A Common MLP (Muscle LIM Protein) Variant Is Associated With Cardiomyopathy
A Common MLP (Muscle LIM Protein) Variant Is Associated With Cardiomyopathy
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DOI：
10.1161/circresaha.109.206243
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发表时间：
2010-03-05
影响因子：
20.1
通讯作者：
Chien, Kenneth R.
中科院分区：
文献类型：
--
作者：
Knoell, Ralph;Kostin, Sawa;Chien, Kenneth R.
基本原理：我们先前发现人肌肉LIM蛋白外显子2存在10 T-> C（Trp 4Arg）错义突变，（MLP，CSRP 3）基因。目的：我们试图研究这种单核苷酸多态性在体内情况下的影响。方法和结果：我们现在报告相应Mlp（W 4 R/+）和Mlp（W 4 R/W 4 R）基因敲入动物的产生和详细分析，其发展为年龄和基因剂量依赖性肥厚型心肌病和心力衰竭表型，其特征在于在儿茶酚胺诱导的应激下收缩储备几乎完全丧失。此外，还观察到骨骼肌病理学证据，这可能与人类突变携带者有关。重要的是，我们发现在杂合子和纯合子W 4 R-MLP基因敲入动物的心脏中MLP mRNA和MLP蛋白表达水平显著降低。我们还检测到一个较弱的在体外相互作用telethonin与W 4 R-MLP比野生型MLP。这些改变可能有助于增加核定位的W 4 R-MLP，这是通过免疫组化observed.Conclusions：鉴于众所周知的高频率的这种突变在高加索人高达1%，我们的数据表明，W 4 R-MLP可能有助于显着人类心血管疾病。(Circ Res. 2010; 106：695-704）。
Rationale: We previously discovered the human 10T -> C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.Objective: We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.Methods and Results: We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age-and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry.Conclusions: Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that W4R-MLP might contribute significantly to human cardiovascular disease. (Circ Res. 2010; 106: 695-704.)