期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 111, 期 6, 页码 869-876出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200317892
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资金
- Canadian Institutes of Health Research [37377-1] Funding Source: Medline
- NHLBI NIH HHS [HL-64018, HL-58010, R01 HL064018, HL-59888, HL-52318, R01 HL059888, R01 HL058010, R01 HL026057, HL-26057, R37 HL026057, P50 HL052318] Funding Source: Medline
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.
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