Friedreich Ataxia: From GAA Triplet–Repeat Expansion to Frataxin Deficiency

Abstract

Friedreich ataxia (FRDA [MIM 229300]), the most prevalent inherited ataxia, is an autosomal recessive disease with onset in early childhood followed by an unremitting course that terminates with death in the fourth or fifth decade of life. It occurs at a frequency of 1–2 per 50,000 individuals. FRDA is characterized clinically by progressive gait and limb ataxia; signs of upper motoneuron dysfunction including dysarthria, areflexia, and loss of the senses of position and vibration; cardiomyopathy; diabetes mellitus; and secondary skeletal abnormalities. The majority (>95%) of patients with FRDA are homozygous for large expansions of a GAA triplet–repeat sequence (66–1800 triplets) located within the first intron of the gene X25, which encodes the protein frataxin (Campuzano et al. 1996). The expansion causes a severe reduction in the levels of frataxin, a 210–amino acid protein that is targeted to mitochondrial matrix and that appears to play a crucial role in iron homeostasis. The severity of the disease is directly correlated with the length of the expansion. A very small minority of patients are compound heterozygotes for the GAA expansion and for point mutations within the X25 gene. Chamberlain and coworkers have recently summarized all point mutations described to date (Pook et al. 2000). In this review, we will discuss recent developments that have increased our understanding of the effect of the GAA expansion on transcription and replication. Approaches used to investigate the unusual conformational properties of the GAA expansion and the unique behavior of the expansion in cultured cells will be described. Insights into the biogenesis of frataxin, including processing of the precursor protein and import into the mitochondria, will be summarized. We will describe advances made in the construction of mouse models for the disease. Finally, we will discuss important advances that have been made in deciphering the structure and function of frataxin, and we will conclude with prospects for therapy.