Zhou Ailing, Han Song, Zhou Zhaolan Joe
Jiaozhou People's Hospital, Jiaozhou, Shangdong 266300, China.
Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Front Biol (Beijing). 2017 Feb;12(1):1-6. doi: 10.1007/s11515-016-1438-7. Epub 2017 Jan 23.
The discovery that mutations in cyclin-dependent kinase-like 5 () gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research.
A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section.
On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage.
Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.
细胞周期蛋白依赖性激酶样5（CDKL5）基因突变与婴儿癫痫性脑病相关这一发现激发了全球范围内的研究工作，以了解CDKL5障碍的分子和遗传基础。鉴于目前已发表的大量文献，本综述旨在总结当前的遗传学研究，就提出的分子功能达成共识，并指出CDKL5研究中的知识空白。
使用PubMed搜索引擎进行系统综述，重点关注近十年的CDKL5研究。我们分析了这些出版物，并将研究结果总结为四个部分：遗传学研究、CDKL5表达模式、分子功能和动物模型。我们还讨论了每个部分的挑战和未来方向。
在临床方面，CDKL5障碍的特征是早发性癫痫发作、智力残疾和刻板行为。在研究方面，对人类患者、细胞培养和动物模型进行的一系列分子和遗传学研究确定了CDKL5与婴儿癫痫性脑病之间的因果关系，并指出CDKL5在调节大脑神经元功能中起关键作用。CDKL5障碍的小鼠模型也已开发出来，值得注意的是，它们表现出行为表型，模拟了CDKL5障碍的许多临床症状，并将CDKL5研究推进到临床前阶段。
鉴于我们目前所了解的情况，未来确定强大、定量和敏感的结果测量方法将是动物模型研究的关键，特别是在杂合子雌性动物中。与此同时，CDKL5的分子和细胞研究应侧重于基于机制的研究，旨在发现可成药靶点，这些靶点有可能挽救或改善与CDKL5障碍相关的表型。
