A Mutation in the Human Phospholamban Gene, Deleting Arginine 14, Results in Lethal, Hereditary Cardiomyopathy

The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a pre...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (5), p.1388-1393
Main Authors: Haghighi, Kobra, Kolokathis, Fotis, Gramolini, Anthony O., Waggoner, Jason R., Pater, Luke, Lynch, Roy A., Fan, Guo-Chang, Tsiapras, Dimitris, Parekh, Rohan R., Dorn, Gerald W., MacLennan, David H., Kremastinos, Dimitrios Th, Kranias, Evangelia G.
Format: Article
Language:English
Subjects:
Adult
Animals
Antibodies
Arginine - genetics
Arrhythmias, Cardiac - metabolism
Biological Sciences
Calcium
Calcium - chemistry
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Cardiomyopathies
Cardiomyopathies - genetics
Cardiomyopathies - mortality
Cell Line
Cellular immunity
Child
Dilated cardiomyopathy
DNA Mutational Analysis
Echocardiography
Electrocardiography
Family Health
Female
Gene Deletion
Gene expression
Genetic mutation
Genetics
Heart
Heart failure
Heterozygote
Homozygote
Humans
Male
Mice
Mice, Transgenic
Microscopy, Fluorescence
Middle Aged
Models, Statistical
Mutation
Pedigree
Phosphorylation
Proteins
Sarcoplasmic Reticulum - metabolism
Time Factors
Transgenic animals
Ventricular tachycardia
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Summary:The sarcoplasmic reticulum Ca²⁺-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca²⁺-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca²⁺-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca²⁺-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0510519103