Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease characterized by relentlessly progressive gait and limb ataxia, absent tendon reflexes in the legs, electrophysiological evidence of axonal sensory neuropathy, hypertrophic cardiomyopathy, skeletal deformities, and increased risk of diabetes mellitus. Age of onset is usually before 25. Almost all patients are chairbound by the age of 45 years and no cure is available. The FRDA gene encodes a 210-aminoacid mitochondrial protein called frataxin. The most common mutation causing FRDA is the hyperexpansion of an intronic polymorphic GAA triplet repeat. As a consequence of the expansion, frataxin gene expression is reduced. Larger GAA expansion sizes correlate with earlier onset and increased severity of disease. Disruption of the yeast frataxin homolog gene (YFH1) impairs oxidative phosphorylation, causes mitochondrial iron accumulation and hypersensitivity to oxidative stress. Similar abnormalities may be occurring in the human disease. The present proposal encompasses the study of the molecular pathogenesis of FRDA from the DNA level to the clinical phenotype. The stability of GAA repeats of different length and orientation and their effect on the expression of a reporter gene will be evaluated in transgenic mice. An animal model of the disease will be established by generating frataxin-deficient mice. The molecular mechanisms of frataxin function, the perturbations to cell homeostasis that follow its deficiency, and the possibilities of pharmacological correction will be investigated in cultured cells and in the animal models. Pathological specimens from FRDA patients will be analyzed for evidence of mitochondrial iron accumulation, of oxidative damage, and of mitochondrial damage. Genotype-phenotype studies will be extended in order to: i) define the clinical variability and the core features of FRDA; ii) investigate in more detail the relation between GAA expansions, frataxin point mutations and clinical phenotype; iii) obtain additional population genetics data; iv) define the indications and limitations of genetic testing.
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