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

• Published in: Journal of Huntington's disease Vol. 10; no. 1; pp. 7 - 33
• Main Author: Monckton, Darren G.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2021; Sage Publications Ltd; IOS Press
• Subjects: Age; Animals; Anticipation, Genetic - genetics; Cell division; DNA repair; DNA Repair - genetics; Genetics - history; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Huntington Disease - genetics; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Mismatch repair; Polyglutamine; Review; Simple sequence repeats; Trinucleotide repeat diseases; Trinucleotide Repeat Expansion - genetics; Trinucleotide repeats; mutation; CAG repeat; anticipation; Somatic expansion; genotype to phenotype; DNA mismatch repair
• ISSN: 1879-6397; 1879-6397; 1879-6400
• DOI: 10.3233/JHD-200429

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.