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Publication Detail

Title: DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Authors: Rodden, Layne N; Gilliam, Kaitlyn M; Lam, Christina; Rojsajjakul, Teerapat; Mesaros, Clementina; Dionisi, Chiara; Pook, Mark; Pandolfo, Massimo; Lynch, David R; Blair, Ian A; Bidichandani, Sanjay I

Published In Sci Rep, (2022 Mar 23)

Abstract: Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. In a series of FRDA patients, deficiency of frataxin-E protein correlated with the length of the expanded GAA triplet-repeat, and with repeat-induced DNA hypermethylation that occurs in close proximity to the intronic origin of FXN-E. CRISPR-induced epimodification to mimic DNA hypermethylation seen in FRDA reproduced FXN-E transcriptional deficiency. Deficiency of frataxin E is a consequence of FRDA-specific epigenetic silencing, and therapeutic strategies may need to address this deficiency.

PubMed ID: 35322126 Exiting the NIEHS site

MeSH Terms: Animals; DNA Methylation; DNA/metabolism; Friedreich Ataxia*/genetics; Humans; Iron-Binding Proteins/genetics; Iron-Binding Proteins/metabolism; Mice; Protein Isoforms/metabolism; Trinucleotide Repeat Expansion

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