Objective: To compare methylation profiles of non-CpG sites in the FXNgene in patients with Friedreich’s ataxia (FA), their heterozygous relatives and a healthy control group.

Background: FA is the most common hereditary ataxia. It is most frequently associated with homozygous GAA repeats expansion in intron 1 of the FXNgene. It is known that the clinical picture of FA depends on the size of the GAA expansion and the methylation profile of the CpG sites. However, methylation profile of non-CpG sites is not well understood and may play a role in the pathogenesis of FA.

Method: We analyzed DNA samples from patients with FA (n=35), their relatives carrying heterozygous GAA expansion (n=23), and healthy age- and sex-matched control group (n=28). Pattern of methylation was studied by direct sequencing of DNA after bisulphide processing of two regions of the FXNgene: promoter containing two non-CpG sites and a 252-bp sequence downstream of the (GAA)n repeats containing 15 non-CpG sites.

Results: In the FXN promoter all non-CpG sites showed significantly lower methylation in FA compared to control samples. All non-CpG sites in the downstream region showed significantly higher methylation in heterozygous GAA carriers compared to FA patients. Some downstream sites showed lower methylation in FA compared to the other two groups. Negative correlations between the methylation rate of some non-CpG sites and the smaller GAA1 allele length were also detected.

Conclusion: This is the first data on the non-CpG methylation pattern in the FXN gene in patients with FA and their heterozygous relatives. The methylation of non-CpG sites depends on the length of the GAA-repeats expansion and may affect the expression of FXN gene, which requires further studies. The study was supported by RSF #17-75-20211.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/non-cpg-methylation-in-the-fxn-gene-in-patients-with-friedreichs-ataxia/