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.