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Science 299 (5611): 1410-1413

Copyright © 2003 by the American Association for the Advancement of Science

Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban

Joachim P. Schmitt,1* Mitsuhiro Kamisago,12* Michio Asahi,3* Guo Hua Li,1 Ferhaan Ahmad,1 Ulrike Mende,2 Evangelia G. Kranias,4 David H. MacLennan,3 J. G. Seidman,1 Christine E. Seidman12dagger

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 rightarrow  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 PLNR9C mice recapitulated human heart failure with premature death. Cellular and biochemical studies revealed that, unlike wild-type PLN, PLNR9C did not directly inhibit SERCA2a. Rather, PLNR9C 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.

1 Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
2 Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
3 Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G1L6, Canada.
4 Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: cseidman{at}rascal.med.harvard.edu

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