A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy
A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy
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DOI：
10.1073/pnas.0510519103
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发表时间：
2006-01-31
影响因子：
11.1
通讯作者：
Kranias, EG
中科院分区：
文献类型：
--
作者：
Haghighi, K;Kolokathis, F;Kranias, EG
肌浆网Ca 2+循环蛋白是心肌收缩力的关键调节因子，肌浆网Ca 2+循环特性的改变已被证明是家族性心肌病的病因。通过对扩张型心肌病患者的基因筛查，我们在一个遗传性心力衰竭大家族中发现了一个以前未被鉴定的受磷蛋白（PLN）基因编码区精氨酸14（PLN-R14 Del）缺失。未发现纯合子个体。到中年时，杂合子个体出现左心室扩张、收缩功能障碍和阵发性室性心律失常，在某些情况下伴有明显的心力衰竭。过表达突变体PLN-R14 Del的转基因小鼠重现了人类心肌病，表现出类似的组织病理学异常和过早死亡。在HEK-293细胞中，正常PLN和多聚PLN的共表达导致肌浆网Ca ~（2+）-ATP酶的超抑制。PLN-R14 Del突变的显性效应不能完全消除，即使在蛋白激酶A磷酸化后也是如此。因此，通过长期抑制肌浆网Ca 2 +-ATP酶活性，突变体PLN-R14 Del的不可逆超抑制功能可能导致人类和小鼠的遗传性扩张型心肌病和过早死亡。
The sarcoplasmic reticulum Ca2+-cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca2+-cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca2+-ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca2+-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.