A NEW HEREDITARY IRON OVERLOAD DISEASE DUE TO MUTATIONS OF THE SLC11A3 GENE

Iron is a vital micronutrient for humans, however when present in excess in the body may lead to cell damage and severe organ disease per se or may aggravate the course of other chronic diseases, such as cardiovascular diseases, diabetes and infection. Both genetic and environmental causes of iron overload exist with HFE associated hereditary hemochromatosis (HC) being the most common form of hereditary human iron overload (HIO). Recently, thanks to the Telethon support (project E 609), we have discovered a new HIO disease that leads to hepatic fibrosis, diabetes, impotence and arrythmias. The disease is due to a mutation of the SCL11A3 gene which encodes for ferroportin/IREG/MTP-1 the main iron export protein in mammals. Based on preliminary clinical observation of the patients, it seems that the disease has very peculiar clinical features including an early anemic phase and late iron overload. The traditional therapeutical approach used for HC (i.e. phlebotomy) is often ineffective or not tolerated. Overall, the underlying cause, natural history and optimal therapy of this new genetic disease are unknown. Recently, new cases of this novel disease have been described in different populations worldwide. Aims of this project are I) to identify the cause for iron accumulation and toxicity in this disease II) to understand how the defective protein is able to deregulate the absorption and circulation of iron in the body II) to develop new tools for the diagnosis and therapy of the disease. This will be accomplished by studying blood cells from patients in vitro and by generating an animal model with the human disease. The results of this study will allow us on one side to unravel obscure aspects of iron metabolism in humans on the other to greatly enhance our chance to diagnose and cure HIO diseases.