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Nat Neurosci. 2015 Jun;18(6):807-16. doi: 10.1038/nn.4014. Epub 2015 May 4.

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

Author information

1
1] Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. [2] Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
2
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
3
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
4
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
5
UCL Institute of Neurology, University College London, London, UK.
6
Department of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa, USA.

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.

PMID:
25938884
DOI:
10.1038/nn.4014
[Indexed for MEDLINE]

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