The pathobiology of splicing
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Open Access
- 13 November 2009
- journal article
- review article
- Published by Wiley in The Journal of Pathology
- Vol. 220 (2), 152-163
- https://doi.org/10.1002/path.2649
Abstract
Ninety‐four percent of human genes are discontinuous, such that segments expressed as mRNA are contained within exons and separated by intervening segments, called introns. Following transcription, genes are expressed as precursor mRNAs (pre‐mRNAs), which are spliced co‐transcriptionally, and the flanking exons are joined together to form a continuous mRNA. One advantage of this architecture is that it allows alternative splicing by differential use of exons to generate multiple mRNAs from individual genes. Regulatory elements located within introns and exons guide the splicing complex, the spliceosome, and auxiliary RNA binding proteins to the correct sites for intron removal and exon joining. Misregulation of splicing and alternative splicing can result from mutations in cis‐regulatory elements within the affected gene or from mutations that affect the activities of trans‐acting factors that are components of the splicing machinery. Mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. An understanding of the role of splicing in disease expands potential opportunities for therapeutic intervention by either directly addressing the cause or by providing novel approaches to circumvent disease processes. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.This publication has 111 references indexed in Scilit:
- hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicingHuman Molecular Genetics, 2007
- Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypesJournal of Medical Genetics, 2007
- Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicingHuman Mutation, 2006
- Targeted Inhibition of the KLF6 Splice Variant, KLF6 SV1, Suppresses Prostate Cancer Cell Growth and SpreadCancer Research, 2005
- Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1Cancer Research, 2004
- Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophyNature Genetics, 2001
- CDKN2A germline splicing mutation affecting both p16ink4 and p14arf RNA processing in a melanoma/neurofibroma kindredGenes, Chromosomes and Cancer, 2001
- Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcriptsProceedings of the National Academy of Sciences of the United States of America, 1997
- Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistanceBritish Journal of Cancer, 1996
- bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell deathCell, 1993