Ruggiero Valeria, Fagioli Claudio, de Pretis Stefano, Di Carlo Valerio, Landsberger Nicoletta, Zacchetti Daniele
Vita-Salute San Raffaele University, Milan, Italy.
Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Front Cell Neurosci. 2023 Oct 30;17:1231493. doi: 10.3389/fncel.2023.1231493. eCollection 2023.
CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5'UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein.
CDKL5是一种在正确的神经元发育和突触形成中具有相关功能的激酶。其表达或活性的降低会导致一种严重的神经发育疾病，称为CDKL5缺乏症（CDD）。CDD由位于该基因编码区的CDKL5突变引起。然而，在一名具有与CDD一致症状的患者中，在CDKL5 5'非翻译区（UTR）鉴定出一个单核苷酸多态性（SNP），以及CDKL5转录本前导序列的复杂性，表明CDKL5表达存在相关的翻译调控，这在生理过程以及CDD的发病机制中具有重要影响。我们对CDKL5的5'UTR进行了生物信息学和分子分析，以鉴定翻译调控特征。我们提出结构顺式作用元件具有重要作用，真核翻译起始因子eIF4B参与其中。通过评估帽依赖性和帽非依赖性翻译起始，我们表明存在一个内部核糖体进入位点（IRES）支持CDKL5 mRNA的翻译，并提出C>T -189 SNP在降低下游蛋白翻译方面具有致病作用。
