CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome
CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome
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DOI：
10.1093/hmg/ddi198
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发表时间：
2005-07-15
影响因子：
3.5
通讯作者：
Landsberger, N
中科院分区：
文献类型：
--
作者：
Mari, F;Azimonti, S;Landsberger, N
Rett综合征（RTT）是一种严重的神经发育障碍，几乎只影响女性，并以广泛的临床表现为特征。大多数受经典RTT影响的患者和较小比例的轻度“保留语言变异”患者在MECP2基因中存在点突变或缺失/重复。最近，在与RTT表型重叠的女性患者中发现了编码一种假定的激酶的CDKL5基因突变。在这里，我们报告了两例RTT早期发作变体患者，携带两个新的CDKL5截断突变，加强了CDKL5与RTT之间的相关性。考虑到MECP2和CDKL5突变引起的相似表型，有人认为这两个基因在共同的致病过程中发挥作用。我们在这里表明，CDKL5是一种核蛋白，在神经成熟和突触发生过程中，其在神经系统中的表达与MeCP2重叠。重要的是，我们证明了MeCP2和CDKL5在体内和体外都相互作用，CDKL5确实是一种激酶，它能够磷酸化自身并介导MeCP2磷酸化，这表明它们属于同一分子途径。此外，这篇论文有助于澄清与CDKL5突变相关的表型，并指出CDKL5应该在每个表现出与RTT相似的临床病程的患者中进行分析，但其特征是由于癫痫发作而缺乏早期正常期。
Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.