The hereditary hemochromatosis gene (HFE)

Abstract

The iron overload disorder, hereditary hemochromatosis, is one of the most common genetic diseases of individuals of Northern European descent. The disorder is characterized by the progressive accumulation of dietary iron in the major organs of the body, which if not diagnosed, leads to numerous medical maladies and eventually death. The locus for this disorder was mapped by genetic linkage to the short arm of chromosome over twenty years ago, but it was not until 1996 that the gene for this disorder was cloned by an identity-by-descent positional cloning approach. The gene, called HFE, encodes a major histocompatibility complex (MHC) class I-like protein that is mutated in approx 85% of all individuals known to have hereditary hemochromatosis (HH). Since the cloning of the HFE gene, considerable work has been carried out which has furthered our understanding of the genetics of this prevalent disorder. In addition, with the identification of the transferrin receptor as a protein capable of interacting with HFE we are now beginning to understand how a protein with the structural characteristics of an MHC class I molecule can influence cellular iron homeostasis.

Modification of the association between lead exposure and amyotrophic lateral sclerosis by iron and oxidative stress related gene polymorphisms

“…Both HFE variants affect iron levels via interference with normal iron transport, and this interference extends to other metals as well (8, 34, 35). If HFE variants alter the distribution of lead in blood and bone, or across the blood brain barrier, this action could account for different associations between lead and ALS because the same blood or bone lead measurement in a variant carrier compared with wild-type may mean different lead concentrations that actually reach the central nervous system.…”

“…The hemochromatosis (HFE) protein is a major histocompatibility class 1-like molecule that is involved in iron regulation (8). Both the H63D and C282Y HFE gene variants are associated with the iron overload disorder known as hemochromatosis, and both are associated with a higher labile iron pool and increased oxidative stress as well as other changes (9, 10).…”

Toenail iron, genetic determinants of iron status, and the risk of glioma

“…An increased risk for cancer has been suggested in several [44-47] though not all [48, 49] studies of HFE genetic variants which have been linked to hemochromatosis, a hereditary disorder that causes elevated body iron stores [50]. Two variants in HFE (rs1800562 and rs1799945) were unrelated to glioma risk in the present data; both are relatively uncommon (minor allele frequencies: 0.068 and 0.154, respectively) and power to detect associations correspondingly limited in our study.…”

Iron Homeostasis and the Inflammatory Response

“…The major form of hereditary hemochromatosis, called Type I hemochromatosis, results from variations in HFE (34). HFE associates with both TfR1 and TfR2, but it is thought that the HFE/TfR2 complex senses Tf saturation to modulate hepcidin transcription (47).…”