A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.
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.
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.
Kristina
K
Bečanović
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Anne
A
Nørremølle
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Scott J
000000021031077X
SJ
Neal
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Chris
C
Kay
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Jennifer A
JA
Collins
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
David
D
Arenillas
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Tobias
T
Lilja
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Giulia
G
Gaudenzi
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Shiana
S
Manoharan
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Crystal N
CN
Doty
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Jessalyn
J
Beck
UCL Institute of Neurology, University College London, London, UK.
Nayana
N
Lahiri
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Elodie
E
Portales-Casamar
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Simon C
SC
Warby
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Colúm
C
Connolly
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Rebecca A G
RA
De Souza
UCL Institute of Neurology, University College London, London, UK.
Sarah J
SJ
Tabrizi
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Ola
O
Hermanson
Department of Psychiatry and Biostatistics, University of Iowa, Iowa City, Iowa, USA.
Douglas R
DR
Langbehn
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Michael R
MR
Hayden
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Wyeth W
WW
Wasserman
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Blair R
BR
Leavitt
D000328:Adult; D017668:Age of Onset; D000483:Alleles; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding
C086055:HTT protein, human; D000071058:Huntingtin Protein; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D004247:DNA