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1 Unite de Genetique des Mammiferes and URA 2579 CNRS, Institut Pasteur, Paris, France
2 UMR 955 INRA-ENVA de Genetique Moleculaire et Cellulaire and UP d'Histologie et d'Anatomie Pathologique, Ecole Nationale Veterinaire d'Alfort, Maisons-Alfort, France
3 Centre Francais des Porphyries, INSERM U 656 , Faculte X. Bichat, Hopital Louis Mourier, Colombes, France
4 INSERM U 492, Universite Paris XII, Faculte de Medecine, Creteil, France
* To whom correspondence should be addressed. E-mail: xmonta{at}pasteur.fr.
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin overproduction by erythrocytes. In humans, it is responsible for painful skin photosensitivity and occasionally liver failure due to the accumulation of protoporphyrin in the liver. The ferrochelatase deficiency mouse mutation is the best animal model available for human EPP. The original description, based on mice with a BALB/cByJIco genetic background, reported a disease resembling the severe form of the human disease with anemia, jaundice and liver failure. We investigated the effect of the genetic background on the severity of the phenotype using congenic strains. Compared with BALB/cByJIco, C57BL/6JIco mice developed moderate but increasing anemia, and intense liver accumulation of protoporphyrin with severe hepatocytes damage and loss. However, bile excretory function was not affected and bilirubin remained low. Despite highest protoporphyrin concentration in erythrocytes, SJL/JOrlIco homozygotes had mild anemia, and few liver deposits of protoporphyrin. Discriminant analysis using six hematological and biochemical parameters showed that homozygotes of the three genetic backgrounds could be clustered in three well-separated groups. These three congenic strains provide strong evidence for independent genetic control of bonemarrow contribution of protoporphyrin overproduction to the development of liver disease, and of biliary protoporphyrin excretion. They provide a tool to investigate the physiological mechanisms involved in these phenotypic differences, and to identify modifying genes.
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