Journal article
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban
Science (American Association for the Advancement of Science), Vol.299(5611), pp.1410-1413
2003
DOI: 10.1126/science.1081578
PMID: 12610310
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 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.
Details
- Title: Subtitle
- Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban
- Creators
- Joachim P SCHMITT - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United StatesMitsuhiro KAMISAGO - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United StatesMichio ASAHI - Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, M5G1L6, CanadaGuo Hua Li - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United StatesFerhaan AHMAD - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United StatesUlrike MENDE - Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, United StatesEvangelia G KRANIAS - Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267, United StatesDavid H MACLENNAN - Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, M5G1L6, CanadaJ. G SEIDMAN - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United StatesChristine E SEIDMAN - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, United States
- Resource Type
- Journal article
- Publication Details
- Science (American Association for the Advancement of Science), Vol.299(5611), pp.1410-1413
- Publisher
- American Association for the Advancement of Science; Washington, DC
- DOI
- 10.1126/science.1081578
- PMID
- 12610310
- ISSN
- 0036-8075
- eISSN
- 1095-9203
- Language
- English
- Date published
- 2003
- Academic Unit
- Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984025433502771
Metrics
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