Genetic Variants Explain Differences in Age Of Onset Of Huntington’s Disease Symptoms

Kristina Bečanovič Ph.D.

Photo: Ulf Sirborn Interview with:
Kristina Bečanovič Ph.D.
Department of Clinical Neuroscience
Karolinska Institutet, Stockholm, Sweden

Medical Research: What is the background for this study?

Dr. Bečanović: While the symptoms normally debut in middle-age, there is wide individual variation in how Huntington disease manifests itself, and even though two people carry the exact same genetic mutation that codes for the huntingtin protein, there can be up to a 20-year difference in onset of motor symptoms. This suggests that genetic variants, transcription factors and environmental factors could contribute to the observed differences in disease expressivity. As the identification of regulatory factors of the huntingtin gene would be targets for therapeutic intervention, we set out to study the regulation of the huntingtin gene as it has not been well-known which factors regulate the expression levels. We were interested in identifying both genetic variants and transcription factors that are of importance for gene regulation. We therefore used DNA from Huntington disease patients to study the regulation of the huntingtin gene promoter in cells.

Medical Research: What are the main findings?

Dr. Bečanović: This study presents multiple findings that are of potential interest for clinicians, patients and other researchers.

Most people who develop Huntington’s disease have a normal and a mutated huntingtin gene. In the present study, we found that when the genetic variant was on the gene copy that codes for the normal Huntingtin protein, the patients developed motor symptoms on average four years earlier than expected; on the other hand, the genetic variant had a protective effect when sitting on the gene copy that codes for the mutated protein, which is toxic for the brain. These patients developed their motor symptoms on average ten years later than expected. We showed that NF-ĸB which is known to be a central player in the inflammatory response, acts as a transcription factor regulating huntingtin gene expression, but that the genetic variant hindered the binding of NF-ĸB which led to lower levels of the huntingtin protein.This study suggests that the genetic variant therefore leads to lower levels of the normal or the mutated protein depending on which gene copy it sits on, and that this explains the differences in disease onset. Our results emphasize the importance of “allelic imbalance”, where the yin-yang relationship of the normal and the mutant Huntingtin protein is of significance, and when altered, affects the Huntingtons’s disease age of onset in patients.

Medical Research: What should clinicians and patients take away from your report?

Dr. Bečanović: Our findings are important for the development of disease-modifying treatments, which not only reduce the symptoms but also protect the brain. Much research has gone into silencing the expression of the huntingtin protein, something that will be tested in patients within the near future. Our work is the first to support the claim that this type of therapy could help people with Huntington’s disease by slowing the progression of the disease. This work further supports continued efforts on allele-specific silencing approaches in Huntington’s disease. This work also suggests the identified genetic variant to be used as a prognostic marker in Huntington’s disease patients.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Bečanović: In this study we went from identifying molecular mechanisms, to showing that this specific genetic variant affects the disease onset in Huntington disease patients. Our study therefore supports continued efforts in the identification of genetic variants, and transcription- and environmental factors that affect gene expression. Differential gene expression contributes to differential disease expressivity. We need to increase our knowledge about these factors to enable the development of disease-modifying therapeutics, not only for Huntington disease, but also for other neurodegenerative diseases.


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, REGISTRY Investigators of the European Huntington’s Disease Network,
Sarah J Tabrizi, Ola Hermanson, Douglas R Langbehn, Michael R Hayden, Wyeth W Wasserman & Blair R Leavitt

Nature Neuroscienc (2015) doi:10.1038/nn.40


[wysija_form id=”3″] Interview with:, & Kristina Bečanovič Ph.D. (2015). Genetic Variants Explain Differences in Age Of Onset Of Huntington’s Disease Symptoms

Last Updated on May 12, 2015 by Marie Benz MD FAAD