DNA repair mechanism in the modulation of age onset of ataxia

A genetic study looking at the DNA repair mechanism in the modulation of age onset in a range of ataxias

Several spinocerebellar ataxias (SCAs), known as polyglutamine diseases, are caused by an expansion in the genes which cause the ataxia. In this group of SCAs the gene is extended because of extra copies of a series of nucleotides (identified by the letters CAG).

It has been known for some time that longer coding CAG repeat expansions are associated with earlier disease onset. However, the difference in age at onset is not always accounted for by CAG repeat length in the DNA, which implies the existence of additional modifying factors.

A study investigating genetic modifiers in Huntington’s disease (another polyglutamine disease caused by a similar genetic defect as these SCAs) has led to the identification of genes (acting in the DNA repair pathways) that can predispose for an earlier appearance of symptoms.

The research team at UCL has followed up this finding by looking at an independent cohort of polyglutamine diseases, including SCAs 1, 2, 3, 6, 7 and 17, and have confirmed the association of DNA repair genes with the age of onset in SCAs. With this current project, they plan to understand in more detail the molecular mechanisms behind it, with the eventual aim of finding ways of modifying the system and developing treatments.

The research team at UCL also plan to expand these findings to other ataxias (including Friedreich’s ataxia, SCA8 and SCA12). Another part of the project involves working on a large number
of samples from people with unidentified ataxias. As mutations in DNA repair genes are causal in some ataxias, the research team will see whether the cause of the ataxia in these patients involves the DNA repair genes.

This may lead to the identification of new genes which cause ataxia and thus specific diagnoses for patients. This project will be run by a PhD student under the co-supervision of Dr Bettencourt and Prof Henry Houlden at the Institute of Neurology and Dr Paola Giunti at the London Ataxia Specialist Centre, located in the same institute at UCL.

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Newsletter Ataxia UK, issue 197, spring 2017, page 6.