DEFECTIVE IRON HOMEOSTASIS IN BETA-2-MICROGLOBULIN KNOCKOUT MICE RECAPITULATES HEREDITARY HEMOCHROMATOSIS IN MAN

Previously, hepatic iron overload resembling that in hereditary hemach romatosis (HH) has been found in beta 2-microglobulin knockout (beta 2 m(-/-)) mice. We have now characterized iron metabolism in beta 2m(-/- ) mice. The mutant mice fail to limit the transfer of iron from mucosa l cells into the plasma. Transferrin saturation is abnormally high. Pa thologic iron depositions occur predominantly in liver parenchymal cel ls. Reconstitution with normal hematopoietic cells redistributes the i ron from parenchymal to Kupffer cells, but does not correct the mucosa l defect. We conclude that (a) iron metabolism is defective in the gut mucosa as well as the liver of beta 2m(-/-) mice; and (b) a beta 2m-d ependent gene product is involved in iron homeostasis. Recently, a nov el gene of the major histocompatibility complex class I family, HLA-H, has been found to be mutated in a large proportion of HH patients. Ou r data provide functional support for the proposed causative role of H LA-H mutations in HH.