Investigating the effects of CAG repeat structure and MSH3 variants on the molecular biology of Huntington's disease

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Huntington's disease (HD) is an inherited degenerative brain condition in which patients develop a mixture of symptoms including involuntary movements, changes in mood and behaviour, and dementia. The disease progresses slowly but relentlessly over 15-20 years, and is life-shortening. We have no treatments that can prevent or slow it. Patients often have complex care needs over a long period of time and these put a considerable strain on their carers and families, as well as on healthcare resources in general. Although HD is a rare condition (affecting about 1 in 8000 people in the UK), it is one of a family of over 30 diseases caused by expansion of repeating sections of DNA in genes. Together these conditions are estimated to affect over 3 million people worldwide (1 in 2000) at considerable human and economic cost. The genetic mutation causing HD was identified in 1993 but it is still unclear exactly how this leads to specific nerve damage and loss in the brain. The mutation consists of expansion of a repeating 'CAG' sequence in the DNA of the huntingtin gene. Unaffected people have between 9 and 35 CAG repeats; HD patients have at least 36, and generally the greater the number of repeats, the earlier the disease starts. The brain nerve cells that are most affected by the disease harbour more repeats than other cells in the same patient.All humans have over 20,000 genes that code for the different proteins required for life. Although we all have the same genes (they make us human) there are thousands of subtle differences between each of us in the exact sequences of these genes: together these differences make us individual. We have capitalised on these natural differences to identify rare gene variants in HD patients that lead to a surprisingly early or late onset of disease symptoms. Interestingly, these variants are found in the specific sequence of the disease-causing CAG repeat (for example, a repeat interrupted with extra CAA triplets is associated with much later disease onset) as well as in various DNA repair genes such as MSH3 and FAN1. These genes are usually involved in ensuring that cellular DNA is repaired after damage, but they are now implicated in expansion/contraction of CAG repeats and hence HD.In this MRC-NIH partnering project we will test these novel protein variants in DNA binding and repair reactions to see whether there are measurable differences between those associated with early or late onset HD. If we can show differences that match our genetic data this will enable us to understand the molecular reactions underpinning HD in much more detail- and this will accelerate the discovery of novel drug targets. This partnering project benefits from combining novel genetic insights with established expertise in biochemical tests and so stands to generate significant impact in understanding what drives HD.