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Review
, 574 (2), 179-92

HFE Gene: Structure, Function, Mutations, and Associated Iron Abnormalities

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Review

HFE Gene: Structure, Function, Mutations, and Associated Iron Abnormalities

James C Barton et al. Gene.

Abstract

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.

Keywords: Hemochromatosis; Iron; Major histocompatibility complex; Transferrin receptor.

Figures

Figure 1.
Figure 1.
HFE protein in association with beta-2 microglobulin (β2M) at the cell surface. The three extracellular domains of HFE are designated α1, α2, and α3. β2M is shown associated with the α3 domain. Abbreviations: cyto, cytoplasmic tail; tm, transmembrane domain. Adapted from R.E. Fleming, W. S. Sly, Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol 64 (2002) 663–680. Used with permission.
Figure 2.
Figure 2.
A model of regulation of hepcidin transcription by iron. Iron as holotransferrin is shown in orange, iron sensors and associated molecule in gray, bone morphogenic protein (BMP) receptor and its transduction pathway in shades of blue, the ligands and co-receptors of the BMP receptor in shades of green, and the negative regulator protease in purple. *Molecules the ablation of which caused iron dysregulation. Adapted from T. Ganz, Hepcidin and iron regulation, 10 years later, Blood 117 (2011) 4425–4433. Used with permission.

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