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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

Authors

  • Schmitt JP
  • Kamisago M
  • Asahi M
  • Li GH
  • Ahmad F
  • Mende U
  • Kranias EG
  • MacLennan DH
  • Seidman JG
  • Seidman CE

Journal

Science (New York, N.Y.)

Publication Data

February 28, 2003

Associated Grants

None

Mesh Terms

  • 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