Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients
Specific phosphorylation of Ser458 of A-type lamins in LMNA-associated myopathy patients
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DOI：
10.1242/jcs.072157
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发表时间：
2010-11-15
影响因子：
4
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
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作者：
Mitsuhashi, Hiroaki;Hayashi, Yukiko K.;Nishino, Ichizo
编码a型核层蛋白的LMNA的突变导致各种人类疾病，包括肌病、心肌病、脂肪营养不良和早衰综合征。迄今为止，人们对单个基因的突变如何导致多种疾病知之甚少。在这里，通过表征一种特异性识别a型层粘连蛋白Ser458磷酸化的抗体，我们发现了可能有助于我们理解层粘连病的发现。该抗体仅在a型纤层蛋白的g-fold基序突变的肌病患者的肌肉活检中与细胞核反应。在对照组患者或任何其他神经肌肉疾病患者的肌肉中未见Ser458磷酸化。体外分析证实，只有与肌病相关的纤层蛋白A突变体诱导Ser458磷酸化，而脂肪营养不良或早衰症相关的突变体则不会。我们还发现Akt1在体外直接磷酸化与肌病相关突变的纤层蛋白A的Ser458。提示a型层板蛋白Ser458磷酸化与横纹肌层板病相关；这可能有助于lmna相关肌病的早期诊断。我们提出，Akt1对a型纤层蛋白的疾病特异性磷酸化有助于LMNA突变引起的肌病。
Mutations in LMNA, which encodes A-type nuclear lamins, cause various human diseases, including myopathy, cardiomyopathy, lipodystrophy and progeria syndrome. To date, little is known about how mutations in a single gene cause a wide variety of diseases. Here, by characterizing an antibody that specifically recognizes the phosphorylation of Ser458 of A-type lamins, we uncover findings that might contribute to our understanding of laminopathies. This antibody only reacts with nuclei in muscle biopsies from myopathy patients with mutations in the Ig-fold motif of A-type lamins. Ser458 phosphorylation is not seen in muscles from control patients or patients with any other neuromuscular diseases. In vitro analysis confirmed that only lamin A mutants associated with myopathy induce phosphorylation of Ser458, whereas lipodystrophy-or progeria-associated mutants do not. We also found that Akt1 directly phosphorylates Ser458 of lamin A with myopathy-related mutations in vitro. These results suggest that Ser458 phosphorylation of A-type lamins correlates with striated muscle laminopathies; this might be useful for the early diagnosis of LMNA-associated myopathies. We propose that disease-specific phosphorylation of A-type lamins by Akt1 contributes to myopathy caused by LMNA mutations.