人类基因组计划开始三十年后,科学家现在已经在人类基因组中鉴定出超过25,000个蛋白质编码基因。绝大多数蛋白质编码基因(>90%)是多外显子的,编码DNA被内含子序列打断,在翻译成蛋白质之前从mRNA转录物中去除,一个叫做剪接成熟的过程。在这个过程中的变化,即通过外显子跳跃,内含子保留,备选5\'拼接站点(5\'ss),3\'拼接站点(3\'ss),或聚腺苷酸化的使用,导致人类组织中显著的转录组和蛋白质组多样性。鉴于其至关重要的生物学重要性,选择性剪接以组织和发育阶段特定的方式受到严格调节。中枢神经系统和骨骼肌是差异表达的替代外显子数量最多的组织,揭示了显著程度的转录组复杂性。因此,剪接失调与无数的神经肌肉疾病有因果关系也就不足为奇了。包括但不限于肌萎缩侧索硬化症(ALS),脊髓性肌萎缩症(SMA),杜氏肌营养不良症(DMD),强直性肌营养不良1型和2型(DM1,DM2)。基因的转录物多样性已经成为药物设计中不可或缺的重要考虑因素,发展和治疗。在这次审查中,我们将讨论神经肌肉疾病背景下的转录物多样性,以及目前解决剪接失调的方法。
Three decades since the Human Genome Project began, scientists have now identified more then 25,000 protein coding genes in the human genome. The vast majority of the protein coding genes (> 90%) are multi-exonic, with the coding DNA being interrupted by intronic sequences, which are removed from the pre-mRNA transcripts before being translated into proteins, a process called splicing maturation. Variations in this process, i.e. by exon skipping, intron retention, alternative 5\' splice site (5\'ss), 3\' splice site (3\'ss), or polyadenylation usage, lead to remarkable transcriptome and proteome diversity in human tissues. Given its critical biological importance, alternative splicing is tightly regulated in a tissue- and developmental stage-specific manner. The central nervous system and skeletal muscle are amongst the tissues with the highest number of differentially expressed alternative exons, revealing a remarkable degree of transcriptome complexity. It is therefore not surprising that splicing mis-regulation is causally associated with a myriad of neuromuscular diseases, including but not limited to amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD), and myotonic dystrophy type 1 and 2 (DM1, DM2). A gene\'s transcript diversity has since become an integral and an important consideration for drug design, development and therapy. In this review, we will discuss transcript diversity in the context of neuromuscular diseases and current approaches to address splicing mis-regulation.