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Review
. 2021;10(1):7-33.
doi: 10.3233/JHD-200429.

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington's Disease: A Historical Perspective

Darren G Monckton  1
Affiliations
Review

The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington's Disease: A Historical Perspective

Darren G Monckton. J Huntingtons Dis. 2021.

Abstract

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington's disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

Keywords: CAG repeat; DNA mismatch repair; Somatic expansion; anticipation; genotype to phenotype; mutation.

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Conflict of interest statement

D.G.M. has been a scientific consultant and/or received honoraria or stock options from Biogen Idec, AMO Pharma, Charles River, Vertex Pharmaceuticals, Triplet Therapeutics, LoQus23, and Small Molecule RNA and has had research contracts with AMO Pharma and Vertex Pharmaceuticals.

Figures

Fig.1
Fig.1
Timeline of some of the key events establishing anticipation as a genuine biological phenomenon and somatic expansion as contributing toward HD pathology.
See this image and copyright information in PMC

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