Dilated cardiomyopathy and heart failure caused by a mutation in
phospholamban
J. Schmitt, M. Kamisago, M. Asahi, G. Li, F. Ahmad, U. Mende, E. Kranias, D. MacLennan, J. Seidman, and C. Seidman. Science, 299 (5611):
1410-3(February 2003)Schmitt, Joachim P Kamisago, Mitsuhiro Asahi, Michio Li, Guo Hua
Ahmad, Ferhaan Mende, Ulrike Kranias, Evangelia G MacLennan, David
H Seidman, J G Seidman, Christine E Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. United States Science (New York,
N.Y.) Science. 2003 Feb 28;299(5611):1410-3..
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.
Schmitt, Joachim P Kamisago, Mitsuhiro Asahi, Michio Li, Guo Hua
Ahmad, Ferhaan Mende, Ulrike Kranias, Evangelia G MacLennan, David
H Seidman, J G Seidman, Christine E Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. United States Science (New York,
N.Y.) Science. 2003 Feb 28;299(5611):1410-3.
%0 Journal Article
%1 Schmitt2003
%A Schmitt, J. P.
%A Kamisago, M.
%A Asahi, M.
%A Li, G. H.
%A Ahmad, F.
%A Mende, U.
%A Kranias, E. G.
%A MacLennan, D. H.
%A Seidman, J. G.
%A Seidman, C. E.
%D 2003
%J Science
%K & *Mutation, AMP-Dependent ATPases ATPases/antagonists Acid Amino Animals Calcium Calcium-Binding Calcium-Transporting Calcium/metabolism Cardiomegaly Cardiomyopathy, Cell Cells/metabolism/physiology Contraction Cyclic Data Dilated/*genetics/pathology/physiopathology Failure/*genetics/pathology/physiopathology Female Heart Humans Kinases/metabolism Line Lod Male Mice Missense Molecular Muscle Myocardial Myocardium/pathology Pedigree Phosphorylation Protein Proteins/chemistry/*genetics/*physiology Reticulum Sarcoplasmic Score Sequence Signaling Substitution Transgenic Ventricles/metabolism/pathology inhibitors/metabolism
%N 5611
%P 1410-3
%T Dilated cardiomyopathy and heart failure caused by a mutation in
phospholamban
%U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12610310
%V 299
%X 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.
@article{Schmitt2003,
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.},
added-at = {2010-12-14T18:12:02.000+0100},
author = {Schmitt, J. P. and Kamisago, M. and Asahi, M. and Li, G. H. and Ahmad, F. and Mende, U. and Kranias, E. G. and MacLennan, D. H. and Seidman, J. G. and Seidman, C. E.},
biburl = {https://www.bibsonomy.org/bibtex/2ca3a46c7f89bb13797877f6f6e5a893c/pharmawuerz},
endnotereftype = {Journal Article},
interhash = {d2fee6ac55ee2c32d81086be1a53d6eb},
intrahash = {ca3a46c7f89bb13797877f6f6e5a893c},
issn = {1095-9203 (Electronic) 1095-9203 (Linking)},
journal = {Science},
keywords = {& *Mutation, AMP-Dependent ATPases ATPases/antagonists Acid Amino Animals Calcium Calcium-Binding Calcium-Transporting Calcium/metabolism Cardiomegaly Cardiomyopathy, Cell Cells/metabolism/physiology Contraction Cyclic Data Dilated/*genetics/pathology/physiopathology Failure/*genetics/pathology/physiopathology Female Heart Humans Kinases/metabolism Line Lod Male Mice Missense Molecular Muscle Myocardial Myocardium/pathology Pedigree Phosphorylation Protein Proteins/chemistry/*genetics/*physiology Reticulum Sarcoplasmic Score Sequence Signaling Substitution Transgenic Ventricles/metabolism/pathology inhibitors/metabolism},
month = {Feb 28},
note = {Schmitt, Joachim P Kamisago, Mitsuhiro Asahi, Michio Li, Guo Hua
Ahmad, Ferhaan Mende, Ulrike Kranias, Evangelia G MacLennan, David
H Seidman, J G Seidman, Christine E Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. United States Science (New York,
N.Y.) Science. 2003 Feb 28;299(5611):1410-3.},
number = 5611,
pages = {1410-3},
shorttitle = {Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban},
timestamp = {2010-12-14T18:21:26.000+0100},
title = {Dilated cardiomyopathy and heart failure caused by a mutation in
phospholamban},
url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12610310},
volume = 299,
year = 2003
}