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| Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human |
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| Author(s): Haghighi K, Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC, Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW, MacLennan DH, Kremastinos DT, Kranias EG |
| Source: JOURNAL OF CLINICAL INVESTIGATION Volume: 111 Issue: 6 Pages: 869-876 Published: MAR 2003 |
| Times Cited: 118 References: 39 |
| 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Kranias, EG (reprint author), Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, 231 Albert Sabin Way, Cincinnati, OH 45267 USA |
Addresses:
1. Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA
2. Onassis Cardiac Surg Ctr, Athens, Greece
3. Univ Cincinnati, Coll Med, Dept Med, Div Cardiol, Cincinnati, OH 45267 USA
4. Univ Cincinnati, Coll Med, Dept Med, Div Pulm, Cincinnati, OH 45267 USA
5. Univ Toronto, Banting & Best Dept Med Res, Toronto, ON Canada |
| Publisher: AMER SOC CLINICAL INVESTIGATION INC, 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA |
| Subject Category: Medicine, Research & Experimental |
| IDS Number: 656FN |
| ISSN: 0021-9738 |
| DOI: 10.1172/JCI200317892 |
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