HFE gene: Structure, function, mutations, and associated iron abnormalities

•HFE, the hemochromatosis gene, is linked to the major histocompatibility complex on chromosome 6p.•HFE encodes HFE, an extracellular protein that binds beta-2 microglobulin.•HFE is a positive upstream regulator of hepcidin.•Common HFE mutations account for most hemochromatosis cases.•Iron phenotypes of mice homozygous for Hfe knockouts are similar to those of HFE hemochromatosis.

The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~ 90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.