Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
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.
Pubmed ID: 12610310 RIS Download
Amino Acid Sequence | Amino Acid Substitution | Animals | Calcium | Calcium Signaling | Calcium-Binding Proteins | Calcium-Transporting ATPases | Cardiomegaly | Cardiomyopathy, Dilated | Cell Line | Cyclic AMP-Dependent Protein Kinases | Female | Heart Failure | Heart Ventricles | Humans | Lod Score | Male | Mice | Mice, Transgenic | Molecular Sequence Data | Muscle Cells | Mutation, Missense | Myocardial Contraction | Myocardium | Pedigree | Phosphorylation | Sarcoplasmic Reticulum Calcium-Transporting ATPases