A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy

Kobra Haghighi, Fotis Kolokathis, Anthony O Gramolini, Jason R Waggoner, Luke Pater, Roy A Lynch, Guo-Chang Fan, Dimitris Tsiapras, Rohan R Parekh, Gerald W Dorn, David H MacLennan, Dimitrios Th Kremastinos, Evangelia G Kranias
Proceedings of the National Academy of Sciences of the United States of America 2006 January 31, 103 (5): 1388-93
The sarcoplasmic reticulum Ca(2+)-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca(2+)-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 Ca(2+)-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 Ca(2+)-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.

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