Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human
Open accessAbstract
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.
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A human nonsense T116G mutation causing PLB deficiency results in severe dilated cardiomyopathy in homozygotes requiring cardiac transplantation.
“a nonsense T116G gene mutation in humans that causes a deficiency of phospholamban results in severe dilated cardiomyopathy in individuals homozygous for the mutation, requiring cardiac transplantation”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Haghighi, et al., 2003
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- Authors
- 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.
- Affiliations
- University of Cincinnati (US)
- Onassis Cardiac Surgery Center (GR)
- University of Toronto (CA)
- Corresponding author
- Kranias, Evangelia G.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2003-03-15
- Volume
- 111
- Issue
- 6
- Pages
- 869-876
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC153772
- OpenAlex
- W2114942701
- Cited by
- 478
- References
- 44
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 26 · 2023: 18 · 2022: 16 · 2021: 23 · 2020: 14 · 2019: 18 · 2018: 21 · 2017: 16 · 2016: 17 · 2015: 25 · 2014: 21 · 2013: 22 · 2012: 23
- FWCI
- 18.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- University of Cincinnati
- National Institutes of Health (HL52318, HL-26057)
- Canadian Institutes of Health Research (37377_1)
- National Heart, Lung, and Blood Institute (HL-64018, HL26057, HL58010, R01HL026057, R37HL026057, HL59888, HL 52318, R01HL059888, P50HL052318, R01HL058010, R01HL064018)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- phospholamban, dilated cardiomyopathy, sarcoplasmic reticulum Ca2+-ATPase, calcium handling, cardiomyocyte hypertrophy, loss-of-function mutations, heart transplantation
- MeSH terms
- Phospholamban, Animals, Calcium, Calcium-Binding Proteins, Cardiomyopathy, Dilated, Cell Line, Disease Models, Animal, Heart Failure, Humans, Male, Mutation, Pedigree, Sarcoplasmic Reticulum, Species Specificity, Rats, Sprague-Dawley, Mice, Rats
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