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Citations to this article

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 Article has an altmetric score of 3

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

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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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 Total
Citations: 7 15 9 12 14 10 8 8 9 8 23 8 11 10 12 8 8 11 7 3 7 5 1 214
Citation information
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Citations to this article in year 2018 (8)

Title and authors Publication Year
Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity
S Hamilton, D Terentyev
Frontiers in physiology 2018
Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes
DK Ceholski, IC Turnbull, CW Kong, S Koplev, J Mayourian, PA Gorski, F Stillitano, AA Skodras, M Nonnenmacher, N Cohen, JL Björkegren, DR Stroik, RL Cornea, DD Thomas, RA Li, KD Costa, RJ Hajjar
Journal of Molecular and Cellular Cardiology 2018
Unique Ca2+-Cycling Protein Abundance and Regulation Sustains Local Ca2+ Releases and Spontaneous Firing of Rabbit Sinoatrial Node Cells
T Vinogradova, ST Sirenko, E Lakatta
International journal of molecular sciences 2018
Targeting protein-protein interactions for therapeutic discovery via FRET-based high-throughput screening in living cells
DR Stroik, SL Yuen, KA Janicek, TM Schaaf, J Li, DK Ceholski, RJ Hajjar, RL Cornea, DD Thomas
Scientific Reports 2018
Phospholamban regulates nuclear Ca2+ stores and inositol 1,4,5-trisphosphate mediated nuclear Ca2+ cycling in cardiomyocytes
M Chen, D Xu, AZ Wu, E Kranias, SF Lin, PS Chen, Z Chen
Journal of Molecular and Cellular Cardiology 2018
Preclinical Studies of Stem Cell Therapy for Heart Disease
BA Tompkins, W Balkan, J Winkler, M Gyöngyösi, G Goliasch, F Fernández-Avilés, JM Hare
Circulation research 2018
PLN Foundation: A Foundation of Patients for Patients
EG Kranias, PA Doevendans, PC Glijnis, RJ Hajjar
Circulation research 2018
Prevalence and cardiac phenotype of patients with a phospholamban mutation
IE Hof, JF van der Heijden, EG Kranias, D Sanoudou, RA de Boer, JP van Tintelen, PA van der Zwaag, PA Doevendans
Netherlands Heart Journal 2018

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