Journal Article

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

Castaldo, I, Giacchetti, M, Monticelli, A, Sacchetti, S, Filla, A, Avvedimento, V E, Pinelli, M, Cocozza, S, Keller, S, Acquaviva, F, Chiariotti, L

2008

Overview

Background:The most frequent mutation of Friedreich ataxia (FRDA) is the abnormal expansion of a GAA repeat located within the first intron of FXN gene. It is 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 organisation and GAA repeat was proposed.Methods:In this study, using pyrosequencing technology, we have performed a quantitative analysis of the methylation status of five 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. 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 FRDA 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 ρ  =  −0.550, p<0.001).Conclusion:Because epigenetic changes may cause or contribute to gene silencing, our data may have relevance for the therapeutic approach to FRDA. Since the analysis can be performed in peripheral blood leucocytes (PBL), evaluation of the methylation status of specific CpG sites in FRDA patients could be a convenient biomarker.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: Adolescent / Age / Age of Onset / Ataxia / Base Sequence / Biological and medical sciences / Child / Child, Preschool / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / DNA - genetics / DNA - metabolism / DNA Methylation / Enzymes / Frataxin / Friedreich Ataxia - epidemiology / Friedreich Ataxia - genetics / Fundamental and applied biological sciences. Psychology / Genetic testing / Genetics of eukaryotes. Biological and molecular evolution / Humans / Introns - genetics / Iron-Binding Proteins - genetics / Medical genetics / Medical sciences / Molecular and cellular biology / Molecular Sequence Data / Neurology / Trinucleotide Repeat Expansion - genetics / Young Adult