JOURNAL ARTICLE

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
16432188
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
16432188
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"