Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia.
Friedreich's ataxia (FRDA) is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.
Translational Medecine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France. martelli@igbmc.fr; hpuccio@igbmc.fr
Alain
A
Martelli
Lisa S
LS
Friedman
Laurence
L
Reutenauer
Nadia
N
Messaddeq
Susan L
SL
Perlman
David R
DR
Lynch
Kathrin
K
Fedosov
Jörg B
JB
Schulz
Massimo
M
Pandolfo
Hélène
H
Puccio
D000818:Animals; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D005621:Friedreich Ataxia / Q000150:complications* / Q000473:pathology*; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000150:complications* / Q000473:pathology*; D009928:Organ Specificity; D010641:Phenotype; D016019:Survival Analysis; D000096923:Frataxin
D019426:Integrases; D033862:Iron-Binding Proteins; D000096923:Frataxin; C045073:Cre recombinase