HEMOCHROMATOSIS: NEW GENES AND THEIR FUNCTION

Disorders of iron metabolism are among the commonest diseases in humans. Genetic diseases which lead to iron overload (hemochromatosis) are frequent and represent a relevant health problem since they severely compromise both the expectancy and the quality of life of the affected patients. It has been recently demonstrated that, besides the common adult-onset hemochromatosis (HFE1), caused by mutations in the HFE gene which maps to chromosome 6p, two other distinct genetic disorders that leads to iron overload exist. The juvenile, severe form (HFE2) has an early-onset and shows severe clinical complications: it maps to chromosome 1q21 and is caused by a still unidentified gene. The third form (HFE3), has clinical features similar to HFE1, and is caused by mutations in TFR2 gene on chromosome 7q. The role of TFR2 in iron metabolism is still uncertain. This project has the following goals: a) to clone the HFE2 gene and to define mutations in patients with the severe juvenile form. b) to assess the frequency of TFR2 mutations in Italy and in the Mediterranean area; c) to clarify the function of TFR2 and HFE2 proteins through the development of mouse models of the disease and the analysis of the proteins in cellular cultures and in patients. The results of this study will contribute to improve the molecular diagnosis of hemochromatosis and to clarify the mechanisms of the regulation of intestinal iron absorption, as a prerequisite to the development of new therapeutical approaches.