Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban

Science. 2003 Feb 28;299(5611):1410-3. doi: 10.1126/science.1081578.

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 types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Calcium / metabolism
  • Calcium Signaling
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / genetics*
  • Calcium-Binding Proteins / physiology*
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Calcium-Transporting ATPases / metabolism
  • Cardiomegaly
  • Cardiomyopathy, Dilated / genetics*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology
  • Cell Line
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Female
  • Heart Failure / genetics*
  • Heart Failure / pathology
  • Heart Failure / physiopathology
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Humans
  • Lod Score
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Muscle Cells / metabolism
  • Muscle Cells / physiology
  • Mutation, Missense*
  • Myocardial Contraction
  • Myocardium / pathology
  • Pedigree
  • Phosphorylation
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases

Substances

  • Calcium-Binding Proteins
  • phospholamban
  • Cyclic AMP-Dependent Protein Kinases
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
  • Calcium