A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes

Liu, H. X., Cartegni, L., Zhang, M. Q., Krainer, A. R. (January 2001) A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genetics, 27 (1). pp. 55-58. ISSN 1061-4036

URL: http://www.ncbi.nlm.nih.gov/pubmed/11137998
DOI: 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 mutations(1-4). 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 unclear(1,2,5,6). 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 polymorphisms(7) (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.

Item Type: Paper
Uncontrolled Keywords: pre-messenger-rna splice-site selection single-nucleotide polymorphisms sr proteins enhancer sequences identification elements surveillance consequences
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon skipping
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > pre-mRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL labs > Zhang lab
Depositing User: Matt Covey
Date: January 2001
Date Deposited: 11 Dec 2013 19:36
Last Modified: 11 Dec 2013 19:36
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28908

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