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

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

doi:10.1038/nn.4014

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

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 HaydenWyeth W Wasserman, Blair R Leavitt, REGISTRY Investigators of the European Huntington's Disease Network

Medical Genetics Program

58 Citations (Scopus)

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.

Original language	English
Journal	Nature Neuroscience
Volume	18
Issue number	6
Pages (from-to)	807-816
Number of pages	10
ISSN	1097-6256
DOIs	https://doi.org/10.1038/nn.4014
Publication status	Published - 28 Jun 2015

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Bečanović, K., Nørremølle, A., Neal, S. J., Kay, C., Collins, J. A., Arenillas, D., Lilja, T., Gaudenzi, G., Manoharan, S., Doty, C. N., Beck, J., Lahiri, N., Portales-Casamar, E., Warby, S. C., Connolly, C., De Souza, R. A. G., Tabrizi, S. J., Hermanson, O., Langbehn, D. R., ... REGISTRY Investigators of the European Huntington's Disease Network (2015). A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nature Neuroscience, 18(6), 807-816. https://doi.org/10.1038/nn.4014

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, RAG, Tabrizi, SJ, Hermanson, O, Langbehn, DR, Hayden, MR, Wasserman, WW, Leavitt, BR & REGISTRY Investigators of the European Huntington's Disease Network 2015, '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, pp. 807-816. https://doi.org/10.1038/nn.4014

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

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.",

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AU - Bečanović, Kristina

AU - Nørremølle, Anne

AU - Neal, Scott J

AU - Kay, Chris

AU - Collins, Jennifer A

AU - Arenillas, David

AU - Lilja, Tobias

AU - Gaudenzi, Giulia

AU - Manoharan, Shiana

AU - Doty, Crystal N

AU - Beck, Jessalyn

AU - Lahiri, Nayana

AU - Portales-Casamar, Elodie

AU - Warby, Simon C

AU - Connolly, Colúm

AU - De Souza, Rebecca A G

AU - Tabrizi, Sarah J

AU - Hermanson, Ola

AU - Langbehn, Douglas R

AU - Hayden, Michael R

AU - Wasserman, Wyeth W

AU - Leavitt, Blair R

AU - REGISTRY Investigators of the European Huntington's Disease Network

PY - 2015/6/28

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N2 - 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.

AB - 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.

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DO - 10.1038/nn.4014

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JO - Nature Neuroscience

JF - Nature Neuroscience

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ER -

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

Abstract

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