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A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease

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  • Kristina Bečanović
  • Anne Nørremølle
  • Scott J Neal
  • Chris Kay
  • Jennifer A Collins
  • David Arenillas
  • Tobias Lilja
  • Giulia Gaudenzi
  • Shiana Manoharan
  • Crystal N Doty
  • Jessalyn Beck
  • Nayana Lahiri
  • Elodie Portales-Casamar
  • Simon C Warby
  • Colúm Connolly
  • Rebecca A G De Souza
  • Sarah J Tabrizi
  • Ola Hermanson
  • Douglas R Langbehn
  • Michael R Hayden
  • Wyeth W Wasserman
  • Blair R Leavitt
  • REGISTRY Investigators of the European Huntington's Disease Network (Joergen E Nielsen, member)
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Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.

Original languageEnglish
JournalNature Neuroscience
Volume18
Issue number6
Pages (from-to)807-16
Number of pages10
ISSN1097-6256
DOIs
Publication statusPublished - Jun 2015

    Research areas

  • Adult, Age of Onset, Alleles, Cohort Studies, DNA, Gene Expression Regulation, Genes, Reporter, Humans, Huntington Disease, Middle Aged, Mutagenesis, Site-Directed, NF-kappa B, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein Binding

ID: 46262268