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C01 Trinucleotide repeat instability in Huntington's disease
  1. B A Pepers1,2,
  2. J T den Dunnen1,3,
  3. G-J B van Ommen1,
  4. W M C van Roon-Mom1
  1. 1Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
  3. 3Leiden Genome Technology Centre, Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands


Background Trinucleotide repeat expansion is the cause of at least 25 inherited neurological disorders, including Huntington's disease (HD), fragile X mental retardation and myotonic dystrophy (DM1). An interesting feature of repeat expansion mutations is that they are genetically unstable, meaning that increased disease severity and decreased age of onset are observed as the mutation is transmitted from parent to offspring. Previous studies on SCA7 and DM1 have identified the cis acting DNA element CTCF to be implicated in the repeat expansion process. CTCF is a regulatory factor implicated in genomic imprinting, chromatin remodelling and DNA conformation change. Mutation or CpG methylation of CTCF binding sites promotes triplet repeat instability both in germline and somatic tissue.

Aim As binding sites for CTCF are associated with many highly unstable repeat loci, CTCF may also be involved in regulating genetic instability in HD.

Methods We have in silico identified putative CTCF binding sites in the HD locus. Confirmation of these CTCF binding sites will be achieved by gel mobility shift assays. Chromatin immunoprecipitation will be performed with a CTCF antibody followed by deep sequencing in two HD patient fibroblast cell lines and two wild-type cell lines. Newly found CTCF binding sites in the HD locus will be confirmed by real time PCR.

Conclusions Differential binding of CTCF to the HD locus could suggest that CTCF can act as a modulator in genetic repeat instability in HD.

  • repeat instability
  • CTCF
  • Huntington's disease

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