ROLE OF THE PLASMA PROTEINS HAPTOGLOBIN AND HEMOPEXIN IN THE PATHOGENESIS OF TYPE 1 HEMOCHROMATOSIS

Hereditary hemochromatosis (HC) is a common autosomal recessive disorder that results in iron overload. It is attributable to inappropriately increased iron absorption that results in iron loading of liver, pancreas, heart and other organs, thus impairing their function.The main objective of this project concern type 1 HC that is characterized by mutations in the HFE gene. HFE mutation is very common but only 1-4% of individuals homozygotes for the HFE mutation present clinical signs of pathology. Variability in the phenotype is certainly due to other genes modulating iron loading. Among possible modifier genes of type 1 HC that need to be investigated there is the gene coding for the plasma protein haptoglobin. Haptoglobin participates in the anti-oxidant reaction by scavenging from circulation free hemoglobin. This function of haptoglobin is closely related to the possibility that it participates in iron metabolism by recovering heme iron. The efficacy of this process could indeed modulate iron stores, thus modifying the severity of iron loading in HC.The availability of mouse models of HFE-associated HC and of haptoglobin null mutation will help us to test the hypothesis that haptoglobin is a modifier of HC. Well use mouse models lacking HFE and/or haptoglobin to study the effect of a null mutation in the haptoglobin gene on the HC phenotype. Moreover, well use the same approaches to investigate the possibility that also the gene coding for hemopexin is a modifier of type 1 HC. Hemopexin is a plasma protein that binds with high affinity heme and its function is closely related to that of haptoglobin. Data obtained by this work will contribute to fill a gap in our understanding of iron homeostasis which concern heme-iron metabolism. Understanding this aspect will be an essential breakthrough in the pathogenesis not only of type 1 HC, but also of other more severe iron disorders such as juvenile HC.