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

Becanovic, K; Norremolle, A; Neal, SJ; Kay, C; Collins, JA; Arenillas, D; Lilja, T; ... Leavitt, BR; + view all (2015) A SNP in the HTT promoter alters NF-kappa B binding and is a bidirectional genetic modifier of Huntington disease. Nature Neuroscience , 18 (6) pp. 807-816. 10.1038/nn.4014. Green open access

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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.

Type: Article
Title: A SNP in the HTT promoter alters NF-kappa B binding and is a bidirectional genetic modifier of Huntington disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nn.4014
Publisher version: http://dx.doi.org/ 10.1038/nn.4014
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Age-of-onset, Transcription Factor-binding, Yac128 Mouse Model, Cag Repeat, Hd Gene, P50/p65 Heterodimer, Sequence, Association, Expression, Polymorphism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1478529
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