Haghighi Kobra, Kolokathis Fotis, Pater Luke, Lynch Roy A, Asahi Michio, Gramolini Anthony O, Fan Guo-Chang, Tsiapras Dimitris, Hahn Harvey S, Adamopoulos Stamatis, Liggett Stephen B, Dorn Gerald W, MacLennan David H, Kremastinos Dimitrios T, Kranias Evangelia G
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA.
J Clin Invest. 2003 Mar;111(6):869-76. doi: 10.1172/JCI17892.
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.
在人类疾病和实验动物模型中，衰竭心肌细胞中钙离子处理能力下降普遍被认为是由于肌浆网（SR）功能受损所致。在小鼠中，编码受磷蛋白（PLN）的PLN基因的破坏或显性负性PLN突变体的表达可增强SR和心脏功能，但PLN突变在人类中的影响尚不清楚。在此，在两个遗传性心力衰竭家族中鉴定出一种T116G点突变，该突变用终止密码子取代了Leu-39（L39stop）。杂合子个体表现出肥大但收缩功能未减弱。令人惊讶的是，两个L39stop纯合子个体均发展为扩张型心肌病和心力衰竭，分别在16岁和27岁时需要进行心脏移植。在一个移植心脏中发现PLN mRNA减少超过50%且未检测到PLN蛋白。重组PLN-L39stop在人胚肾（HEK）293细胞和成年大鼠心肌细胞中的表达显示，PLN对SR钙ATP酶没有抑制作用，且几乎不存在稳定的PLN表达；在有PLN表达的地方，它被错误地转运到细胞质或质膜。这些发现描述了一种自然发生的人类PLN功能丧失突变（PLN缺失）。与报道的PLN缺失对小鼠心力衰竭有益的情况相反，缺乏PLN的人类会发展为致命的扩张型心肌病。
