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首页> 外文期刊>Molecular and Cellular Biology >Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts
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Expression of a Mutant Lamin A That Causes Emery-Dreifuss Muscular Dystrophy Inhibits In Vitro Differentiation of C2C12 Myoblasts

机译：导致金刚砂-Dreifuss肌营养不良的突变型核纤层蛋白A的表达抑制C2C12成肌细胞的体外分化。

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Autosomal dominantly inherited missense mutations in lamins A and C cause several tissue-specific diseases, including Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD). Here we analyze myoblast-to-myotube differentiation in C2C12 clones overexpressing lamin A mutated at arginine 453 (R453W), one of the most frequent mutations in EDMD. In contrast with clones expressing wild-type lamin A, these clones differentiate poorly or not at all, do not exit the cell cycle properly, and are extensively committed to apoptosis. These disorders are correlated with low levels of expression of transcription factor myogenin and with the persistence of a large pool of hyperphosphorylated retinoblastoma protein. Since clones mutated at arginine 482 (a site responsible for FPLD) differentiate normally, we conclude that C2C12 clones expressing R453W-mutated lamin A represent a good cellular model to study the pathophysiology of EDMD. Our hypothesis is that lamin A mutated at arginine 453 fails to build a functional scaffold and/or to maintain the chromatin compartmentation required for differentiation of myoblasts into myocytes.
机译：lamins A和C中的常染色体显性遗传的错义突变会引起几种组织特异性疾病，包括Emery-Dreifuss肌营养不良症（EDMD）和Dunnigan型家族性部分脂肪营养不良症（FPLD）。在这里，我们分析了在过量表达Lamin A的C2C12克隆中成肌细胞向成肌细胞的分化，其在精氨酸453（R453W）处突变，这是EDMD中最常见的突变之一。与表达野生型核纤层蛋白A的克隆相反，这些克隆分化差或根本没有分化，不能正确地退出细胞周期，并且广泛地致力于细胞凋亡。这些疾病与转录因子肌生成素的低水平表达和大量高磷酸化视网膜母细胞瘤蛋白的持续存在有关。由于在精氨酸482（负责FPLD的位点）处突变的克隆正常分化，因此我们得出结论，表达R453W突变的层粘连蛋白A的C2C12克隆代表了研究EDMD病理生理的良好细胞模型。我们的假设是，在精氨酸453处突变的核纤层蛋白A无法建立功能性支架和/或维持成肌细胞分化为肌细胞所需的染色质区室。

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