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Genetic control of the pathogenesis of diseases based on iron accumulation

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Genetics unravels iron-associated disorders

Understanding the mechanisms underlying various iron-related diseases is important for developing appropriate therapies. A European consortium studied iron metabolism and the genes that generate iron overload disorders.

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Iron accumulation is caused by genetic abnormalities in proteins that are involved in iron metabolism and leads to the disorders Genetic Iron Overload (GIO) and Anaemia of Chronic Diseases (ACD). Iron metabolism is governed by the liver hormone hepcidin which inhibits iron transport through binding to the iron channel ferroportin, present in gut enterocytes and reticuloendothelial cells (macrophages). Under homeostasis, inhibition of ferroportin shuts off the iron transport out of these cells, preventing iron loss. To elucidate the mechanisms behind iron disorders, the EU funded the project ‘Genetic control of the pathogenesis of diseases based on iron accumulation’ (Euroiron1). More specifically, project partners were interested in the genetic factors involved in the expression of key genes of iron metabolism associated with pathological iron accumulation. They studied chronic systemic iron over-load diseases such as HFE Haemochromatosis – one of the most frequent hereditary recessive diseases in Europe – and ACD, which is the second most common form of anaemia worldwide, and is related to iron accumulation in macrophages. Using animal models and in vitro culture systems, scientists investigated genes involved in the control of systemic iron regulation to identify hepcidin-regulated genes and genes (SMAD4, BMP6, HFE) responsible for hepcidin modulation. Furthermore, they discovered that various conditions causing endoplasmic reticulum stress can affect the levels of hepcidin and hence iron accumulation. Collectively, these findings illustrated the importance of hepcidin levels in patients with iron metabolism disorders. .Another important outcome of the project came through genetic studies in patients with HFE Haemochromatosis, which revealed associations between genetic polymorphisms and disease severity. Moreover, scientists identified a novel form of secondary iron overload which corresponded to acquired aceruloplasminemia. Overall, the Euroiron1 project dissected the genetic and molecular mechanisms accounting for the development of body iron misdistributions and for their phenotypic variability. Identification of the parameters that intervene in iron metabolism is expected to lead to the development of novel diagnostic markers and new potential therapeutic targets.

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