The Hereditary Hemochromatosis Gene and Iron Homeostasis

Feder, John N.; Penny, David M.; Irrinki, Alivelu; Mintier, Gabriel A.; Lebrón, José Antonio; Gross, Cindy N.; Lee, L.; Tsuchihashi, Zenta; Enns, Caroline A.; Björkman, Pamela J.; Schatzman, Randall C.

doi:10.1007/978-1-4615-4797-6_43

Cited by 4 publications

(4 citation statements)

References 13 publications

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“…In this regard, most patients of Northern European ancestry with HH have been shown to be homozygous for HLA-A3 (3,4). In 1996, the hemochromatosis gene, now called HFE, was cloned and shown to code for an HLA class I-like protein that requires interaction with ß2-microglobulin for its expression on the cell surface (5,6). The HFE protein is heavily expressed in duodenal crypt cells, in association with ß2-microglobulin and transferrin, and has been shown to regulate the transferrin receptor-dependent iron uptake by these cells (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…In 1996, the hemochromatosis gene, now called HFE, was cloned and shown to code for an HLA class I-like protein that requires interaction with ß2-microglobulin for its expression on the cell surface (5,6). The HFE protein is heavily expressed in duodenal crypt cells, in association with ß2-microglobulin and transferrin, and has been shown to regulate the transferrin receptor-dependent iron uptake by these cells (6)(7)(8)(9). Two missense mutations were identified initially in the HFE gene in Caucasian patients with HH, namely a G to A transition at nucleotide 845 which leads to a substitution of cysteine for tyrosine at amino acid position 282 (C282Y) and a C to G change at nucleotide 187 that results in a substitution of histidine for aspartic acid at position 63 (H63D) (5).…”

Section: Introductionmentioning

confidence: 99%

“…Two missense mutations were identified initially in the HFE gene in Caucasian patients with HH, namely a G to A transition at nucleotide 845 which leads to a substitution of cysteine for tyrosine at amino acid position 282 (C282Y) and a C to G change at nucleotide 187 that results in a substitution of histidine for aspartic acid at position 63 (H63D) (5). The C282Y mutation has been shown to disrupt the interaction between ß2-microglobulin and the HFE protein and to prevent its cell surface expression, while the H63D mutation is thought to alter the conformation of the HFE gene product, decreasing its affinity for ligands (6).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Bittencourt

Palácios

Couto

et al. 2002

Braz J Med Biol Res

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The hemochromatosis gene, HFE, is located on chromosome 6 in close proximity to the HLA-A locus. Most Caucasian patients with hereditary hemochromatosis (HH) are homozygous for HLA-A3 and for the C282Y mutation of the HFE gene, while a minority are compound heterozygotes for C282Y and H63D. The prevalence of these mutations in non-Caucasian patients with HH is lower than expected. The objective of the present study was to evaluate the frequencies of HLA-A antigens and the C282Y and H63D mutations of the HFE gene in Brazilian patients with HH and to compare clinical and laboratory profiles of C282Y-positive and -negative patients with HH. The frequencies of HLA-A and C282Y and H63D mutations were determined by PCR-based methods in 15 male patients (median age 44 (20-72) years) with HH. Eight patients (53%) were homozygous and one (7%) was heterozygous for the C282Y mutation. None had compound heterozygosity for C282Y and H63D mutations. All but three C282Y homozygotes were positive for HLA-A3 and three other patients without C282Y were shown to be either heterozygous (N = 2) or homozygous (N = 1) for HLA-A3. Patients homozygous for the C282Y mutation had higher ferritin levels and lower age at onset, but the difference was not significant. The presence of C282Y homozygosity in roughly half of the Brazilian patients with HH, together with the findings of HLA-A homozygosity in C282Y-negative subjects, suggest that other mutations in the HFE gene or in other genes involved in iron homeostasis might also be linked to HH in Brazil.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Bittencourt

Palácios

Couto

et al. 2002

Braz J Med Biol Res

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“…Experimental iron loading or deficiency has been associated with minor changes in HFE expression in the small intestine (16,23,32). Cell culture experiments have shown inconsistent results on the effect of exogenous iron on the expression of HFE (13,20). No iron responsive elements are found in the HFE mRNA, and no metal response elements have been identified in the promoter region of the HFE gene (25,30).…”

Section: Hfe Gene and Proteinmentioning

confidence: 99%

Iron Imports. VI. HFE and regulation of intestinal iron absorption

Fleming

Britton²

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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The majority of clinical cases of iron overload is caused by mutations in the HFE gene. However, the role that HFE plays in the physiology of intestinal iron absorption remains enigmatic. Two major models have been proposed: 1) HFE exerts its effects on iron homeostasis indirectly, by modulating the expression of hepcidin; and 2) HFE exerts its effects directly, by changing the iron status (and therefore the iron absorptive activity) of intestinal enterocytes. The first model places the primary role of HFE in the liver (hepatocytes and/or Kupffer cells). The second model places the primary role in the duodenum (crypt cells or villus enterocytes). These models are not mutually exclusive, and it is possible that HFE influences the iron status in each of these cell populations, leading to cell type-specific downstream effects on intestinal iron absorption and body iron distribution.

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The hereditary hemochromatosis gene (HFE)

Feder

1999

Immunol Res

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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.

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The Hereditary Hemochromatosis Gene and Iron Homeostasis

Cited by 4 publications

References 13 publications

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Analysis of HLA-A antigens and C282Y and H63D mutations of the HFE gene in Brazilian patients with hemochromatosis

Iron Imports. VI. HFE and regulation of intestinal iron absorption

The hereditary hemochromatosis gene (HFE)

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