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- Title
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
- Authors
Schmitt, Joachim P; Kamisago, Mitsuhiro; Asahi, Michio; Li, Guo Hua; Ahmad, Ferhaan; Mende, Ulrike; Kranias, Evangelia G; MacLennan, David H; Seidman, J G; Seidman, Christine E
- Abstract
Molecular etiologies of heart failure, an emerging cardiovascular epidemic affecting 4.7 million Americans and costing 17.8 billion health-care dollars annually, remain poorly understood. Here we report that an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN), a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2+-adenosine triphosphatase (SERCA2a) pump. Transgenic PLN(R9C) mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA), which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes. These results indicate that myocellular calcium dysregulation can initiate human heart failure-a finding that may lead to therapeutic opportunities.
- Publication
Science (New York, N.Y.), 2003, Vol 299, Issue 5611, p1410
- ISSN
1095-9203
- Publication type
Journal Article
- DOI
10.1126/science.1081578