Journal article
A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease
Nature neuroscience, Vol.18(6), pp.807-816
06/2015
DOI: 10.1038/nn.4014
PMID: 25938884
Abstract
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.
Details
- Title: Subtitle
- A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease
- Creators
- Kristina Bečanović - 1] Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, SwedenAnne Nørremølle - Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, DenmarkScott J Neal - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaChris Kay - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaJennifer A Collins - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaDavid Arenillas - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaTobias Lilja - Department of Neuroscience, Karolinska Institutet, Stockholm, SwedenGiulia Gaudenzi - Department of Neuroscience, Karolinska Institutet, Stockholm, SwedenShiana Manoharan - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaCrystal N Doty - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaJessalyn Beck - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaNayana Lahiri - UCL Institute of Neurology, University College London, London, UKElodie Portales-Casamar - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaSimon C Warby - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaColúm Connolly - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaRebecca A G De Souza - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaSarah J Tabrizi - UCL Institute of Neurology, University College London, London, UKOla Hermanson - Department of Neuroscience, Karolinska Institutet, Stockholm, SwedenDouglas R Langbehn - Department of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa, USAMichael R Hayden - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaWyeth W Wasserman - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaBlair R Leavitt - Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, CanadaREGISTRY Investigators of the European Huntington's Disease Network
- Resource Type
- Journal article
- Publication Details
- Nature neuroscience, Vol.18(6), pp.807-816
- DOI
- 10.1038/nn.4014
- PMID
- 25938884
- NLM abbreviation
- Nat Neurosci
- ISSN
- 1097-6256
- eISSN
- 1546-1726
- Publisher
- United States
- Grant note
- MR/L012936/1 / Medical Research Council MR/L02053X/1 / Medical Research Council
- Language
- English
- Date published
- 06/2015
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984003404902771
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