Molecular Pathogenesis of Hereditary Haemochromatosis

Disturbance of iron homeostasis in man leads to an iron toxicity syndrome known as hereditary haemochromatosis. Moreover, iron is an independent determinant of the prognosis of alcoholic liver disease and chronic hepatitis. Although identification of iron transport and storage proteins has recently improved our understanding of iron metabolism in humans, the mechanisms of progressive iron deposition in the presence of HFE and transferrin receptor 2 gene mutations are still elusive. Furthermore, sustained intake of alcohol, which is associated with secondary iron overload, causes increased expression of asialoglycoforms of transferrin. We wish to test the hypothesis that mutations in the transferrin receptor 2 gene and in the HFE 1 gene associated with adult haemochromatosis, affect transferrin receptor- mediated iron uptake and modify expression of iron transporters in the intestine and liver. We further propose that increased concentrations of asialoglycoforms of serum transferrin influence iron delivery to the liver and affect regulatory programming of mucosal iron uptake in the duodenum. For this aim we would like to examine animal models of haemochromatosis for the expression of iron-related proteins including ferritin, transferrin receptor 1, divalent metal transporter 1, ferroportin 1, duodenal cytochrome b and hepcidin before and after treatment of animals with transferrin and its asialoglycoforms prepared form human serum of affected individuals. Elucidation of the crosstalk between HFE, transferrin receptor 2 and transferrin-variants could improve our understanding of iron disorders, and therefore could have a substantial impact on prognosis of haemochromatosis and alcoholic liver disease.