title: A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Kobra
authors.initials: K
authors.lastname: Haghighi
authors.forename: Fotis
authors.initials: F
authors.lastname: Kolokathis
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Gramolini
authors.forename: Jason R
authors.initials: JR
authors.lastname: Waggoner
authors.forename: Luke
authors.initials: L
authors.lastname: Pater
authors.forename: Roy A
authors.initials: RA
authors.lastname: Lynch
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Dimitris
authors.initials: D
authors.lastname: Tsiapras
authors.forename: Rohan R
authors.initials: RR
authors.lastname: Parekh
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: David H
authors.initials: DH
authors.lastname: MacLennan
authors.forename: Dimitrios Th
authors.initials: DT
authors.lastname: Kremastinos
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000328:Adult; D000818:Animals; D001120:Arginine / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000737:chemistry; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000401:mortality*; D002460:Cell Line; D002648:Child; D004252:DNA Mutational Analysis; D004452:Echocardiography; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation; D010375:Pedigree; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors; D000099211:Phospholamban
chemical_list: D001120:Arginine; D002118:Calcium; D002135:Calcium-Binding Proteins; D000099211:Phospholamban