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Functional roles of alternative splicing factors in human disease

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Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell‐type or tissue‐specific manner, and at different developmental stages. AS is regulated by RNA‐binding proteins, including cell‐ or tissue‐specific splicing factors. In the past few years, technological advances have defined genome‐wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact. WIREs RNA 2015, 6:311–326. doi: 10.1002/wrna.1276 This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease
The biochemical steps of intron splicing and mechanisms of alternative splicing regulation. (a) Removal of an intron occurs in two catalytic steps that are directed by the core splice sites. In the first catalytic step of splicing, an adenosine residue in the branchpoint sequence (BPS) carries out nucleophilic attack at the 5′ end of the intron to form a branched 2′→5′ phosphodiester bond and lariat intermediate (middle). In the second catalytic step, the 3′ OH of the 5′ exon carries out nucleophilic attack at the 3′ splice site to ligate the exons in a 5′→3′ phosphodiester bond. The intron is released as a lariat product that is debranched and degraded. (b) Schematic of a model of combinatorial control of alternative splicing. An alternatively spliced cassette exon (gray) is flanked by two constitutively spliced exons (green). The positions of the core splice sites and BPS are indicated by thick lines. Intronic splicing enhancer (ISE) and exonic splicing enhancer (ESE) sequence elements are indicated in red together with splicing regulatory proteins (SRP) that bind them to promote exon splicing. Intronic splicing silencer (ISS) and exonic splicing silencer (ESS) are indicated in blue along with corresponding SRPs that promote exon skipping. The net combined activities of factors that promote splicing or skipping determine the level of exon splicing. These activities determine, at least in part, whether U1 binds to the 5′ splice site, U2AF to the PPT and 3′ splice site, and U2 to the BPS and subsequent steps of spliceosome assembly.
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RBM10 and QKI regulate NUMB alternative splicing to suppress NOTCH signaling. (a) RBM10 and QKI bind to distinct cis‐ISS regulatory elements in the intron upstream of and at the 5′ end of exon 9 leading to exon skipping. The resulting NUMB‐PRRS protein isoform lacking the domain encoded by exon 9 is expressed at higher levels (due to an unknown mechanism) leading to suppression of NOTCH signaling through ITCH‐mediated ubiquitination and degradation of the NOTCH intracellular domain (NICD). (b) In the absence of functional RBM10 or QKI, exon 9 is included leading to less expression of NUMB protein and enhanced transcriptional activation of NOTCH target genes (HES1, HEY1, and HEY2) and increased cell proliferation.
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RBM20 regulates Titin alternative splicing. (a) RBM20 promotes the skipping of large cassettes of tandem exons in the Titin pre‐mRNA via multiple binding sites. This results in the expression of shorter Titin isoforms, N2B and N2BA in normal heart, that are stiffer and thus require more force to stretch. (b) Loss of RBM20 function by deletion or from mutations in RBM20 that are associated with human dilated cardiomyopathy impede its ability to repress the tandem exons in the middle tandem Ig segment and the PEVK (rich in proline, glutamic acid, valine, and lysine residues) region. As a result larger Titin isoforms (N2BA‐G) are produced that are more compliant and distensible. Green boxes indicate regions with tandem Ig‐like repeats.
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Schematic study of the different types of alternative splicing. Green boxes indicate constitutive exon sequences and red or brown boxes are alternatively spliced exons or regions. Solid lines indicate introns and dashed lines indicate alternative patterns. The hashmarks in the APA3 and APA5 events indicate that there can also be numerous additional cassette exons between the proximal and distal 3′ terminal exons.
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RNA in Disease and Development > RNA in Disease
RNA Processing > Splicing Mechanisms
RNA Processing > Splicing Regulation/Alternative Splicing

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