Alternative Splicing and Disease

Abstract

Almost all protein-coding genes are spliced and their majority is alternatively spliced. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. A fine-tuned balance of factors regulates splice site selection. Here, we discuss well-studied examples that show how a disturbance of this balance can cause human disease. The rapidly emerging knowledge of splicing regulation now allows the development of treatment options. General principles of alternative splicingAlternative pre-mRNA splicing regulates the function of the majority of protein-coding genes An average human protein-coding gene contains a mean of 8.8 exons with a mean size of 145 nt. The mean intron length is 3365 nt and the 5′ and 3′ UTR are 770 and 300 nt, respectively; as a result, this "standard" gene spans about 27 kbp. After pre-mRNA processing the average mRNA exported into the cytosol consists of 1340 nt coding sequence, 1070 nt untranslated regions and a poly (A) tail [1]. This shows that more than 90% of the pre-mRNA is removed as introns, and only about 10% of the average pre-mRNA are joined as exonic sequences by pre-mRNA splicing. Almost all protein-coding genes contain introns that are removed in the nucleus by RNA splicing during pre-mRNA processing. Exon usage is often alternative, i.e. the cell decides whether to remove a part of the pre-mRNA as an intron or include this part in the mature mRNA as an alternative exon [2]; (Figure 1). Alternative pre-mRNA processing is a key regulator of gene expression as it generates numerous transcripts from a single protein-coding gene, which largely increases the use of genetic information. The process is more widely used than previously thought and was recently estimated to affect more than 88% of human protein-coding genes [3]. AnCorrespondence to: Stefan Stamm. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript estimated 75% of alternative exons encode protein parts [4] and their alternate use allows to generate multiple proteins from a single gene, which increases the coding potential of the genome. Mapping of alternatively spliced regions on known protein structures suggest that most alternative exons are in coiled or loop regions that are located on the surface [5]. Alternative splicing generates protein isoforms with different biological properties that differ in protein:protein intera...