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DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients.
J Med Genet. 2008 Dec; 45(12):808-12.JM

Abstract

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 rho = -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.

Authors+Show Affiliations

Department of Cellular and Molecular Biology and Pathology, University of Naples Federico II, via Pansini 5, 80131, Naples, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18697824

Citation

Castaldo, I, et al. "DNA Methylation in Intron 1 of the Frataxin Gene Is Related to GAA Repeat Length and Age of Onset in Friedreich Ataxia Patients." Journal of Medical Genetics, vol. 45, no. 12, 2008, pp. 808-12.
Castaldo I, Pinelli M, Monticelli A, et al. DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients. J Med Genet. 2008;45(12):808-12.
Castaldo, I., Pinelli, M., Monticelli, A., Acquaviva, F., Giacchetti, M., Filla, A., Sacchetti, S., Keller, S., Avvedimento, V. E., Chiariotti, L., & Cocozza, S. (2008). DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients. Journal of Medical Genetics, 45(12), 808-12. https://doi.org/10.1136/jmg.2008.058594
Castaldo I, et al. DNA Methylation in Intron 1 of the Frataxin Gene Is Related to GAA Repeat Length and Age of Onset in Friedreich Ataxia Patients. J Med Genet. 2008;45(12):808-12. PubMed PMID: 18697824.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DNA methylation in intron 1 of the frataxin gene is related to GAA repeat length and age of onset in Friedreich ataxia patients. AU - Castaldo,I, AU - Pinelli,M, AU - Monticelli,A, AU - Acquaviva,F, AU - Giacchetti,M, AU - Filla,A, AU - Sacchetti,S, AU - Keller,S, AU - Avvedimento,V E, AU - Chiariotti,L, AU - Cocozza,S, Y1 - 2008/08/12/ PY - 2008/8/14/pubmed PY - 2009/2/3/medline PY - 2008/8/14/entrez SP - 808 EP - 12 JF - Journal of medical genetics JO - J Med Genet VL - 45 IS - 12 N2 - 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 rho = -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. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/18697824/DNA_methylation_in_intron_1_of_the_frataxin_gene_is_related_to_GAA_repeat_length_and_age_of_onset_in_Friedreich_ataxia_patients_ L2 - https://jmg.bmj.com/lookup/pmidlookup?view=long&amp;pmid=18697824 DB - PRIME DP - Unbound Medicine ER -