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.
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We thank M. Hastings for comments on the manuscript, and members of the Krainer laboratory for many helpful discussions. This work was supported by NIH grants GM42699 and CA13106 (A.R.K.), by NIH grant HG01696 (M.Q.Z.), and by postdoctoral fellowships from the U.S. Army Medical Research and Matériel command (H.-X.L.) and the Human Frontiers Science Program (L.C.).
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Liu, H., Cartegni, L., Zhang, M. et al. A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nat Genet 27, 55–58 (2001) doi:10.1038/83762
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