Characterisation of CDKL5 Transcript Isoforms in Human and Mouse
Characterisation of CDKL5 Transcript Isoforms in Human and Mouse
复制标题
DOI：
10.1371/journal.pone.0157758
复制
发表时间：
2016-06-17
期刊：
影响因子：
3.7
通讯作者：
Cobb, Stuart R.
中科院分区：
文献类型：
--
作者：
Hector, Ralph D.;Dando, Owen;Cobb, Stuart R.
X-连锁的细胞周期蛋白依赖性激酶样蛋白5基因(CDKL5)的突变会导致早发性婴儿痉挛，并随后导致受影响儿童的严重发育延迟。据报道，CDKL5的整个编码区都存在有害突变。一些研究指出CDKL5在外显子使用和转录表达方面具有复杂的基因结构。分子诊断的改进和对CDKL5的神经生物学和CDKL5疾病的病理生理学的更广泛的研究需要对该基因进行最新的分析。在这项研究中，我们从生物信息和实验两方面分析了人和小鼠CDKL5的转录模式。我们已经确定了大脑中主要的CDKL5亚型，这是一个9.7kb的转录本，由18个外显子组成，带有一个6.6kb的3‘非翻译区，我们将其命名为hCDKL5_1。此外，我们还描述了新的外显子区域和一系列新的剪接和UTR异构体。这使得在这两个物种中描述更新的基因模型和CDKL5转录本的标准化命名系统成为可能。图谱显示组织和大脑发育阶段不同转录物亚型之间的表达差异。这些发现为CDKL5相关疾病的诊断、该基因及其蛋白产物的基础生物学研究以及合理设计基于基因的和分子治疗这些疾病提供了重要的背景。
Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3'-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue-and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders.