par Rodden, Layne L.N.;Gilliam, Kaitlyn K.M.;Lam, Christina;Rojsajjakul, Teerapat;Mesaros, Clementina;Dionisi, Chiara
;Pook, Mark;Pandolfo, Massimo
;Lynch, David D.R.;Blair, Ian I.A.;Bidichandani, Sanjay S.I.
Référence Scientific reports, 12, 1, 5031
Publication Publié, 2022-12
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![](/vufind/images/ULB/publications_list.png)
Référence Scientific reports, 12, 1, 5031
Publication Publié, 2022-12
Article révisé par les pairs
Résumé : | 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. |