CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders
CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders
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DOI：
10.1093/hmg/ddi391
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发表时间：
2005-12-15
影响因子：
3.5
通讯作者：
Rosner, MR
中科院分区：
文献类型：
--
作者：
Lin, C;Franco, B;Rosner, MR
X 连锁细胞周期蛋白依赖性激酶样 5（CDKL5 或 STK9）最近被发现与非典型 Rett 和 X 连锁 West 综合征、与精神发育迟滞、沟通和运动技能丧失以及婴儿痉挛症和癫痫发作相关的严重神经系统疾病有关，主要发生在女性中。除了 CDKL5 之外，这些疾病表型还与 MECP2 和 ARX 基因的突变有关。在这里，我们表达并表征了 CDKL5 及其突变形式。 CDKL5是一种118 kDa的蛋白质，广泛分布于所有组织中，在脑、胸腺和睾丸中含量最高。整体胚胎染色显示 CDKL5 无处不在。在细胞内，CDKL5 主要位于细胞核中。 C 末端结构域的去除会增加 CDKL5 的表达，增强自磷酸化活性并导致核周定位，表明 C 末端调节 CDKL5 功能。尽管我们检测到 MeCP2 但未检测到 ARX 与 CDKL5 的结合，但我们的结果表明这些蛋白都不是 CDKL5 激酶的直接底物。最后，通过自磷酸化评估，与疾病表型相关的 CDKL5 突变导致激酶活性丧失。这些结果表明 CDKL5 激酶失活可导致严重的神经发育障碍。
X-linked cyclin-dependent kinase-like 5 (CDKL5 or STK9) has recently been implicated in atypical Rett and X-linked West syndromes, severe neurological disorders associated with mental retardation, loss of communication and motor skills and infantile spasms and seizures in predominantly females. Besides CDKL5, these disease phenotypes are also linked to mutations in the MECP2 and ARX genes. Here, we have expressed and characterized CDKL5 and its mutant forms. CDKL5 is a 118 kDa protein that is widely distributed in all tissues, with highest levels in brain, thymus and testes. Whole mount embryo staining reveals CDKL5 to be ubiquitous. Within cells, CDKL5 is localized primarily in the nucleus. Removal of the C-terminal domain increases CDKL5 expression, enhances autophosphorylation activity and causes perinuclear localization, indicating that the C-terminus regulates CDKL5 function. Although we detect MeCP2 but not ARX binding to CDKL5, our results suggest that neither of these proteins are direct substrates of the CDKL5 kinase. Finally, the CDKL5 mutations associated with the disease phenotype cause loss of kinase activity as assessed by autophosphorylation. These results suggest that inactivation of the CDKL5 kinase can lead to severe neurodevelopmental disorders.