Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is ca used in almost all cases by homozygous intronic expansions resulting in the loss of frataxin, a mitochondrial protein conserved through evolution, and involved in mitochondrial iron homeostasis. Yeast knockout models, and his tological and biochemical data from patient heart biopsies or autopsies ind icate that the frataxin defect causes a specific iron-sulfur protein defici ency and mitochondrial iron accumulation leading to the pathological change s. Affected human tissues are rarely available to further examine this hypo thesis. To study the mechanism of the disease, we generated a mouse model b y deletion of exon 4 leading to inactivation of the Frda gene product. We s how that homozygous deletions cause embryonic lethality a few days after im plantation, demonstrating an important role for frataxin during early devel opment. These results suggest that the milder phenotype in humans is due to residual frataxin expression associated with the expansion mutations. Surp risingly, in the frataxin knockout mouse, no iron accumulation was observed during embryonic resorption, suggesting that cell death could be due to a mechanism independent of iron accumulation.