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Background  Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the  FXN  gene that results in epigenetic silencing of the  FXN  promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues.    Methodology / Principal Findings  The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human  FXN  gene with an expanded GAA triplet-repeat in intron 1, is deficient for  FXN  transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of  FXN  transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts.  FXN  promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse.    Conclusions / Significance  Deficient transcriptional initiation accounts for  FXN  transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.

FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia