DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich's ataxia patients.

BACKGROUND: The most frequent mutation of Friedreich's ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It's known that the length of GAA is directly correlated with disease severity. The effect of mutation is a severe reduction of mRNA. Recently, a link among aberrant CpG methylation, chromatin organization and GAA repeat was proposed. METHODS: In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of 5 CpG sites located within the region upstream of GAA repeat, in 67 FRDA patients. RESULTS: We confirm previous observation about differences in the methylation degree between FRDA individuals and controls. We showed a direct correlation between CpG methylation and triplet expansion size. Statistical significant differences were found for each CpG tested (ANOVA p< 0.001). These differences were largest for CpG1 and CpG2: 84.45 % and 76.80% respectively in FA patients compared to 19.65% and 23.34% in the controls. Most importantly, we found a strong inverse correlation between CpG2 methylation degree and age of onset (Spearman's rho = -0.550, p<0.001 ). CONCLUSION: Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance on the therapeutical approach of FRDA. Since the analysis can be performed in PBL, evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.