Reduced levels of
frataxin, an essential
mitochondrial protein involved in the regulation of
iron-
sulfur cluster biogenesis, are responsible for the recessive neurodegenerative
Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential for disease development which causes partial silencing of
frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the
frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94-2, with a history of alcohol and
drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of
frataxin. Our study reveals no impairment of the structure or activity of the
protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the
protein concentration in the patient and discuss the possible mechanism of disease.