Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis
Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis
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DOI：
10.1016/s1096-7192(03)00142-2
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发表时间：
2003-09-01
影响因子：
3.8
通讯作者：
Bowles, NE
中科院分区：
文献类型：
--
作者：
Mohapatra, B;Jimenez, S;Bowles, NE
扩张型心肌病（DCM）是发病和死亡的主要原因。已鉴定出 X 连锁形式的两个基因（肌营养不良蛋白和tafazzin），而多个基因的突变会导致常染色体显性 DCM。肌肉 LIM 蛋白 (MLP) 是富含半胱氨酸蛋白 (CRP) 家族的成员，与肌生成和肌小节组装有关。在后一种作用中，它结合酶蛋白和α-肌动蛋白，这两者都参与肌动蛋白的组织。 MLP 缺陷小鼠已被描述；这些小鼠出现扩张型心肌病和心力衰竭。根据这些数据以及最近对 DCM 或肥厚型心肌病患者 MLP 突变的描述，我们对患者进行了 MLP 和 α-actinin-2 基因突变的筛查。我们确定了一名患有 DCM 和 EFE 的患者，其 MLP 发生突变，其中残基赖氨酸 69 被精氨酸 (K69R) 取代。该区域位于与参与 α-肌动蛋白结合的第一个 LIM 结构域相邻的高度保守区域内。细胞培养系统中的分析表明，突变消除了 MLP 和 α-actinin-2 之间的相互作用，并且 MLP 的细胞定位发生了改变。在另一名 DCM 患者中，发现了 W4R 突变。然而，这种突变并没有与这个家族的疾病分离。在另一名 DCM 患者中，在 alpha-actinin-2 中发现了 Q9R 突变。该突变还破坏了与 MLP 的相互作用，并且似乎抑制了培养细胞中的 α-辅肌动蛋白功能，涉及肌动蛋白的核定位和细胞分化的启动。 (C) 2003 Elsevier Inc. 保留所有权利。
Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in alpha-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation. (C) 2003 Elsevier Inc. All rights reserved.