Frataxin (FXN) gene GAA repeat expansion (FXN GAA expansion)

The GAA repeat expansion in the first intron of the Frataxin (FXN) gene is the primary molecular cause of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disorder [1.1.2, 1.3.3]. In healthy individuals, this GAA tract typically contains 5 to 33 repeats, whereas in FRDA patients, it expands to hundreds or even thousands of repeats [1.3.1, 1.4.2]. These expanded repeats trigger the formation of non-B DNA structures, such as H-DNA triplexes and R-loops, and recruit repressive epigenetic marks that lead to heterochromatin formation and transcriptional silencing of the FXN gene [1.1.1, 1.3.2]. The resulting deficiency in the mitochondrial protein frataxin disrupts iron-sulfur cluster biogenesis and mitochondrial iron homeostasis, leading to oxidative stress and progressive cellular damage in the nervous system and heart [1.2.1, 1.5.3]. Therapeutic approaches targeting this expansion include histone deacetylase (HDAC) inhibitors to reverse epigenetic silencing, anti-gene oligonucleotides to disrupt inhibitory DNA structures, and CRISPR-based gene editing to excise the repeats [1.1.3, 1.3.1, 1.5.2]. While omaveloxolone is currently the only FDA-approved treatment for FRDA, it targets downstream pathways; thus, direct modulation of the FXN GAA expansion remains a critical goal for achieving disease modification [1.3.2, 1.5.2].

Other names

GAA trinucleotide repeat expansionFXN triplet repeatFriedreich's ataxia repeatGAA·TTC expansionFrataxin gene expansion

Mechanisms include epigenetic reactivation of the FXN gene via histone deacetylase (HDAC) inhibition, transcriptional upregulation through the disruption of inhibitory non-B DNA structures (H-DNA and R-loops), and Nrf2 pathway activation to mitigate downstream oxidative stress and mitochondrial dysfunction.