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

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.

Automated summary

The discovery of unstable simple sequence repeats as the causative mutation for inherited human disorders such as Huntington's disease in the early 1990s opened up new insights into the genetic mechanisms underlying these diseases. Understanding the unstable nature of these repeats in both germline and somatic cells has shed light on the wide symptomatic variability observed in Huntington's disease and related disorders. These insights have also provided new avenues for potential therapies by targeting the somatic expansion of these repeats and identifying novel protein targets for intervention. Exciting prospects lie ahead in translating these findings into novel treatments for Huntington's disease and related disorders.