Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human

Kobra Haghighi, Fotis Kolokathis, Luke Pater, Roy A. Lynch, Michio Asahi, Anthony O. Gramolini, Guo Chang Fan, Dimitris Tsiapras, Harvey S. Hahn, Stamatis Adamopoulos, Stephen B. Liggett, Gerald W. Dorn, David H. MacLennan, Dimitrios T. Kremastinos, Evangelia G. Kranias

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313 Scopus citations

Abstract

In human disease and experimental animal models, depressed Ca2+ 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 ofPLN 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 Ca2+-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.

Original languageEnglish
Pages (from-to)869-876
Number of pages8
JournalJournal of Clinical Investigation
Volume111
Issue number6
DOIs
StatePublished - Mar 2003
Externally publishedYes

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    Haghighi, K., Kolokathis, F., Pater, L., Lynch, R. A., Asahi, M., Gramolini, A. O., Fan, G. C., Tsiapras, D., Hahn, H. S., Adamopoulos, S., Liggett, S. B., Dorn, G. W., MacLennan, D. H., Kremastinos, D. T., & Kranias, E. G. (2003). Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. Journal of Clinical Investigation, 111(6), 869-876. https://doi.org/10.1172/JCI17892