Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism, A ffected individuals evidence iron accumulation in tissue parenchyma in asso ciation with absent serum ceruloplasmin. Genetic studies of such patients r eveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of acerulo plasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although norm al at birth, Cp-/- mice demonstrate progressive accumulation of iron such t hat by one year of age all animals have a prominent elevation in serum ferr itin and a 3- to Q-fold increase in the iron content of the liver and splee n. Histological analysis of affected tissues in these mice shows abundant i ron stores within reticuloendothelial cells and hepatocytes, Ferrokinetic s tudies in Cp+/+ and Cp-/- mice reveal equivalent rates of iron absorption a nd plasma iron turnover, suggesting that iron accumulation results from alt ered compartmentalization within the iron cycle. Consistent with this conce pt, Cp-/- mice showed no abnormalities in cellular iron uptake but a striki ng impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for cerulopl asmin in determining the rate of iron efflux from cells with mobilizable ir on stores.