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Review
. 2021;10(1):175-202.
doi: 10.3233/JHD-200445.

What is the Pathogenic CAG Expansion Length in Huntington's Disease?

Jasmine Donaldson  1 , Sophie Powell  1 , Nadia Rickards  1 , Peter Holmans  1 , Lesley Jones  1
Affiliations
Review

What is the Pathogenic CAG Expansion Length in Huntington's Disease?

Jasmine Donaldson et al. J Huntingtons Dis. 2021.

Abstract

Huntington's disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds- the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70- 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60- 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.

Keywords: DNA repair; DNA repeat expansion; Huntington’s disease; spinocerebellar ataxias; trinucleotide repeat.

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Conflict of interest statement

LJ is a member of the Scientific Advisory Boards of LoQus23 Therapeutics and Triplet Therapeutics. JD, SP, NR and PH have no conflicts of interest.

Figures

Fig. 1
Fig. 1
A model for the pathogenic threshold in HD. A) HD pathogenesis is largely determined by an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within exon 1 of the huntingtin (HTT) gene, which is translated into an expanded polyglutamine tract in the corresponding HTT protein. Wild-type HTT possesses 5– 35 CAG repeats (non-expanded HTT gene), and can undergo expansion into the disease range in the germline to create apparent de novo HD subjects, but ≥36 + repeats is associated with a significantly increased risk of developing HD (expanded HTT gene). B) An expanded HTT allele with 36 or more repeats is unstable and licenced to further expand in cells over the lifespan of the HD at-risk individual. HD symptoms would manifest and progress as increasing numbers of disease-relevant cells undergo somatic expansion beyond an unknown intracellular pathogenic threshold that renders the gene toxic in those cells. Figures created using BioRender.com. Figure 1A adapted from a figure by National Institute of General Medical Sciences, National Institutes of Health.
Fig. 2
Fig. 2
Potential relationship of CAG tract expansion and clinical Huntington’s disease events. The premanifest period of the disease may reflect the presence of a proportion of disease-relevant cells with sufficient somatic expansion to induce neuronal dysfunction, but too few to manifest overt clinical symptoms. Premanifest HD includes a presymptomatic period where no signs or symptoms are present, and prodromal HD, characterised by the onset of subtle signs and symptoms, which may be the result of the HTT CAG length expanding beyond an unknown pathogenic threshold in increasing numbers of disease-relevant cells. Manifest HD— characterised by chorea and gradual worsening of motor and cognitive difficulties— may then arise once a significant number of disease-relevant cells have passed this threshold. Somatic expansion in susceptible cell populations is likely to be occurring throughout the premanifest and prodromal stages of disease as indicated by the hypothetical dashed line, although the actual trajectory of this expansion will depend on the inherited repeat length and is likely to differ in different cell types. Therefore, the relationship between the trajectory of somatic expansion and clinical phenotypes is currently hypothetical. Figure adapted from Ross et al. [45] and Bates et al. [3] and created using BioRender.com.
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References

    1. Hannan AJ. Tandem repeats mediating genetic plasticity in health and disease. Nat Rev Genet. 2018;19(5):286–98. - PubMed
    1. Khristich AN, Mirkin SM. On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability. J Biol Chem. 2020;295(13):4134–70. - PMC - PubMed
    1. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. Huntington disease. Nat Rev Dis Prim. 2015;1(1):15005. - PubMed
    1. Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci. 2007;30(1):575–621. - PubMed
    1. Coutelier M, Coarelli G, Monin ML, Konop J, Davoine CS, Tesson C, et al. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelo-pathies. Brain. 2017;140(6):1579–94. - PubMed

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