Martín-Carrascosa María Del Carmen, Palacios-Martínez Christian, Galindo Máximo Ibo
Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, Valencia, Spain.
Laboratory of Developmental Biology and Disease Mechanisms, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Front Cell Dev Biol. 2025 Apr 30;13:1582684. doi: 10.3389/fcell.2025.1582684. eCollection 2025.
The human CDK-like (CDKL) family of serine‒threonine kinases has five members (CDKL1-5), with a conserved N-terminal kinase domain and variable C-termini. Among these, CDKL5 is of particular interest because of its involvement in CDKL5 deficiency disorder (CDD), a rare epileptic encephalopathy with several comorbidities for which there are no specific treatments. Current CDD vertebrate models are seizure resistant, which could be explained by the genetic background, including leaky expression of other CDKLs. Thus, phylogenetic analysis of the protein family would be valuable for understanding current models and developing new ones. Our phylogenetic studies revealed that ancestral CDKLs were present in all major eukaryotic clades and had ciliary/flagellar functions, which may have diversified throughout evolution. The original CDKL, which was likely similar to human CDKL5, gave rise to the remaining family members through successive duplications. In addition, particular clades have undergone further gene duplication and loss, a pattern that suggests some functional redundancy among them. A separate study focusing on the C-terminal tail of CDKL5 suggested that this domain is only functionally relevant in jawed vertebrates. We have developed a model of CDD in based on downregulation of the single gene by RNAi, which results in phenotypes similar to those of CDD patients, that are rescued by re-expression of fly and human . CDKL proteins contain a conserved kinase domain, originally involved in ciliary maintenance; therefore, invertebrate model organisms can be used to investigate CDKL functions that involve the aforementioned domain.
人类丝氨酸 - 苏氨酸激酶的类周期蛋白依赖性激酶（CDKL）家族有五个成员（CDKL1 - 5），具有保守的N端激酶结构域和可变的C端。其中，CDKL5特别受关注，因为它与CDKL5缺陷障碍（CDD）有关，CDD是一种罕见的癫痫性脑病，伴有多种合并症，目前尚无特异性治疗方法。当前的CDD脊椎动物模型具有抗癫痫发作能力，这可能由遗传背景来解释，包括其他CDKL的渗漏表达。因此，对该蛋白家族进行系统发育分析，对于理解现有模型和开发新模型将具有重要价值。我们的系统发育研究表明，祖先的CDKL存在于所有主要的真核生物进化枝中，并具有纤毛/鞭毛功能，这些功能在整个进化过程中可能已经多样化。最初的CDKL可能与人类CDKL5相似，通过连续复制产生了其余的家族成员。此外，特定的进化枝经历了进一步的基因复制和丢失，这种模式表明它们之间存在一些功能冗余。另一项针对CDKL5 C末端尾巴的研究表明，该结构域仅在有颌脊椎动物中具有功能相关性。我们通过RNA干扰下调单个基因，建立了一种CDD模型，该模型产生的表型与CDD患者相似，通过果蝇和人类的重新表达得以挽救。CDKL蛋白包含一个保守的激酶结构域，最初参与纤毛维持；因此，无脊椎动物模型生物可用于研究涉及上述结构域的CDKL功能。
