X-ray crystallography has shown that human frataxin consists of a β-sheet that supports a pair of parallel α-helices, forming a compact αβ sandwich.

[9] Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart).

Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat in the FXN gene, which encodes the protein frataxin.).

In the typical case, the length of the allele with the shorter GAA expansion inversely correlates with frataxin levels.

[18] Although nearly all organisms express a frataxin homologue, the GAA repeat in intron 1 only exists in humans and other primates, so the mutation that causes FDRA can't occur naturally in other animals.

One approach is to silence frataxin expression in just one specific tissue type of interest: the heart (mice modified this way are called MCK), all neurons (NSE), or just the spinal cord and cerebellum (PRP).

[19] Another approach involves inserting a GAA expansion into the first intron of the mouse FXN gene, which should inhibit frataxin production, just like in humans.

The final approach involves creating transgenic mice with a GAA-expanded version of the human frataxin gene.

This restored expression of the frataxin gene was accompanied by a substantial reduction in the number of DNA double-strand breaks.

[21] The impaired frataxin in FRDA cells appears to cause reduced capacity for repair of DNA damage and this may contribute to neurodegeneration.