title: Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
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.
authors.affiliation: Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Schmitt
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kamisago
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Guo Hua
authors.initials: GH
authors.lastname: Li
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.forename: David H
authors.initials: DH
authors.lastname: MacLennan
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006332:Cardiomegaly; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008126:Lod Score; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism / Q000502:physiology; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D010375:Pedigree; D010766:Phosphorylation; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D017868:Cyclic AMP-Dependent Protein Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban