Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy.
Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy.
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DOI：
10.1371/journal.pgen.1000372
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Feldman, Eva L.
中科院分区：
文献类型：
--
作者：
Dowling, James J.;Vreede, Andrew P.;Low, Sean E.;Gibbs, Elizabeth M.;Kuwada, John Y.;Bonnemann, Carsten G.;Feldman, Eva L.
肌管蛋白是一种脂质磷酸酶，在体外与内体运输有关，但在体内功能未知。肌管蛋白的突变会导致肌管性肌病，这是一种严重的先天性肌病，发病机制不清楚，目前尚无治疗方法。肌管性肌病是最早被描述的由膜运输相关蛋白突变引起的一系列疾病之一。为了增进对肌管蛋白功能和疾病发病机制的理解，我们利用吗啉代反义技术创建了一个肌管性肌病的斑马鱼模型。肌管蛋白水平降低的斑马鱼运动功能明显受损，肌肉有明显的组织病理学改变。这些改变包括细胞核形状和位置异常以及肌纤维萎缩。这些发现与人类疾病中观察到的情况一致。我们首次证明肌管蛋白在脊椎动物体内具有调节PI3P水平的功能，并且同源的肌管蛋白相关蛋白能够在功能上补偿肌管蛋白的缺失。最后，我们在肌管蛋白斑马鱼吗啉代反义寡核苷酸诱导的基因沉默模型的肌肉中发现了管状网状网络的异常，并将这些变化与肌管性肌病患者活检组织中T管组织的异常相关联。总之，我们创建了一个新的肌管性肌病模型，并利用该模型揭示了肌管蛋白的一种新功能以及人类疾病的一种新的发病机制，这可能解释了与该疾病相关的肌无力（兴奋 - 收缩偶联缺陷）。此外，我们关于管状网状异常和兴奋 - 收缩偶联缺陷的发现从机制上将肌管性肌病与其他几种遗传性肌肉疾病联系起来，最显著的是由兰尼碱受体突变引起的那些疾病。基于我们的发现，我们推测先天性肌病，通常被认为是具有相似临床特征但发病机制差异很大的疾病，可能从根本上是钙稳态失调的疾病。
先天性肌病是遗传性肌肉疾病，通常在儿童早期发病。它们单个来说很罕见，但作为一组可能与肌肉营养不良等疾病一样常见。斑马鱼是一个新兴的用于研究肌病的实验系统。我们利用斑马鱼开发了一个肌管性肌病模型，这是最严重的儿童肌肉疾病之一，其发病机制了解甚少。我们培育出了具有人类肌管性肌病特征性行为和组织学特征的鱼。利用这个模型，我们对肌管性肌病的发病机制有了新的见解，包括发现了肌肉管状网状系统的异常。我们随后在肌管性肌病患者的肌肉中发现了类似的变化，证实了我们斑马鱼研究结果的重要性。因为正常的肌肉收缩需要一个功能性的管状网状复合体，我们推测在肌管性肌病中观察到的肌无力是由这个网络的破坏引起的。总之，我们的研究首次确定了一种潜在的发病机制来解释肌管性肌病的临床特征。此外，通过揭示管状网状系统的异常，我们提供了肌管性肌病与其他几种先天性肌病之间的一种新的联系。
Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation–contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis. Congenital myopathies are inherited muscle conditions typically presenting in early childhood. They are individually rare, but as a group are likely as common as conditions such as muscular dystrophy. The zebrafish is an emerging experimental system for the study of myopathies. We have utilized the zebrafish to develop a model of myotubular myopathy, one of the most severe childhood muscle diseases and a condition whose pathogenesis is poorly understood. We have generated fish that have the characteristic behavioral and histological features of human myotubular myopathy. Using this model, we then made novel insights into the pathogenesis of myotubular myopathy, including the identification of abnormalities in the muscle tubulo-reticular system. We subsequently identified similar changes in muscle from patients with myotubular myopathy, corroborating the importance of our zebrafish findings. Because a functional tubulo-reticular complex is required for normal muscle contraction, we speculate that the weakness observed in myotubular myopathy is caused by breakdown of this network. In all, our study is the first to identify a potential pathomechanism to explain the clinical features of myotubular myopathy. Furthermore, by revealing abnormalities in the tubulo-reticular system, we provide a novel link between myotubular myopathy and several other congenital myopathies.
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影响因子：
3.3
作者：
Cao, Canhong;Backer, Jonathan M.;Wandinger-Ness, Angela
通讯作者：
Wandinger-Ness, Angela
影响因子：
3.5
作者：
Blondeau, F;Laporte, J;Mandel, JL
通讯作者：
Mandel, JL
影响因子：
3.7
作者：
Deniziak, Marzanna;Thisse, Christine;Lescure, Alain
通讯作者：
Lescure, Alain
DOI：
10.1073/pnas.0700942104
发表时间：
2007-04-24
影响因子：
11.1
作者：
Hall, Thomas E.;Bryson-Richardson, Robert J.;Currie, Peter D.
通讯作者：
Currie, Peter D.
人类和斑马鱼肌肉中兰尼碱受体钙释放通道活性需要硒蛋白 N
DOI：
10.1073/pnas.0806015105
发表时间：
2008-08-26
影响因子：
11.1
作者：
Jurynec, Michael J.;Xia, Ruohong;Grunwald, David Jonah
通讯作者：
Grunwald, David Jonah