Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy
Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy
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DOI：
10.1016/j.bbrc.2007.03.128
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发表时间：
2007-05-25
影响因子：
3.1
通讯作者：
Kimura, Akinori
中科院分区：
文献类型：
--
作者：
Arimura, Takuro;Hayashi, Takeharu;Kimura, Akinori
扩张型心肌病（Dilated cardiomyopathy，DCM）是一种以心室扩张和收缩功能障碍为主要特征的心脏病。大多数DCM患者是散发性病例，但某些DCM患者群体可能是由肌节/Z盘组分（包括肌联蛋白/连接蛋白）的基因突变引起的家族性病例。然而，仅在部分家族性扩张型心肌病患者中发现致病基因突变，提示扩张型心肌病可能存在其他致病基因。为了探索DCM的新疾病基因，我们在DCM患者中搜索编码4.5 LIM蛋白2（FHL 2）的FHL 2突变，因为已知FHL 2与肌联蛋白/连接蛋白相关。在一名家族性扩张型心肌病患者中发现了一种错义突变Gly 48 Ser。功能分析表明，FHL 2突变影响与titin/connectin的结合。由于已知FHL 2蛋白将代谢酶系在肌联蛋白/连接蛋白上，因此这些观察结果表明Gly 48 Ser突变可能通过代谢酶向肌节的募集受损而参与DCM的发病机制。(c)2007爱思唯尔公司All rights reserved.
Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilated ventricle and systolic dysfunction. Most of the DCM patients are sporadic cases, but a certain population of DCM patients can be familial cases caused by mutations in genes for sarcomere/Z-disc components including titin/connectin. However, disease-causing mutations could be identified only in a part of the familial DCM patients, suggesting that there should be other disease causing genes for DCM. To explore a novel disease gene for DCM, we searched for mutations in FHL2, encoding for four and half LIM protein 2 (FHL2) in DCM patients, because FHL2 is known to associate with titin/connectin. A missense mutation, Gly48Ser, was identified in a patient with familial DCM. Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. Because FHL2 protein is known to tether metabolic enzymes to titin/connectin, these observations suggest that the Gly48Ser mutation may be involved in the pathogenesis of DCM via impaired recruitment of metabolic enzymes to the sarcomere. (c) 2007 Elsevier Inc. All rights reserved.