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.
Tuesday, April 5, 2022
DNA methylation in Friedreich ataxia silences expression of frataxin isoform E
Layne N. Rodden, Kaitlyn M. Gilliam, Christina Lam, Teerapat Rojsajjakul, Clementina Mesaros, Chiara Dionisi, Mark Pook, Massimo Pandolfo, David R. Lynch, Ian A. Blair & Sanjay I. Bidichandani. Sci Rep 12, 5031 (2022). https://doi.org/10.1038/s41598-022-09002-5
