A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes
- 1 January 2001
- journal article
- letter
- Published by Springer Nature in Nature Genetics
- Vol. 27 (1), 55-58
- https://doi.org/10.1038/83762
Abstract
Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage caused by nonsense mutations1,2,3,4. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons (PTCs), targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS), and its underlying mechanism is unclear1,2,5,6. By analyzing NAS in BRCA1, we show here that inappropriate exon skipping can be reproduced in vitro, and results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by single nonsense, missense and translationally silent point mutations, without recognition of an open reading frame as such. These results argue against a nuclear reading-frame scanning mechanism for NAS. Coding-region single-nucleotide polymorphisms7 (cSNPs) within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene.Keywords
This publication has 26 references indexed in Scilit:
- Splicing Defects in the Ataxia-Telangiectasia Gene, ATM: Underlying Mutations and ConsequencesAmerican Journal of Human Genetics, 1999
- A Perfect MessageCell, 1999
- A BRCA1 Nonsense Mutation Causes Exon SkippingAmerican Journal of Human Genetics, 1998
- Nonsense Surveillance in Lymphocytes?Immunity, 1998
- Disruption of the splicing enhancer sequence within exon 27 of the dystrophin gene by a nonsense mutation induces partial skipping of the exon and is responsible for Becker muscular dystrophy.JCI Insight, 1997
- The Regulation of Splice-Site Selection, and Its Role in Human DiseaseAmerican Journal of Human Genetics, 1997
- The SR protein family: pleiotropic functions in pre-mRNA splicingTrends in Biochemical Sciences, 1996
- INTERRELATIONSHIPS OF THE PATHWAYS OF mRNA DECAY AND TRANSLATION IN EUKARYOTIC CELLSAnnual Review of Biochemistry, 1996
- The role of exon sequences in splice site selection.Genes & Development, 1993
- The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: Causes and consequencesHuman Genetics, 1992