J Med Genet 42:737-748 doi:10.1136/jmg.2004.029538
  • Review

Splicing in action: assessing disease causing sequence changes

  1. D Baralle1,
  2. M Baralle2
  1. 1Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK
  2. 2International Centre for Genetic Engineering and Biotechnology, Trieste, Italy
  1. Correspondence to:
 Dr Diana Baralle
 Department of Medical Genetics, Box 134, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK;
  • Received 3 December 2004
  • Accepted 7 February 2005
  • Revised 2 February 2005


Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA splicing. These mutations can result in either complete skipping of the exon, retention of the intron, or the introduction of a new splice site within an exon or intron. Sometimes mutations that do not disrupt or create a splice site activate pre-existing pseudo splice sites, consistent with the proposal that introns contain splicing inhibitory sequences. These variants can also affect the fine balance of isoforms produced by alternatively spliced exons and in consequence cause disease. Available genomic pathology data reveal that we are still partly ignorant of the basic mechanisms that underlie the pre-mRNA splicing process. The fact that human pathology can provide pointers to new modulatory elements of splicing should be exploited.


  • Competing interests: none declared

  • The numbers used to designate the mutations refer to the coding sequence of the NF1 gene (accession number NM 000267). The symbols + or – designate upstream or downstream, respectively.