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PMID: 25938884 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature neuroscience ·Vol. 18 ·No. 6 ·2015-06-00 ·Pages 807-16

Bečanović K, Nørremølle A, Neal SJ, Kay C, Collins JA, Arenillas D, Lilja T, Gaudenzi G, Manoharan S, Doty CN, Beck J, Lahiri N, Portales-Casamar E, Warby SC, Connolly C, De Souza RA, REGISTRY Investigators of the European Huntington's Disease Network, Tabrizi SJ, Hermanson O, Langbehn DR, Hayden MR, Wasserman WW, Leavitt BR

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.

MeSH Terms
Adult Age of Onset Alleles Cohort Studies DNA/genetics Gene Expression Regulation/physiology Genes, Reporter/genetics Humans Huntingtin Protein Huntington Disease/genetics,metabolism,physiopathology Middle Aged Mutagenesis, Site-Directed NF-kappa B/metabolism Nerve Tissue Proteins/genetics,metabolism Polymorphism, Single Nucleotide/genetics Protein Binding
Chemicals
HTT protein, human Huntingtin Protein NF-kappa B Nerve Tissue Proteins DNA
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Bečanović Kristina
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.
Nørremølle Anne
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Neal Scott J ORCID
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Kay Chris
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Collins Jennifer A
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Arenillas David
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Lilja Tobias
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Gaudenzi Giulia
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Manoharan Shiana
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Doty Crystal N
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Beck Jessalyn
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Lahiri Nayana
UCL Institute of Neurology, University College London, London, UK.
Portales-Casamar Elodie
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Warby Simon C
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Connolly Colúm
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
De Souza Rebecca A G
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
REGISTRY Investigators of the European Huntington's Disease Network
Tabrizi Sarah J
UCL Institute of Neurology, University College London, London, UK.
Hermanson Ola
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Langbehn Douglas R
Department of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa, USA.
Hayden Michael R
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Wasserman Wyeth W
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Leavitt Blair R
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1546-1726
DOI
10.1038/nn.4014
Published
2015-06-00
Epub
2015-00-04
Pages
807-16
Language
English
Region
United States
NLM ID
9809671
Subset
IM
Grants
Medical Research Council · MR/L012936/1 · United Kingdom
External Links
PubMed source DOI: 10.1038/nn.4014 View journal details
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