Science. 2003 Feb 28;299(5611):1410-3.

Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.

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

Source

Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115, USA.

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.

PMID:: 12610310; [PubMed - indexed for MEDLINE]

Free full text

Publication Types, MeSH Terms, Substances

Publication Types

MeSH Terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

COS Scholar Universe

Medical

Molecular Biology Databases

CALCIUM, ELEMENTAL - HSDB

Miscellaneous

Mouse Genome Informatics (MGI)

Supplemental Content

Save items

Related citations in PubMed

Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition. [Circulation. 2009]
Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition.
Schmitt JP, Ahmad F, Lorenz K, Hein L, Schulz S, Asahi M, Maclennan DH, Seidman CE, Seidman JG, Lohse MJ. Circulation. 2009 Jan 27; 119(3):436-44. Epub 2009 Jan 12.
Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A. [Proc Natl Acad Sci U S A. 2011]
Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and phosphorylation by protein kinase A.
Ha KN, Masterson LR, Hou Z, Verardi R, Walsh N, Veglia G, Robia SL. Proc Natl Acad Sci U S A. 2011 Feb 15; 108(7):2735-40. Epub 2011 Jan 31.
Review Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy. [Biochem Biophys Res Commun. 2004]
Review Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy.
Haghighi K, Gregory KN, Kranias EG. Biochem Biophys Res Commun. 2004 Oct 1; 322(4):1214-22.
Cardiac-specific overexpression of sarcolipin in phospholamban null mice impairs myocyte function that is restored by phosphorylation. [Proc Natl Acad Sci U S A. 2006]
Cardiac-specific overexpression of sarcolipin in phospholamban null mice impairs myocyte function that is restored by phosphorylation.
Gramolini AO, Trivieri MG, Oudit GY, Kislinger T, Li W, Patel MM, Emili A, Kranias EG, Backx PH, Maclennan DH. Proc Natl Acad Sci U S A. 2006 Feb 14; 103(7):2446-51. Epub 2006 Feb 6.
Review Phospholamban: a crucial regulator of cardiac contractility. [Nat Rev Mol Cell Biol. 2003]
Review Phospholamban: a crucial regulator of cardiac contractility.
MacLennan DH, Kranias EG. Nat Rev Mol Cell Biol. 2003 Jul; 4(7):566-77.

See reviews... See all...

Cited by 76 PubMed Central articles

Structure-function relation of phospholamban: modulation of channel activity as a potential regulator of SERCA activity. [PLoS One. 2013]
Structure-function relation of phospholamban: modulation of channel activity as a potential regulator of SERCA activity.
Smeazzetto S, Saponaro A, Young HS, Moncelli MR, Thiel G. PLoS One. 2013; 8(1):e52744. Epub 2013 Jan 4.
Review Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy. [Nat Rev Cardiol. 2012]
Review Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy.
Kho C, Lee A, Hajjar RJ. Nat Rev Cardiol. 2012 Dec; 9(12):717-33. Epub 2012 Oct 23.
Cardiomyopathy classification: ongoing debate in the genomics era. [Biochem Res Int. 2012]
Cardiomyopathy classification: ongoing debate in the genomics era.
McCartan C, Mason R, Jayasinghe SR, Griffiths LR. Biochem Res Int. 2012; 2012:796926. Epub 2012 Aug 8.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
ClinVar
Clinical variations associated with publication
Compound (MeSH Keyword)
PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Gene
Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
Gene (GeneRIF)
Gene records that have the current articles as Reference into Function citations (GeneRIFs). NLM staff reviewing the literature while indexing MEDLINE add GeneRIFs manually.
Gene (OMIM)
Gene records associated with Online Mendelian Inheritance in Man (OMIM) records that cite the current articles in their reference lists.
HomoloGene
HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
MedGen
Related information in MedGen
MedGen (OMIM)
Related information in MedGen (OMIM)
Nucleotide (RefSeq)
NCBI nucleotide Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Nucleotide (Weighted)
Nucleotide records associated with the current articles through the Gene database. These are the related sequences on the Gene record that are added manually by NCBI.
OMIM (calculated)
Online Mendelian Inheritance in Man (OMIM) records that include the current articles as references in the light bulb links within or in the citations at the end of the OMIM record. The references available through the light bulb link are collected using the PubMed related articles algorithm to identify records with similar terminology to the OMIM record.
OMIM (cited)
Online Mendelian Inheritance in Man (OMIM) records that include the current articles as reference cited at the end of the OMIM record.
Protein (RefSeq)
NCBI protein Reference Sequences (RefSeqs) that are cited in the current articles, included in the corresponding Gene Reference into Function, or that include the PubMed articles as references.
Protein (Weighted)
Protein records associated with the current articles through related Gene database records. These are the related sequences on the Gene record that are added manually by NCBI.
Substance (MeSH Keyword)
PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.
Taxonomy via GenBank
Taxonomy records associated with the current articles through taxonomic information on related molecular database records (Nucleotide, Protein, Gene, SNP, Structure).
UniGene
UniGene clusters of expressed sequences that are associated with the current articles through references on the clustered sequence records and related Gene records.
Protein
Protein translation features of primary database (GenBank) nucleotide records reported in the current articles as well as Reference Sequences (RefSeqs) that include the articles as references.
GEO Profiles
Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban.
Science. 2003 Feb 28 ;299(5611):1410-3.

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: