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

Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage c aused by nonsense mutations(1-4). In-frame nonsense codons located at a min imum distance upstream of the last exon-exon junction are recognized as pre mature termination codons (PTCs), targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during p re-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediate d 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 c an be reproduced in vitro, and results from disruption of a splicing enhanc er in the coding sequence. Enhancers can be disrupted by single nonsense, m issense and translationally silent point mutations, without recognition of an open reading frame as such. These results argue against a nuclear readin g-frame scanning mechanism for NAS. Coding-region single-nucleotide polymor phisms(7) (cSNPs) within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenot ypic variability and variable penetrance of mutations elsewhere in a gene.