 8. Department of Medicine-Cardiology, University of Bonn, Bonn, Germany 9. Institute for Anatomy and Cell Biology, Ludwig-Maximilians University, 80336, Munich, Germany |
| Abstract: | Cyclase-associated proteins are highly conserved proteins that have a role in the regulation of actin dynamics. Higher eukaryotes have two isoforms, CAP1 and CAP2. To study the in vivo function of CAP2, we generated mice in which the CAP2 gene was inactivated by a gene-trap approach. Mutant mice showed a decrease in body weight and had a decreased survival rate. Further, they developed a severe cardiac defect marked by dilated cardiomyopathy (DCM) associated with drastic reduction in basal heart rate and prolongations in atrial and ventricular conduction times. Moreover, CAP2-deficient myofibrils exhibited reduced cooperativity of calcium-regulated force development. At the microscopic level, we observed disarrayed sarcomeres with development of fibrosis. We analyzed CAP2’s role in actin assembly and found that it sequesters G-actin and efficiently fragments filaments. This activity resides completely in its WASP homology domain. Thus CAP2 is an essential component of the myocardial sarcomere and is essential for physiological functioning of the cardiac system, and a deficiency leads to DCM and various cardiac defects. |
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