Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human
Kobra Haghighi, … , Dimitrios T. Kremastinos, Evangelia G. Kranias
Kobra Haghighi, … , Dimitrios T. Kremastinos, Evangelia G. Kranias
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):869-876. https://doi.org/10.1172/JCI17892.
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Article Cardiology

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

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 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 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.

Authors

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 II, David H. MacLennan, Dimitrios T. Kremastinos, Evangelia G. Kranias

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Figure 1

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Mutation in the PLN gene and analysis of inheritance in kindred I. (a) P...
Mutation in the PLN gene and analysis of inheritance in kindred I. (a) Partial nucleotide sequences of the PLN coding region in normal subjects and in patients with dilated cardiomyopathy who were homozygous or heterozygous for the T116G transversion, which converts the codon for Leu-39 (TTA) to a stop codon (TGA). (b) Pedigree for the presence or absence of the T116G mutation in kindred I. Probands III-4 and III-6, who were homozygous for the L39stop mutation, were diagnosed with dilated cardiomyopathy and required cardiac transplantation. Squares represent males and circles represent females. A line denotes that the patient is deceased. (c) Histological analysis of explanted hearts from probands III-4 and III-6 (who were homozygous for the L39stop mutation), which were stained with Masson’s trichrome, illustrated the massive interstitial fibrosis and myocardial disarrangement (arrows). Scale bar, 50 μm.