Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.
In human disease and experimental animal models, depressed Ca(2+) handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy.
Haghighi
Kobra
K
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA.
Kolokathis
Fotis
F
Pater
Luke
L
Lynch
Roy A
RA
Asahi
Michio
M
Gramolini
Anthony O
AO
Fan
Guo-Chang
GC
Tsiapras
Dimitris
D
Hahn
Harvey S
HS
Adamopoulos
Stamatis
S
Liggett
Stephen B
SB
Dorn
Gerald W
GW
MacLennan
David H
DH
Kremastinos
Dimitrios T
DT
Kranias
Evangelia G
EG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics*; D002460:Cell Line; D004195:Disease Models, Animal; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D010375:Pedigree; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013045:Species Specificity; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000099211:Phospholamban