Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state

Biochem Biophys Res Commun. 2018 Jun 2;500(2):163-169. doi: 10.1016/j.bbrc.2018.04.015. Epub 2018 Apr 9.


Cockayne syndrome (CS) is a severe disorder with no effective treatment. The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UVSS), a disorder that causes mild symptoms. How the CSB gene determines a patient's fate is unknown, but one intriguing point is that in UVSS patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region. In contrast, in CS patient cells, there is at least one allele with several mutations downstream of the PGBD3 inserted region, or there are homozygous mutations in exon 1. Here, we designed and synthesized 24 splice switching oligonucleotides (SSOs) to skip exon 3 in CSB mRNA. Use of these SSOs induced a frame shift in order to generate an alternative stop codon at the upstream region of the PGBD3 invasion site. As a result, a reduction of mitochondrial membrane potential following H2O2 treatment in CS cell was recovered. It was demonstrated that up-regulation of several gene expression brought about by SSOs are related to mitochondrial dysfunction in CS cells.

Keywords: Antisense oligonucleotides; Cockayne syndrome; DNA repair; Exon skipping; UV sensitive syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cockayne Syndrome / genetics*
  • Cockayne Syndrome / pathology*
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism
  • DNA Repair Enzymes / genetics*
  • DNA Repair Enzymes / metabolism
  • Exons
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Membrane Potential, Mitochondrial
  • Oligonucleotides / metabolism*
  • Poly-ADP-Ribose Binding Proteins / genetics*
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transfection
  • Ultraviolet Rays


  • Oligonucleotides
  • Poly-ADP-Ribose Binding Proteins
  • RNA, Messenger
  • Hydrogen Peroxide
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes