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Exon skipping through the creation of a putative exonic splicing silencer as a consequence of the cystic fibrosis mutation R553X
  1. Isabel Aznarez1,
  2. Julian Zielenski1,
  3. Johanna M Rommens1,
  4. Benjamin J Blencowe2,
  5. Lap-Chee Tsui3
  1. 1Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
  3. 3University of Hong Kong, Hong Kong
  1. Correspondence to:
 Dr L-C Tsui
 Vice Chancellor’s Office, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, Hong Kong; tsuilc{at}


Nonsense mutations that occur more than 50 bases upstream of terminal spliced junctions are generally thought to lead to degradation of the corresponding transcripts by the process of nonsense-mediated mRNA decay. It has also been proposed that some nonsense mutations may affect splicing by the process of nonsense-associated altered splicing (NAS), or by the disruption of a splicing regulatory element. In this study, the effect of the R553X mutation on the splicing of exon 11 of the cystic fibrosis transmembrane conductance regulator gene was investigated. Evidence that R553X causes exon 11 to skip through the creation of a putative exonic splicing silencer (ESS) was provided. The putative ESS appears to be active when located immediately upstream of a 5′ splice site. These findings argue against the possibility that R553X-associated exon 11 skipping is caused by NAS. The study further suggests that aminoglycoside antibiotic treatment would not be effective for patients with the R553X mutation, owing to the skipping of exon 11, and further emphasises the need for detailed mechanistic characterisation of the consequences of nonsense disease mutations.

  • CFTR, cystic fibrosis transmembrane conductance regulator
  • ESE, exonic splicing enhancer
  • ESS, exonic splicing silencer
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • HEK, human embryonic kidney
  • IB3, human bronchial epithelial
  • NAS, nonsense-associated altered splicing
  • NMD, nonsense-mediated mRNA decay
  • 2′OMeAO, 2′-O-methyl antisense oligonucleotides
  • PTC, premature termination codon
  • RT-PCR, reverse transcriptase-polymerase chain reaction

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  • Competing interests: None declared.