Methylated and unmethylated epialleles support variegated epigenetic silencing in Friedreich ataxia.

ABSTRACT: Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat in intron 1 of the FXN gene, which results in transcriptional deficiency via epigenetic silencing. Most patients are homozygous for alleles containing >?500 triplets, but a subset (~20%) have at least one expanded allele with ?500 triplets, a significantly higher prevalence of unmethylated epialleles (median=9.8%) was observed in patients with at least one allele containing 20%) and later onset (>15y). The higher prevalence in mild FRDA of somatic FXN epialleles devoid of DNA methylation is consistent with variegated epigenetic silencing mediated by expanded triplet-repeats. The proportion of unsilenced somatic FXN genes is an unrecognized phenotypic determinant in FRDA, and has implications for the deployment of effective therapies.

SUBMITTER: Rodden LN 

PROVIDER: S-EPMC7861014 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature