Alternative Splicing and Isoforms: From Mechanisms to Diseases

Abstract

Alternative splicing of pre-mRNA is a key mechanism for increasing the complexity of proteins in humans, causing a diversity of expression of transcriptomes and proteomes in a tissue-specific manner. Alternative splicing is regulated by a variety of splicing factors. However, the changes and errors of splicing regulation caused by splicing factors are strongly related to many diseases, something which represents one of this study's main interests. Further understanding of alternative splicing regulation mediated by cellular factors is also a prospective choice to develop specific drugs for targeting the dynamic RNA splicing process. In this review, we firstly concluded the basic principle of alternative splicing. Afterwards, we showed how splicing isoforms affect physiological activities through specific disease examples. Finally, the available treatment methods relative to adjusting splicing activities have been summarized.

Keywords: alternative splicing; diseases; drugs; splicing factors.

Figure 1

Schematic figure representing seven modes of alternative splicing of pre-mRNA: cassette exon, intron retention, alternative 5′ splice site, mutually exclusive exons, alternative 3′ splice site, alternative promoters, and alternative polyadenylation. Alternative splicing sites are connected by dashed lines. Boxes represent exons and lines represent introns.

Figure 2

Schematic representation of CCND1 pre-mRNA splicing mechanism, isoforms, and nuclear transport.

Figure 3

Mutated i-kappa-B kinase complex associated protein (IKBKAP) plays a role in the development of familial dysautonomia (FD). The single nucleotide mutation from T to C disrupts the interaction between pre-mRNA and U1 snRNP and induce the exon 20 exclusion.

Figure 4

Graphical representation of assembly of alternative splicing factors (hnRNPA1, SRSF7, SRSF3, and NOVA1) on the INSR pre-mRNA and insulin receptor (IR) splice variants. Splicing factors are listed in the green box. Alternative splicing sites are connected by dashed lines. The boxes represent exons and the lines represent introns.

Figure 5

Application of splice-switch ASO in the treatment of breast cancer. Oncogene STAT expresses two isoforms: STAT3α and STAT3β. ASO targets the ESE and induce exon23 inclusion, thereby improving the production of STAT3β and leading to cell apoptosis in breast tumors.