Genetic Modifiers in Huntington Disease

Abstract

Huntington disease (HD) is a neurodegenerative disorder that is caused by an elongation of a normally occurring polyglutamine stretch within the huntingtin (HTT) protein. Since the mutation was first identified, multiple HD‐disease‐modifying gene candidates that can hasten or delay age of onset (AO) have been discovered. For the past several decades, candidate disease‐modifying genes have been chosen for investigation based on functionality or prior implication in the disease process. More recent approaches take advantage of newly available genomic‐wide assays to identify changes as small as single‐nucleotide polymorphisms (SNPs) in other parts of the genome. New information regarding disease‐modifying genes will continue to elucidate potential HD therapeutic candidates.

Key Concepts

  • Huntington disease is a neurodegenerative disease that results from excess CAG trinucleotide repeats in exon 1 of the HD gene, which is located in chromosome 4p16.3 and encodes the HTT protein.
  • The number of CAG repeats in the HD gene inversely affects the age of onset (AO) in HD patients.
  • Genetic modifiers are identified genes that have the ability to either hasten or delay AO of HD; however, the exact mechanism of many of these genes in association with the disease is unknown.
  • HD genetic modifiers can significantly delay specific physiological HD symptoms, such as chorea.
  • Some HD genetic modifiers can alter HD AO by up to 8 years.
  • Genetic modifiers have been discovered by either the candidate approach, which involves exploring genes known to be associated with the HTT protein and genotyping any variants, or via a more unbiased genomic approach, which involves a broad search for genes that are not known to be associated with the HTT protein.
  • Modifiers that affect HD do not necessarily need to be within close vicinity of the actual gene, but can be distributed elsewhere in the genome, even in noncoding regions.

Keywords: genome wide association; gain of function; loss of function; polyglutamine repeat disease; age of onset; huntingtin (HTT); chorea; genetic disease modifiers; Huntington disease (HD); triplet repeat disorder

Figure 1. Huntington disease is characterised by alterations in motor control, cognitive function and emotional well‐being.
Figure 2. Age of onset (AO) is strongly correlated with the number of CAG repeats found in HD exon 1. An increase in CAG repeats results in an earlier AO in HD patients. See also: Huntington Disease
Figure 3. Polymorphisms in other genes found on human chromosome 4 can affect HD age of onset, including MSX1, PPARGC1A and UCHL1. UCHL1 has been shown to function as a genetic modifier of HD in some populations (Metzger et al., ), but not in others (Andresen et al., ).
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Further Reading

Hmida‐Ben Brahim D, Chourabi M, Amor S, Harrabi I, et al. (2014) Modulation at age of onset in Tunisian Huntington disease patients: implication of new modifier genes. Genetic Research International 210418: 1–5.

Kaltenbach LS, Romero E, Becklin RR, et al. (2007) Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genetics 3 (5).

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Metzger S, Walter C, Riess O, et al. (2013) The V471A polymorphism in autophagy‐related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLoS One 8 (7): e68951.

Miller JP and Hughes RE (2011) Protein interactions and target discovery in Huntington's disease. In: Lo DC and Hughes RE (eds) Neurobiology of Huntington's Disease: Applications to Drug Discovery, pp. 55–76. Boca Raton, FL: CRC Press.

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Clabough, Erin BD, Thompson, Jefferson C, Lau, James H, Savarese, Melchior F, Harris, Evan C, Manos, Sean T, Kyle, Charles T, Meinhardt, John T, Sheffield, John W, Boudin, Michael D, Abdi, Myshake S, Mohay, John AS, Harriss, Robert W, Luck, Mason E, Owens, Alan M, and Britt, John W(Feb 2016) Genetic Modifiers in Huntington Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026547]