Background Age at onset (AO) of Huntington’s disease (HD) usually occurs in midlife and it is strongly associated with the length of CAG expansion. However, a variation in the AO has been observed between individuals carrying comparable numbers of (CAG)n repeats. It has led to the search of the modifying factors impacting the variation in the AO, with the genetic imprinting suggested as a potential factor. Interestingly, the epigenetic modifications have been found to play a role in the pathogenesis of other neurodegenerative disorders associated with expanded trinucleotide repeats, e.g. fragile X syndrome and Friedreich’s ataxia.
Aim The aim of the study is to investigate whether DNA methylation status including genetic imprinting is involved in pathogenesis, in particular the AO of HD. This issue is addressed by examining what proportion of variation in the AO is explained by the parental sex in a population of HD patients with the dominant impact of (CAG)n repeats included in statistical analyses. Further, DNA methylation status of selected regions is analysed in both HD patients and healthy subjects.
Methods/techniques Nested regression models are used to assess the proportion of variation in the AO explained by the parental sex. Gene methylation levels are determined in DNA extracted from the whole blood by using CpG methylation-sensitive enzyme digestion followed by qPCR.
Results No differences in DNA methylation within the HTT promoter between HD patients and healthy subjects have been found to date. Further analyses to evaluate the hypothesis are conducted.
Conclusions To our best knowledge this is the first study to examine a question as to whether DNA methylation status including genetic imprinting will add to an impact of (CAG)n repeat to the variation in the AO in HD. We believe that our research may contribute considerable insight into the molecular mechanism of HD.
This project is funded by National Research Centre, Poland, No UMO-2011/03/B/NZ2/01422.
- DNA methylation
- genetic imprinting
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