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Hereditary haemochromatosis is an iron overloading disorder caused by common mutations in the HFE gene. However, information with respect to the function of HFE protein does not explain how mutations in HFE lead to hereditary haemochromatosis. We propose a molecular model in which HFE has two mutually exclusive activities in cells: inhibition of uptake or inhibition of release of iron. The balance between serum transferrin saturation and serum transferrin-receptor concentrations determines which of these functions predominates. With this input, HFE enables the intestinal crypt cells and reticuloendothelial system to interpret the body's iron requirements and regulate iron absorption and distribution. In our model, mutations in HFE result in over absorption of dietary iron, and patterns of tissue iron deposition in agreement with clinical observations of hereditary haemochromatosis.

Original publication

DOI

10.1016/s0140-6736(02)07885-6

Type

Journal article

Journal

Lancet (London, England)

Publication Date

03/2002

Volume

359

Pages

786 - 790

Addresses

Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, Oxford OX3 9DS, UK. townsend@pinnacle.jr2.ox.ac.uk

Keywords

Animals, Humans, Anemia, Hemochromatosis, Iron Overload, Disease Models, Animal, Iron, Transferrin, Receptors, Transferrin, Membrane Proteins, Histocompatibility Antigens Class I, HLA Antigens, Intestinal Absorption, Mutation, Models, Molecular, Hemochromatosis Protein