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

Nat Genet. 2001 Jan;27(1):55-8. doi: 10.1038/83762.


Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage caused by nonsense mutations. 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. 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 (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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Substitution / genetics
  • BRCA1 Protein / chemistry
  • BRCA1 Protein / genetics
  • Base Sequence
  • Codon, Nonsense / genetics*
  • Enhancer Elements, Genetic / genetics
  • Exons / genetics*
  • Genes, BRCA1 / genetics*
  • Humans
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Nuclear Proteins / chemistry
  • Open Reading Frames / genetics
  • Phenotype
  • Phosphoproteins / chemistry
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins
  • Serine-Arginine Splicing Factors


  • BRCA1 Protein
  • Codon, Nonsense
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Serine-Arginine Splicing Factors