Research at the UCL Institute of Neurology, led by Paola Giunti, and the MRC National Institute for Medical Research, and published in the journal PloS Genetics, has shown how the length and the nature of gene repeat expansions affects spinocerebellar ataxia type 1 (SCA1).
These findings are significant for the genetic counselling and prognosis of people with SCA1 and were not possible with conventional diagnostic techniques.
At least nine of inherited neurodegenerative disorders, including Huntington’s disease share similar genetic causes and molecular mechanisms. They all involve a fault in their respective genes that consists of sections of the gene (CAG repeat) that repeat an abnormal number of times.
It is has been shown that patients with a longer number of repeats generally have a more severe condition and an earlier age at onset. In some patients, however, this is not the case, but the reason why was unknown.
This research team found that 11% of people with SCA1 have “interruptions” – short sections that break up the repeat expansions in the affected gene, ATXN1.
The research team was able to develop a genetic screening test that allowed them to divide their SCA1 patients into two groups based on whether or not their expanded repeat stretches in the ATXN1 gene contained an interruption.
In the participant sub-group, with interruptions, the research team found that their age at symptom onset is better predicted by the longest stretch of uninterrupted repeats rather than by the overall repeat length (including interruptions), as has previously been done.
“We recommend that diagnostic laboratories should use enzyme analysis to identify the presence of interruptions in expanded alleles,” said Dr Giunti.
“If an interruption is present, sequencing will allow better prediction of the age at onset in these patients. In addition, the diagnostic service at UCLH is currently looking into amending their repeat sizing calculations to account for the differences observed by the two different methods.”
This information will be important both for people who have ataxia and for people at risk of ataxia. It will be useful in diagnosis and counselling, particularly with respect to predicting people’s age at onset and the progression of their condition, as well as the probability of further genetic repeat expansion when transmitted to future generations.
In respect to the latter Dr Paola Giunti, lead author said:
“The interruption acts as a stabiliser, which is important as it is known that having the interruption will preclude further expansion in future generations, as the mutation in polyglutamine diseases is unstable through generations”.
“Without the contribution of the BRC, this research would not have been possible. With continued support, polyglutamine diseases can be looked at on the basis of this study, and here at UCL and UCLH we are in a privileged position to be able to do so”.
Read more:
Menon, P.R. et al. (2013) The Role of Interruptions in polyQ in the Pathology of SCA1. PLoS Genetics, 9(7), e1003648. DOI: 10.1371/journal.pgen.1003648