Hélène Puccio1, Delphine Simon1,
Mireille Cossée1, Paola Criqui-Filipe1, Francesco Tiziano2,
Judith Melki2, Colette Hindelang1, Robert Matyas1, Pierre Rustin3
& Michel Koenig1
Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histologicaland biochemical data from heart biopsies or autopsies of FRDA patients haveshown that frataxin defects cause a specific iron-sulfur protein deficiencyand intramitochondrial iron accumulation. We have recently shown thatcomplete absence of frataxin in the mouse leads to early embryoniclethality8,demonstrating an important role for frataxin during mouse development.Through a conditional gene-targeting approach, we have generated in parallela striated muscle frataxin-deficient line and a neuron/cardiac musclefrataxin-deficient line, which together reproduce important progressivepathophysiological and biochemical features of the human disease: cardiachypertrophy without skeletal muscle involvement, large sensory neurondysfunction without alteration of the small sensory and motor neurons, anddeficient activities of complexes I&endash;III of the respiratory chain and of theaconitases. Our models demonstrate time-dependent intramitochondrial ironaccumulation in a frataxin-deficient mammal, which occurs after onset of thepathology and after inactivation of the Fe-S dependent enzymes. Thesemutant mice represent the first mammalian models to evaluate treatmentstrategies for the human disease.
1. Institut de Génétique et de
Biologie Moléculaire et Cellulaire (IGBMC),
CNRS/INSERM/Université Louis Pasteur, B.P. 163, Illkirch, CU
de Strasbourg, France.
2. Laboratoire de Neurogénétique Moléculaire, INSERM E9913, GENOPOLE, Evry, France.
3. Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital des Enfants Malades, Paris, France.
the journal Nature Genetics, http://www.nature.com/ng/: volume 27 no. 2 pp 181 - 186