The expansion mutation causes a severe reduction of the steady-state level of the FRDA transcript, encoding a novel protein that we named frataxin. Frataxin is a mitochondrial protein conserved through evolution. Mutation of the yeast frataxin homologue causes 10 fold mitochondrial iron accumulation, reminiscent of the cardiac iron deposits found in patients at autopsy. Iron accumulation suggests a pathogenic mechanism involving free radicals production and oxidative stress, a process that might be sensitive to anti-oxidant therapies. We have constructed frataxin knock-outs in the mouse.
Homozygous animals present early embryonic lethality.
The milder presentation of the Friedreich ataxia patients suggest that they synthesise low residual levels of the normal frataxin, which would be exlained by the unique intronic triplet repeat expansion mutation they all share. Embryonic resorption of the frataxin knock-out mice is reminiscent of the developpmental defect seen in vitamin E deficient pregnat rats, a suggests a common pathological mechanism by oxidative stress.