* 613609

HOMEOSTATIC IRON REGULATOR; HFE


Alternative titles; symbols

HFE GENE
HLAH


HGNC Approved Gene Symbol: HFE

Cytogenetic location: 6p22.2     Genomic coordinates (GRCh38): 6:26,087,429-26,098,343 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6p22.2 Hemochromatosis, type 1 235200 AR 3

TEXT

Cloning and Expression

El Kahloun et al. (1993) used a yeast artificial chromosome with a 320-kb insert of genomic DNA that included the major histocompatibility complex class I HLA-A gene (142800) to screen a human duodenal mucosa cDNA library. They isolated 7 cDNA clones that corresponded to 7 new non-class I structural genes. Since these genes were located within the hemochromatosis (HFE1; 235200) candidate gene region, they referred to the genes as HCG (hemochromatosis candidate gene) I-VII. El Kahloun et al. (1993) concluded that HCG I, III, V, and VI are probably single-copy genes situated 180, 155, 140, and 230 kb, respectively, centromeric to HLA-A. There were several copies of the other 3 genes. Each of the genes was associated with a CpG/HTF island.

Using cDNA hybridization selection with a 320-kb YAC containing the HLA-A gene to screen a human duodenal cDNA library, Goei et al. (1994) isolated and characterized 10 novel gene fragments. Also in search of the HFE gene, Yaouanq et al. (1994) identified a zone of linkage disequilibrium which suggested that the HFE gene may reside within a 400-kb expanse of DNA between the locus they referred to as i97 and HLA-F (143110). Totaro et al. (1996) generated a detailed 1.2-Mb physical and transcription map of 6p spanning the HLA class I region from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes were detected and integrated into the map. Thirteen cDNA fragments showed no similarity with known sequences, and could be candidates for hemochromatosis.

By linkage disequilibrium and full haplotype analysis of hereditary hemochromatosis patients, Feder et al. (1996) identified a 250-kb region more than 3 Mb telomeric of the MHC on chromosome 6 that is identical by descent in 85% of patient chromosomes. Within this region, they identified a gene, which they termed HLA-H, that encodes a predicted 343-amino acid protein related to the MHC class I gene family. The protein comprises a signal sequence, peptide-binding regions (alpha-1 and alpha-2 domains), a transmembrane region, and a small cytoplasmic portion. One of the most conserved structural features of MHC class I molecules in HLA-H are the 4 cysteine residues that form disulfide bridges in the alpha-2 and alpha-3 domains. Northern blot analysis detected a 4-kb major mRNA transcript in all tissues tested, except brain.

Searching for new human MHC class I related genes, Hashimoto et al. (1995) identified MHC-related protein-1 (MR1; 600764) and a second gene, MR2. The HLA-H gene (HFE) reported by Feder et al. (1996) as a candidate gene for hereditary hemochromatosis turned out to be identical to the MR2 gene of Hashimoto et al. (1995). Hashimoto et al. (1997) isolated the murine homolog of this gene. It was found to be similar to its human counterpart with an overall predicted amino acid sequence similarity of approximately 66% and expression in various tissues as in human. An extra 8 amino acid residues between the alpha-1 and the alpha-2 domains in the mouse molecule compared to the human counterpart could be explained by the creation of the additional coding sequence from the intron.

Thenie et al. (2001) isolated an antisense transcript originating from the HFE gene locus. The RNA spans exon 1, exon 2, part of intron 1 of the HFE gene, and 1 kb upstream of it. The antisense transcript is polyadenylated, but displays no open reading frame, and appears to be expressed at low levels in all tissues and cell lines tested. In vitro coupled transcription-translation experiments revealed that HFE expression is decreased by this antisense RNA, suggesting that it may play a role in the regulation of HFE gene expression.


Nomenclature

Mercier et al. (1997) urged strongly that the symbol HFE be used for the hemochromatosis gene rather than 'HLA-H' as used by Feder et al. (1996). The designation HLA-H was used also for a presumed pseudogene in the HLA class I region; see 142800. Similarly, Bodmer et al. (1997) argued that 'HLA-H' is an undesirable designation and pointed to the accepted authority of the WHO Nomenclature Committee for Factors of the HLA System in determining symbols of genes in this region.


Biochemical Features

Crystal Structure

Lebron et al. (1998) determined the 2.6-angstrom crystal structure of the HFE protein.


Gene Structure

Feder et al. (1996) determined that the HFE gene contains 7 exons spanning 12 kb.


Mapping

By fluorescence in situ hybridization analysis, Hashimoto et al. (1995) mapped the HFE gene to chromosome 6p22.

The HFE gene maps within the MHC region on chromosome 6p21.3 (Feder et al., 1996).

Hashimoto et al. (1997) showed that whereas the human gene is located telomeric to the MHC region on 6p, the mouse homolog was translocated from the site telomeric to MHC on chromosome 17 to chromosome 13 along with other genes.


Gene Function

Parkkila et al. (1997) generated an antibody to a C-terminal peptide and used it for immunolocalization of the HLA-H protein in the gastrointestinal tract of Finnish and American subjects presumed not to have hereditary hemochromatosis. Although staining for the HLA-H protein was seen in some epithelial cells in every segment of the alimentary canal, its cellular and subcellular expression in the small intestine was distinct from that in other segments. In contrast to the stomach and colon, where staining is polarized and restricted to the basal lateral surfaces, and in contrast to the epithelial cells of the esophagus and submucosal leukocytes, which showed nonpolarized staining around the entire plasma membrane, the staining in the small intestine was mainly intracellular and perinuclear, limited to cells in deep crypts. Parkkila et al. (1997) concluded that the unique subcellular localization in the crypts of the small intestine in proximity to the presumed sites of iron absorption supported the implication of this protein in the molecular basis of hemochromatosis.

By immunohistochemistry, Parkkila et al. (1997) demonstrated that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses showed that the HFE protein is associated with beta-2-microglobulin (B2M; 109700) in placental membranes. Unexpectedly, the transferrin receptor (TFR; 190010) was also found to be associated with the HFE protein/B2M complex. These studies placed the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raised the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis.

Feder et al. (1998) demonstrated that the HFE protein forms stable complexes with the transferrin receptor. Studies on cell-associated transferrin at 37 degrees C suggested that overexpression of HFE protein decreases the affinity of TFR for transferrin. Feder et al. (1998) demonstrated that the mutant H63D (613609.0002) HFE protein found in patients with hemochromatosis formed stable complexes with TFR, but that overexpression of H63D did not decrease the affinity of TFR for transferrin. In contrast, the mutant C282Y (613609.0001) HFE protein only associated with TFR to a small degree. The results established a molecular link between the HFE protein and the transferrin receptor, raising the possibility that alterations in this regulatory mechanism of iron transport may play a role in the pathogenesis of hereditary hemochromatosis.

By analyzing the crystal structure of the HFE protein, Lebron et al. (1998) identified a patch of histidines that could be involved in pH-dependent interactions. Soluble TFR and HFE bound tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TFR:HFE stoichiometry (2:1) differed from TFR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TFR, consistent with the demonstration that HFE, transferrin, and TFR form a ternary complex. Lebron et al. (1998) used the crystal structure to reveal the locations of hemochromatosis mutations.

At the cell surface, HFE complexes with TFRC, increasing the dissociation constant of transferrin (TF) for its receptor 10-fold. HFE does not remain at the cell surface, but traffics with TFRC to transferrin-positive internal compartments. Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, Roy et al. (1999) showed that the expression of HFE reduced uptake of radioactive iron from TF by 33%, but did not affect the endocytic or exocytic rates of TFRC cycling. Therefore, HFE appears to reduce cellular acquisition of iron from TF within endocytic compartments. HFE specifically reduces iron uptake from TF, as non-TF-mediated iron uptake from Fe-nitrilotriacetic acid was not altered. These results explained the decreased ferritin levels seen in the HeLa cell system, and demonstrated the specific control of HFE over the TF-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in persons with hereditary hemochromatosis lacking functional HFE.

The HFE protein normally binds to TFR in competition with transferrin and, in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These observations suggest, paradoxically, that expression of wildtype HFE may lead to iron accumulation in these specialized cell types. Drakesmith et al. (2002) showed that wildtype HFE protein raises cellular iron by inhibiting iron efflux from the monocyte/macrophage cell line, and extended these results to macrophages derived from healthy individuals and HH patients. They found that the HH-associated mutant H63D (H41D of the mature protein) lost the ability to inhibit iron release despite binding to TFR as well as wildtype HFE. They also showed that the ability of HFE to block iron release is not competitively inhibited by transferrin. They concluded that HFE has 2 mutually exclusive functions: binding to TFR in competition with transferrin and inhibition of iron release.

Zoller et al. (2003) studied the mRNA and protein expression and activity of cytochrome b reductase-1 (CYBRD1; 605745) in duodenal biopsies of patients with iron deficiency anemia, hereditary hemochromatosis, and controls. They found that CYBRD1 activity in iron deficiency is stimulated via enhanced protein expression, whereas in hemochromatosis due to mutations in the HFE gene it is upregulated posttranslationally. Hemochromatosis patients with no mutations in HFE did not have increased CYBRD1 activity. Zoller et al. (2003) concluded that there are different kinetics of intestinal iron uptake between iron deficiency and hemochromatosis due to mutations in HFE, and that duodenal iron accumulation in hereditary hemochromatosis due to mutations in HFE and hereditary hemochromatosis due to mutations in other genes is pathophysiologically different.

Drakesmith et al. (2005) found that the Nef protein of human immunodeficiency virus-1 (HIV-1) downregulated macrophage-expressed HFE. Iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wildtype HFE. The effect was lost with Nef-deleted HIV-1 or with infected macrophages from hemochromatosis patients expressing mutant HFE. Iron accumulation in HIV-1-infected wildtype macrophages was paralleled by increased cellular HIV-1 Gag protein expression.

Like classic class Ia MHC molecules, HFE has a peptide-binding groove, but the HFE groove has no ligand. Rohrlich et al. (2005) studied the interactions of human and mouse HFE with T lymphocytes and found that the mouse alpha/beta TCR recognized human HFE, leading to Zap70 (176947) phosphorylation. Cytotoxic T lymphocytes from mice lacking Hfe were able to recognize murine Hfe. Rohrlich et al. (2005) proposed that the immune system may be involved in control of iron metabolism.

Gao et al. (2008) found that expression of HFE decreased uptake of both TF-bound iron and non-TF-bound iron in human HepG2 hepatoma cells. Knockdown of ZIP14 (SLC39A14; 608736) in HepG2 cells abolished the inhibitory effect of HFE on uptake of non-TF-bound iron. HFE appeared to reduce the stability of ZIP14 protein and had no effect on ZIP14 mRNA.


Molecular Genetics

In patients with hereditary hemochromatosis (HFE1; 235200), Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y, 613609.0001 and H63D, 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of hemochromatosis cases are related to C282Y homozygosity.

By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2, 4, and 5 of the HFE gene, Barton et al. (1999) identified novel mutations in 4 of 20 hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for the previously undescribed mutations ile105-to-thr (I105T; 613609.0009) and gly93-to-arg (G93R; 613609.0010). Probands 3 and 4 were heterozygous for the previously described but uncommon HFE mutation ser65-to-cys (S65C; 613609.0003). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda (see 176100), and proband 4 had hereditary stomatocytosis (185000). Each of these 4 probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in these probands. In 176 normal control subjects, 2 were heterozygous for S65C, but I105T and G93R were not detected.

Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2 (604720)-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.


Animal Model

To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, Zhou et al. (1998) studied the effects of a targeted disruption of the murine homolog of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates, and hepatic iron concentration was 8-fold higher than that of wildtype littermates. Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different from that in littermates. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. The study showed that HFE protein is involved in the regulation of iron homeostasis and that mutations in the gene are responsible for hereditary hemochromatosis. Beutler (1998) emphasized the pathologic and clinical importance of the knockout mouse model for hemochromatosis.

The puzzling linkage between genetic hemochromatosis and the histocompatibility loci became even more puzzling when the gene involved, HFE, was identified. Indeed, within the well-defined, mainly peptide-binding, MHC-class I family of molecules, HFE seems to perform an unusual but essential function. Understanding of HFE function in iron homeostasis was only partial; an even more open question was its possible role in the immune system. To advance knowledge in both of these areas, Bahram et al. (1999) studied deletion of the HFE alpha-1 and alpha-2 putative ligand-binding domains in vivo. HFE-deficient mice were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion developed iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allowed a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. However, extensive phenotyping of primary and secondary lymphoid organs including the gut provided no compelling evidence for an obvious immune-linked function for HFE.

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (HAMP; 606464) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. HAMP is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Roy et al. (2004) reported that mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggested a previously unidentified role for Hfe in innate immunity and ACD.

Nairz et al. (2009) found that mice lacking 1 or both Hfe alleles were protected from Salmonella typhimurium septicemia, displaying reduced bacterial replication and prolonged host survival. Increased resistance was associated with enhanced production of the enterochelin-binding protein Lcn2 (600181), which reduced iron availability for Salmonella. Macrophages lacking both Hfe and Lcn2 were unable to efficiently control S. typhimurium or to withhold iron from the bacterium. Salmonella lacking enterochelin overcame protection in Hfe -/- mice, as did wildtype bacteria in Hfe -/- Lcn2 -/- double-knockout mice. Nairz et al. (2009) concluded that loss of HFE confers host resistance to systemic Salmonella infection by inducing the iron-capturing peptide LCN2, thereby providing an evolutionary advantage that may account for the high prevalence of genetic hemochromatosis.

Jenkitkasemwong et al. (2015) found that loss of Slc39a14 prevented hepatic iron overload in the Hfe -/- and Hfe2 (HJV; 608374) -/- mouse models of hemochromatosis. However, loss of Slc39a14 did not prevent iron accumulation in other tissues and cells of Hfe -/- or Hfe2 -/- mice, but instead resulted in altered patterns of iron accumulation compared with single-knockout or wildtype mice. Jenkitkasemwong et al. (2015) concluded that SLC39A14 is required for development of hepatic iron overload in hereditary hemochromatosis.


ALLELIC VARIANTS ( 11 Selected Examples):

.0001 RECLASSIFIED - HFE POLYMORPHISM

HFE, CYS282TYR
  
RCV000000019...

This variant has been reclassified as a polymorphism because the C282Y variant is present in the gnomad database (v2.1.1) in 9,544 of 282,608 alleles and in 276 homozygotes, with an allele frequency of 0.03377 (Hamosh, 2023).

Drakesmith et al. (2002) used a numbering system beginning from the first amino acid of the mature protein, omitting the 22 amino acids of the signal sequence, so that C282 of the immature protein is C260 of the mature protein.

Hemochromatosis, Type 1

In patients with hemochromatosis (HFE1; 235200), Feder et al. (1996) identified an 845G-A transition in the HFE gene (which they referred to as HLA-H or 'cDNA 24'), resulting in a cys282-to-tyr (C282Y) substitution. This missense mutation occurs in a highly conserved residue involved in the intramolecular disulfide bridging of MHC class I proteins, and could therefore disrupt the structure and function of this protein. Using an allele-specific oligonucleotide-ligation assay on their group of 178 patients, they detected the C282Y mutation in 85% of all HFE chromosomes. In contrast, only 10 of the 310 control chromosomes (3.2%) carried the mutation, a carrier frequency of 10/155 = 6.4%. One hundred forty-eight of 178 HH patients were homozygous for this mutation, 9 were heterozygous, and 21 carried only the normal allele. These numbers were extremely discrepant from Hardy-Weinberg equilibrium. The findings corroborated heterogeneity among the hemochromatosis patients, with 83% of cases related to C282Y homozygosity.

Jazwinska et al. (1996) provided convincing evidence that the C282Y mutation in homozygous form in the HFE gene is the cause of hemochromatosis. In studies in Australia, patients properly characterized at the genotypic and phenotypic level all showed homozygosity for the C282Y substitution. Irrespective of haplotype, all HH heterozygotes were cys/tyr heterozygotes, and all homozygous normal controls were cys/cys homozygotes. The presence of a single mutation in all patients contrasted with the data of Feder et al. (1996), who reported a lower frequency of the mutation. Jazwinska et al. (1996) suggested that different clinical criteria for the diagnosis of HH may account for the difference, or that HH may not be as homogeneous as previously believed. They noted that a key question is why there is a variation in severity of iron loading in HH that is haplotype-related when the mutation is identical in all haplotypes tested. Jazwinska et al. (1996) hypothesized that the HFE locus is the primary HH locus, but that there are likely to be other 6p-linked modifying genes that would explain both the HLA-linked haplotype variation in expression of the disorder and the large region of linkage disequilibrium present in all populations and spanning at least 4.5 Mb distal of D6S265.

Jouanolle et al. (1996) commented on the significance of the C282Y mutation on the basis of a group of 65 unrelated affected individuals who had been under study in France for more than 10 years and identified by stringent criteria. Homozygosity for the C282Y mutation was found in 59 of 65 patients (90.8%); 3 of the patients were compound heterozygotes for the C282Y mutation and the H63D mutation (613609.0002); 1 was homozygous for the H63D mutation; and 2 were heterozygous for H63D. These results corresponded to an allelic frequency of 93.1% for the C282Y and 5.4% for the H63D mutations, respectively. Of note, the C282Y mutation was never observed in the family-based controls, whereas it was present in 5.8% of the general Breton population. This corresponds to a theoretical frequency of about 1 per 1,000 for the disease, which is slightly lower than generally estimated. In contrast, the H63D allelic frequency was nearly the same in both control groups (15% and 16.5% in the family-based and general population controls, respectively). While the experience of Jouanolle et al. (1996) appeared to indicate a close relationship of C282Y to hemochromatosis, the implication of the H63D variant was not clear.

Beutler et al. (1996) reported mutation analysis of 147 patients with hereditary hemochromatosis and 193 controls; 121 (82.3%) HH patients were homozygous for the C282Y mutation and 10 (6.8%) were heterozygous. All of the C282Y homozygous patients were also homozygous for the wildtype nucleotide 187C (see H63D; 613609.0002), and all C282Y heterozygotes had at least 1 copy of 187C. Thus, the 2 nucleotides, 845 and 187, were in complete linkage disequilibrium; nucleotide 187 was a C on all chromosomes with the 845A (C282Y) mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G (H63D).

Among 132 unrelated hemochromatosis patients in Brittany, Jouanolle et al. (1997) found that 92% were homozygous for the C282Y mutation and that all 264 chromosomes except 5 carried either the C282Y mutation or the H63D mutation. The UK Haemochromatosis Consortium (1997) genotyped 115 unrelated hereditary hemochromatosis patients and found that 105 (91%) were homozygous for the C282Y mutation. One of 101 controls was also found to be homozygous but was subsequently found to have evidence of iron overload. Compound heterozygosity for the C282Y and H63D mutations was found in 3 patients who had mild disease and in 4 controls who had no signs of iron overload. Five patients lacked either mutation, 2 of whom had atypical, early-onset disease.

Feder et al. (1997) confirmed the prediction that the C282Y mutation would disrupt a critical disulfide bond in the alpha-3 loop of the HFE protein and abrogate binding of the mutant HFE protein to beta-2-microglobulin (B2M; 109700), as well as its transport to and presentation on the cell surface. In vitro, the C282Y mutant HFE protein failed to associate with endogenous B2M in human embryonic kidney cells stably transfected with the mutant cDNA. Waheed et al. (1997) found that whereas the wildtype and H63D HFE proteins associate with beta-2 microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. They presented biochemical and immunofluorescence data indicating that the C282Y mutant protein is retained in the endoplasmic reticulum and middle Golgi compartments, fails to undergo late Golgi processing, and is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provides a possible basis for impaired function of this mutant protein in hereditary hemochromatosis.

In 478 hemochromatosis probands in Brittany selected from their iron status markers, primarily serum iron, serum ferritin, and transferrin saturation, Mura et al. (1997) investigated the relationships between the hemochromatosis phenotype and genotypes at the HLA-H locus and surrounding markers. They found that the C282Y substitution is unambiguously associated with the hemochromatosis phenotype; 81.2% of all patients were homozygous. The subgroup of heterozygous individuals showed lower values for serum ferritin, transferrin saturation, and iron removed by phlebotomy than did the subgroup of hemochromatosis patients homozygous for C282Y. In the subgroup not homozygous for C282Y, no other mutation in the HLA-H gene was found; hence, the genotype remained unclear. The authors suggested additional nongenetic cause, other mutations, or another gene as explanations for the results in these patients.

Rhodes et al. (1997) reported haplotype and mutation analysis in a 3-generation family. Three sibs with overt hemochromatosis, 1 male and 2 females aged 50 to 53 years, showed homozygosity for the C282Y mutation. However, homozygosity for the mutation was detected in an asymptomatic and biochemically normal 50-year-old male sib of the affected individuals. Rhodes et al. (1997) concluded that this finding caused them to question the possibility of population and presymptomatic screening by genetic testing for hemochromatosis.

Roth et al. (1997) found no instance of the C282Y substitution in the HFE gene of individuals originating from Algeria, Ethiopia, or Senegal, whereas it is highly prevalent in populations of European ancestry. The geographic distribution supported the previously suggested Celtic origin of hemochromatosis. In contrast, the H63D substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the central Ethiopians and Algerians genotyped for this study. Thus, the H63D substitution must have occurred earlier than the C282Y substitution.

Merryweather-Clarke et al. (1997) reported the prevalence of the C282Y and H63D mutations in 2,978 people from 42 different populations worldwide. The authors found the highest frequency of C282Y in northern European populations, consistent with the theory of a north European origin for the mutation. In this report, C282Y was seen rarely in the African, Asian, and Australasian chromosomes studied, while H63D was more widely distributed.

Although hemochromatosis is common in Caucasians, affecting more than 1 in 300 individuals of northern European origin, the disorder has not been recognized in other populations. Cullen et al. (1998) used PCR and restriction-enzyme digestion to analyze the frequency of the C282Y and H63D mutations in HLA-typed samples of non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders. They found that the C282Y mutation was present in these populations (allele frequency 0.32%), and that it was always seen in conjunction with HLA haplotypes common in Caucasians, suggesting that C282Y may have been introduced into these populations by Caucasian admixture. They found the H63D mutation at an allele frequency of 2.68% in the 2 populations analyzed (Australian Aboriginal and Chinese). In the Australian Aboriginal samples, H63D was found to be associated with HLA haplotypes common in Caucasians, again suggesting that it was introduced by recent admixture. In the Chinese samples analyzed, on the other hand, H63D was present in association with a wide variety of HLA haplotypes, showing that this mutation is widespread and likely to predate the more genetically restricted C282Y mutation.

In European populations, Lucotte (1998) found the frequency of the C282Y mutation to be 6.88% in Celtics, 6.46% in Nordics, 5.95% in Anglo-Saxons, 2.53% in southern Europeans, and 1.76% in Russians. They believed these findings supported the suggestion concerning the Celtic origin of the mutation. Celtic origin of the mutation was also supported by the finding of Ryan et al. (1998) of a 14% carrier frequency of the C282Y allele in Ireland, the highest frequency reported to the time of report.

Jeffrey et al. (1999) identified a single nucleotide polymorphism (5569G-A; 613609.0004) in intron 4 of the HFE gene that caused overestimation of C282Y homozygote prevalence in hemochromatosis.

Beutler et al. (2002) screened 41,038 individuals attending a health appraisal clinic in the U.S. for the C282Y and H63D (613609.0002) HFE mutations, and analyzed laboratory data on signs and symptoms of hemochromatosis as elicited by questionnaire. The most common symptoms of hemochromatosis were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls; there was no measurable loss of such individuals from the population during aging. However, there was a significantly increased prevalence of a history of hepatitis or 'liver trouble' among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only 1 of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of hemochromatosis. Beutler et al. (2002) concluded that the penetrance of hereditary hemochromatosis is much lower than generally thought. They estimated that less than 1% of homozygotes develop frank clinical hemochromatosis.

Poullis et al. (2002) concluded that Beutler et al. (2002) underestimated the penetrance of the C282Y HFE mutation. The immigration of Hispanic and Asian populations into southern California may have influenced the frequency.

Within South Wales, McCune et al. (2002) performed a systematic review of patients with HH over a 2-year period which revealed that only 1.2% of adult C282Y homozygotes had been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% had more than 4 grams of iron (the diagnostic threshold for iron overload). McCune et al. (2002) stated that screening the general UK population by genetic testing could identify thousands of individuals homozygous for the C282Y mutation, but the majority would not express a phenotype leading to a diagnosis of HH and would likely remain healthy. They concluded that until the cofactors determining disease expression were more fully understood, the benefits of such screening, both to the individual and to the community, would likely be outweighed by the costs.

Andersen et al. (2004) undertook to determine the progression rate of iron overload in hereditary hemochromatosis in individuals in the general population, and to answer the question of how frequently asymptomatic C282Y homozygotes identified in the population need to be screened for manifestations of hemochromatosis in later years. As a function of biologic age, transferrin saturation and ferritin levels increase slightly in male and female C282Y homozygotes. None of the C282Y homozygotes developed clinically overt hemochromatosis. The authors concluded that most such homozygotes need to be screened for manifestation of hemochromatosis every 10 to 20 years.

Saric et al. (2006) estimated the frequency of the C282Y mutation to be 1.6% in the population of Serbia and Montenegro. The authors noted that the frequency of C282Y decreases going from northwest to southeast Europe, consistent with a Viking or Celtic origin.

Livesey et al. (2004) analyzed the presence of the common mtDNA 16189T-C variant, which appears to be a risk factor for type 2 diabetes (125853), in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. The frequency of the 16189 variant was found to be elevated in individuals with hemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic. They concluded that iron loading in C282Y homozygotes with hemochromatosis was exacerbated by the presence of the 16189 variant.

Allen et al. (2008) reported on a study of HFE mutations in 31,192 persons of northern European descent between ages 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1,438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), they obtained clinical and biochemical data, including 2 sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. The proportion of C282Y homozygotes with documented iron overload-related disease was 28.4% for men and 1.2% for women. Only 1 non-C282Y homozygote (a compound heterozygote with his63 to asp) had documented iron overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1,000 micrograms per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wildtype gene. Waalen and Beutler (2008) and Rienhoff (2008) commented that the study by Allen et al. (2008) may have overestimated the clinical prevalence and penetrance of iron-overload disease in C282Y homozygotes.

Levy et al. (1999) produced 2 mutations in the murine Hfe gene. The first mutation deleted a large portion of the coding sequence, generating a null allele. The second mutation introduced the C282Y change into the Hfe gene but otherwise left the gene intact. Homozygosity for either mutation resulted in postnatal iron loading. The effects of the null mutation were more severe than the effects of the C282Y mutation. The mice heterozygous for either mutation accumulated more iron than normal controls. Although liver iron stores were greatly increased, splenic iron was decreased. Levy et al. (1999) concluded that the C282Y mutation does not result in a null allele.

Hemochromatosis, Juvenile

Merryweather-Clarke et al. (2003) reported an individual with a juvenile hemochromatosis (602390) phenotype who was heterozygous for the C282Y mutation in the HFE gene as well as a 4-bp HAMP frameshift mutation (606464.0003). In another family, they found the C282Y mutation in HFE together with a G71D mutation in HAMP (606464.0004). There was a correlation between severity of iron overload, heterozygosity for a G71D HAMP mutation, and heterozygosity or homozygosity for the HFE C282Y mutation.

Porphyria Cutanea Tarda

Roberts et al. (1997) analyzed 41 patients with sporadic porphyria cutanea tarda and 101 controls for the presence of the C282Y and H63D mutations. They identified the C282Y mutation in 18 (44%) patients compared to 11 (11%) controls (relative risk = 6.2; p = 0.00003); 7 patients were homozygotes. In 12 patients, the C282Y mutation was associated with markers of the HLA-A3-containing ancestral hemochromatosis haplotype. There was no difference in the frequency of the H63D mutation between the 2 groups. Roberts et al. (1997) concluded that inheritance of one or more hemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda. They noted that some C282Y homozygotes present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with hemochromatosis.

Among 8 patients with porphyria cutanea tarda, Mehrany et al. (2004) found that 6 had mutations in the HFE gene: 3 were homozygous for C282Y, 1 was compound heterozygous for C282Y and H63D, and 2 were heterozygous for C282Y. Mehrany et al. (2004) noted that early detection and treatment of hereditary hemochromatosis limits progression of PCT and improves life expectancy.

Porphyria Variegata

De Villiers et al. (1999) found that the mutant allele frequency of the C282Y mutation was significantly lower in 73 apparently unrelated variegate porphyria (176200) patients with the arg59-to-trp mutation in the PPOX gene (600923.0003) than in 102 controls drawn from the same population (P = 0.005). The authors concluded that the population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supported previous data on involvement of the HFE gene in the porphyria phenotype. Iron overload is a well-established precipitating or aggravating factor in porphyria variegata.

Transferrin Serum Level Quantitative Trait Locus 2

In a genomewide association study of Australians of European descent, Benyamin et al. (2009) found that the C282Y variant (rs1800562) was associated with serum iron (p = 3.5 x 10(-11)), serum transferrin (see TFQTL2, 614193) (p = 1.1 x 10(-10)), transferrin saturation (p = 4.3 x 10(-15)), and serum ferritin (see FTH1, 134770) (p = 4.5 x 10(-5)). C282Y explained 9.5%, 9.1%, 13.2%, and 3.7% of the variation in means of serum iron, serum transferrin, transferrin saturation, and serum ferritin levels, respectively. Three SNPs in the TF gene plus the HFE C282Y mutation explained about 40% of genetic variation in serum transferrin (p = 7.8 x 10(-25)).

Microvascular Complications of Diabetes 7, Susceptibility to

Walsh and Malins (1978) reported an association between diabetic retinopathy (MVCD7; 603933) and idiopathic hemochromatosis. Peterlin et al. (2003) searched for a relationship between the C282Y and H63D gene mutations and the development of proliferative diabetic retinopathy in Caucasians with type 2 diabetes (125853). A significantly higher frequency of C282Y heterozygosity was found in patients with proliferative diabetic retinopathy compared to subjects without it, whereas no association was demonstrated with H63D. Logistic regression analysis revealed that the C282Y mutation was a significant independent risk factor for the development of PDR (odds ratio = 6.1; p = 0.027).

Oliva et al. (2004) analyzed the C282Y HFE polymorphism in 225 Spanish patients with type 2 diabetes and detected a younger age of onset and longer duration of disease in patients carrying at least 1 C282Y allele. They also found an increased prevalence of retinopathy (p = 0.014) and of nephropathy (p = 0.04) in individuals carrying at least 1 C282Y allele; the increased prevalence of retinopathy, but not nephropathy, in C282Y carriers was related to increased duration of disease. Multivariate logistic regression analysis confirmed that the prevalence of nephropathy was higher in the group of patients carrying at least 1 Y allele.

Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses.

Alzheimer Disease

Robson et al. (2004) noted that there is evidence that iron may play a role in the pathology of Alzheimer disease (104300). Thus, genetic factors that contribute to iron deposition resulting in tissue damage might exacerbate AD. The authors examined the interaction between the C2 variant of the TF gene (190000.0004) and the C282Y allele of the HFE gene, the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 (see 107741) were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that their results indicated that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition.


.0002 RECLASSIFIED - HFE POLYMORPHISM

HFE, HIS63ASP
  
RCV000000026...

This variant has been reclassified as a polymorphism because the H63D variant is present in the gnomad database (v2.1.1) in 30,592 of 282,855 alleles and in 2,023 homozygotes, with an allele frequency of 0.1082 (Hamosh, 2023).

Drakesmith et al. (2002) used a numbering system beginning with the first amino acid of the mature HFE protein, omitting the 22 amino acids of the signal sequence, so that H63 of the immature protein is H41 in the mature protein.

Hemochromatosis, Type 1

In 9 patients with hemochromatosis (HFE1; 235200) who were heterozygous for the C282Y mutation (613609.0001), Feder et al. (1996) identified a C-to-G transversion in exon 2 of the HFE gene, resulting in a his63-to-asp substitution (H63D). This variant was present in 8 of the 9 (89%) nonancestral chromosomes, representing a significant enrichment over the 17% frequency observed in control chromosomes. One patient was homozygous for the H63D variant.

An analysis of the H63D mutation in 13 families by Jouanolle et al. (1996) did not support a relationship to HFE. The mutation was present in 3 of 26 heterozygous parents of probands and in each case it was present on the normal chromosome; the analysis of these individuals did not support a compound heterozygous contribution to HFE.

In a study of 115 unrelated patients with hereditary hemochromatosis, the UK Haemochromatosis Consortium (1997) found 1 patient who was homozygous for the H63D mutation. However, 3 homozygotes with no evidence of iron overloading were found among 101 control samples derived from healthy blood donors. In addition, compound heterozygosity for the H63D and C232Y mutations was found in 3 patients and 4 controls.

Beutler (1997), commenting on the conclusion of Carella et al. (1997) that H63D is a polymorphic change, assembled evidence supporting the likelihood that it is a hemochromatosis-causing mutation with reduced penetrance. He suggested that most of the heterozygotes with mild disease manifestations reported before discovery of the HFE gene will prove, in fact, to be compound heterozygotes for C282Y (613609.0001) and H63D.

Aguilar-Martinez et al. (2001) investigated the phenotypic consequences of H63D homozygosity in 56 French homozygotes identified from a series of blood samples submitted for HFE genotyping in response to a confirmed (12) or suspected (38) clinical diagnosis of hemochromatosis or a family history of hemochromatosis (6). Of these, 50 (89%) had evidence of iron overload. In 16 individuals (32%) this appeared to be a phenomenon secondary to dysmetabolic iron overload syndrome, porphyria cutanea tarda, alcohol use, or hepatitis. In the remaining 34 (68%) individuals a secondary cause of iron overload was not identified: 12 had a phenotypic diagnosis of hemochromatosis and the remaining 22 had ill-defined, variable degrees of iron overload with no apparent cause. Extended genetic analysis failed to demonstrate any association between phenotype and other HFE mutations/polymorphisms or the TFR2 Y250X mutation (604720.0001)/TFR2 polymorphisms. The authors commented that, in this selected population, H63D homozygosity was associated with extremely variable phenotypes. They suggested that factors such as age and sex may be important nongenetic phenotypic modifiers.

Cardoso et al. (2002) analyzed linkage disequilibrium between HLA alleles and HFE mutations in a Portuguese population. The results confirmed linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. Extensions of these studies showed significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a coselection of H63D and the HLA-A29 allele itself. Insight into the biologic significance of this association was given by the finding of significantly higher CD8+ T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

To examine whether the HFE H63D mutation is pathogenic, Tomatsu et al. (2003) generated knockin mice homozygous for H67D (corresponding to human H63D), mice homozygous for C294Y (corresponding to human C282Y), and mice compound heterozygous for both mutations. The biochemical and histopathologic severity of hepatic iron loading was significantly increased in all 3 groups compared to control mice, but was less in H67D homozygotes than in compound heterozygotes, and was highest in C294Y homozygotes. Only the C294Y homozygous mice showed a significant increase in transferrin saturation compared to controls. Tomatsu et al. (2003) concluded that the H67D allele, when homozygous or combined with a more severe mutation, leads to partial loss of Hfe function in mice and to increased hepatic iron loading.

Microvascular Complications of Diabetes 7, Susceptibility to

Moczulski et al. (2001) analyzed the H63D polymorphism in 563 Polish patients with type 2 diabetes (125853) and 196 controls and observed an increased frequency of the 63D allele (odds ratio, 1.8) among patients with diabetic nephropathy (MVCD7; 612635).

In a study of 225 Spanish patients with type 2 diabetes, Oliva et al. (2004) found that the prevalence of nephropathy was higher in the group of patients carrying the homozygous D/D genotype compared to the group carrying the wildtype or heterozygous D genotypes.

Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses.


.0003 HEMOCHROMATOSIS, TYPE 1

HFE, SER65CYS
  
RCV000000028...

Mura et al. (1999) reported on the analysis of the cys282-to-tyr (C282Y; 613609.0001), his63-to-asp (H63D; 613609.0002), and ser65-to-cys (S65C) mutations of the HFE gene in a series of 711 probands with hereditary hemochromatosis (235200) and 410 controls. The results confirmed that the C282Y substitution is the main mutation involved in HH, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, the screening showed that the S65C substitution, which results from a 193A-T transversion, was significantly enriched in probands with at least 1 chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggested that the S65C substitution is associated with a mild form of hemochromatosis.

Barton et al. (1999) identified the S65C mutation in 2 patients. One was also heterozygous for C282Y, i.e., was a compound heterozygote, and had porphyria cutanea tarda (see 176100). The other patient had hereditary stomatocytosis (185000). Iron overload due to the HFE mutations probably precipitated or exacerbated the porphyria cutanea tarda in the first patient. In the second patient, iron overload from the hereditary stomatocytosis undoubtedly exacerbated the iron overload due to the HFE mutation.


.0004 HFE INTRONIC POLYMORPHISM

HFE, 5569G-A
  
RCV000000031...

In a population screening study of 5,211 voluntary blood donors, Jeffrey et al. (1999) identified 31 putative 5474A (613609.0001) homozygotes. When they validated the assay by genomic DNA sequence analysis, only 16 individuals were confirmed to be 5474A homozygotes and the remaining 15 were heterozygous for this mutation. Each of the 5474A heterozygotes was also heterozygous for a previously unrecognized 5569G-A single nucleotide polymorphism located in the binding region of the antisense primer. Jeffrey et al. (1999) developed a new antisense primer that excluded the site of this newly found polymorphism and confirmed the 15 putative homozygotes to be 5474A heterozygotes using restriction endonuclease digestion. Hill and Robertson's maximum likelihood estimate of linkage disequilibrium D (Hill and Robertson, 1968) was 0.71 (P less than 0.005), confirming the presence of moderate to strong linkage disequilibrium between the 2 variant sites. It was considered unlikely that the 5569A polymorphism has functional significance, because it is within intron 4 and does not disrupt a splice site consensus sequence. Moreover, all 5474A/5569A compound heterozygotes had a transferrin saturation in the normal range. In their population survey, Jeffrey et al. (1999) found that 21% of 113 normal patients, corresponding to an allele frequency of 0.106, had the polymorphism. In their sample, the prevalence of hemochromatosis was reduced from 1 in 168 to 1 in 327 by the use of new primers. These results had major public health implications regarding the use of population screening for hemochromatosis. Individuals previously considered to be nonexpressing 5474A homozygotes on the basis of PCR-based restriction endonuclease digestion assay using the original Feder et al. (1996) primers require confirmatory testing.

The European Haemochromatosis Consortium (1999), representing 11 laboratories, retyped 944 samples for the C282Y mutation (613609.0001) by a primer external to the 5569G-A polymorphism or by sequencing. Five hundred seventy-five previously diagnosed C282Y homozygotes were confirmed using the new primer, as well as 192 C282Y wildtype homozygotes, including 10 carrying the polymorphism in homozygosity, and 177 heterozygotes. Of the heterozygotes, 28 were C282Y/5569G-A compound heterozygotes which had been reported correctly using the original Feder reverse primer. The European Haemochromatosis Consortium (1999) did not observe nonamplification of the polymorphic allele, demonstrating that the validity of their previous publications was not compromised by findings reported by Jeffrey et al. (1999). Noll et al. (1999) confirmed the observations of the European Haemochromatosis Consortium (1999). Gomez et al. (1999) reevaluated 221 putative C282Y homozygotes; 219 were confirmed and 2 were found to be 5569A/282Y compound heterozygotes without clinical evidence of iron overload. There was a significantly higher prevalence of the 5569A allele in a group of healthy controls (33 of 314, or 10.5%) than in the putative HFE C282Y homozygous group (2 of 442, or 0.45%), suggesting that the polymorphism is very common, but is not found on the same founder chromosome as the C282Y mutation.


.0005 HFE POLYMORPHISM

HFE, VAL53MET
  
RCV000000032...

In a mutation analysis of the HFE gene using DNA samples from members of 4 different ethnic groups in South Africa, de Villiers et al. (1999) identified a 157G-A transition in exon 2 of the HFE gene, resulting in a val53-to-met (V53M) substitution. The mutation was detected only in South African Black and Bushman (Khoisan) populations. The mutation created a new NlaIII site and abolished an MaeII site.


.0006 HFE POLYMORPHISM

HFE, VAL59MET
  
RCV000000033...

In a mutation analysis of the HFE gene using DNA samples from members of 4 different ethnic groups in South Africa, de Villiers et al. (1999) identified a 175G-A transition in exon 2 of the HFE gene, resulting in a val59-to-met (V59M) substitution in a South African Caucasian. The mutation created an NlaIII site.


.0007 HEMOCHROMATOSIS, TYPE 1

HFE, GLN127HIS
  
RCV000000034

In an 11-year-old girl with hemochromatosis (235200) and variegate porphyria (176200), de Villiers et al. (1999) identified compound heterozygosity for mutations in the HFE gene: a 381A-C transversion in exon 3 resulting in a gln127-to-his (Q127H) substitution, and a his63-to-asp (613609.0002) substitution. The severely affected patient carried the R59W mutation (600923.0003) in the PPOX gene, which accounts for dominantly inherited variegate porphyria in more than 80% of affected South Africans. Iron overload is a well-established precipitating or exacerbating factor in porphyria variegata.


.0008 HEMOCHROMATOSIS, TYPE 1

HFE, ARG330MET
  
RCV000000035

Among 13 Caucasian South African patients referred for a molecular diagnosis of hereditary hemochromatosis (235200), de Villiers et al. (1999) identified a 989G-T transversion in exon 5 of the HFE gene, resulting in an arg330-to-met (R330M) substitution.


.0009 HEMOCHROMATOSIS, TYPE 1

HFE, ILE105THR
  
RCV000000029...

In a patient with hemochromatosis (235200), Barton et al. (1999) identified compound heterozygosity for a 314T-C transition in exon 2 of the HFE gene, resulting in an ile105-to-thr (I105T) substitution, and the H63D mutation (613609.0002).


.0010 HEMOCHROMATOSIS, TYPE 1

HFE, GLY93ARG
  
RCV000000030

In a patient with hemochromatosis (235200), Barton et al. (1999) identified compound heterozygosity for a 277G-C transversion in exon 2 of the HFE gene, resulting in a gly93-to-arg (G93R) substitution, and the C282Y mutation (613609.0001).


.0011 HEMOCHROMATOSIS, TYPE 1

HFE, GLN283PRO
  
RCV000000036...

In affected members of a French family with hemochromatosis (235200), Le Gac et al. (2003) identified compound heterozygosity for 2 mutations in the HFE gene: an 848A-C transversion in exon 4, resulting in a gln283-to-pro (Q283P) substitution within the alpha-3 domain, and a C282Y (613609.0001) substitution. Molecular modeling studies predicted a destabilizing effect for the Q283P substitution on the tertiary structure of the protein.

By performing immunoprecipitation studies in HeLa cells, Ka et al. (2005) found that the Q283P mutation prevented the normal interaction between HFE protein and beta-2-microglobulin (B2M; 109700) and between HFE protein and transferrin receptor (TFRC; 190010). Further studies showed that the Q283P mutation decreased the capacity of HFE to reduce transferrin-mediated iron uptake. Ka et al. (2005) noted that the Q283P mutation is adjacent to the disulfide bridge formed by cys225 and cys282, and concluded that the Q283P protein is retained in the endoplasmic reticulum and middle Golgi compartments, similar to the C282Y mutant protein. The results indicated that the Q283P mutation leads to structural and functional consequences similar to those described for the more common C282Y mutation.


REFERENCES

  1. Aguilar-Martinez, P., Bismuth, M., Picot, M. C., Thelcide, C., Pageaux, G.-P., Blanc, F., Blanc, P., Schved, J.-F., Larrey, D. Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause? Gut 48: 836-842, 2001. [PubMed: 11358905, related citations] [Full Text]

  2. Allen, K. J., Gurrin, L. C., Constantine, C. C., Osborne, N. J., Delatycki, M. B., Nicoll, A. J., McLaren, C. E., Bahlo, M., Nisselle, A. E., Vulpe, C. D., Anderson, G. J., Southey, M. C., Giles, G. G., English, D. R., Hopper, J. L., Olynyk, J. K., Powell, L. W., Gertig, D. M. Iron-overload-related disease in HFE hereditary hemochromatosis. New Eng. J. Med. 358: 221-230, 2008. [PubMed: 18199861, related citations] [Full Text]

  3. Andersen, R. V., Tybjaerg-Hansen, A., Appleyard, M., Birgens, H., Nordestgaard, B. G. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 103: 2914-2919, 2004. [PubMed: 15070663, related citations] [Full Text]

  4. Bahram, S., Gilfillan, S., Kuhn, L. C., Moret, R., Schulze, J. B., Lebeau, A., Schumann, K. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc. Nat. Acad. Sci. 96: 13312-13317, 1999. [PubMed: 10557317, images, related citations] [Full Text]

  5. Barton, J. C., Rothenberg, B. E., Bertoli, L. F., Acton, R. T. Diagnosis of hemochromatosis in family members of probands: a comparison of phenotyping and HFE genotyping. Genet. Med. 1: 89-93, 1999. [PubMed: 11336458, related citations] [Full Text]

  6. Barton, J. C., Sawada-Hirai, R., Rothenberg, B. E., Acton, R. T. Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Molec. Dis. 25: 147-155, 1999. [PubMed: 10575540, related citations] [Full Text]

  7. Benyamin, B., McRae, A. F., Zhu, G., Gordon, S., Henders, A. K., Palotie, A., Peltonen, L., Martin, N. G., Montgomery, G. W., Whitfield, J. B., Visscher, P. M. Variants in TF and HFE explain about 40% of genetic variation in serum-transferrin levels. Am. J. Hum. Genet. 84: 60-65, 2009. [PubMed: 19084217, images, related citations] [Full Text]

  8. Beutler, E., Felitti, V. J., Koziol, J. A., Ho, N. J., Gelbart, T. Penetrance of 845G-A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359: 211-218, 2002. [PubMed: 11812557, related citations] [Full Text]

  9. Beutler, E., Gelbart, T., West, C., Lee, P., Adams, M., Blackstone, R., Pockros, P., Kosty, M., Venditti, C. P., Phatak, P. D., Seese, N. K., Chorney, K. A., Ten Elshof, A. E., Gerhard, G. S., Chorney, M. Mutation analysis in hereditary hemochromatosis. Blood Cells Molec. Dis. 22: 187-194, 1996. [PubMed: 8931958, related citations] [Full Text]

  10. Beutler, E. The significance of the 187G (H63D) mutation in hemochromatosis. (Letter) Am. J. Hum. Genet. 61: 762-764, 1997. [PubMed: 9326341, related citations]

  11. Beutler, E. Targeted disruption of the HFE gene. Proc. Nat. Acad. Sci. 95: 2033-2034, 1998. [PubMed: 9482831, related citations] [Full Text]

  12. Bodmer, J. G., Parham, P., Albert, E. D., Marsh, S. G. E. Putting a hold on 'HLA-H'. (Letter) Nature Genet. 15: 234-235, 1997. [PubMed: 9054933, related citations] [Full Text]

  13. Cardoso, C. S., Alves, H., Mascarenhas, M., Goncalves, R., Oliveira, P., Rodrigues, P., Cruz, E., de Sousa, M., Porto, G. Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium? Immunogenetics 53: 1002-1008, 2002. [PubMed: 11904676, related citations] [Full Text]

  14. Carella, M., D'Ambrosio, L., Totaro, A., Grifa, A., Valentino, M. A., Piperno, A., Girelli, D., Roetto, A., Franco, B., Gasparini, P., Camaschella, C. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am. J. Hum. Genet. 60: 828-832, 1997. [PubMed: 9106528, related citations]

  15. Cullen, L. M., Gao, X., Easteal, S., Jazwinska, E. C. The hemochromatosis 845 G-to-A and 187 C-to-G mutations: prevalence in non-Caucasian populations. Am. J. Hum. Genet. 62: 1403-1407, 1998. [PubMed: 9585606, related citations] [Full Text]

  16. Davis, T. M. E., Beilby, J., Davis, W. A., Olynyk, J. K., Jeffrey, G. P., Rossi, E., Boyder, C., Bruce, D. G. Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care 31: 1795-1801, 2008. [PubMed: 18566337, related citations] [Full Text]

  17. de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J. Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999. [PubMed: 10401000, related citations] [Full Text]

  18. Drakesmith, H., Chen, N., Ledermann, H., Screaton, G., Townsend, A., Xu, X.-N. HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proc. Nat. Acad. Sci. 102: 11017-11022, 2005. [PubMed: 16043695, images, related citations] [Full Text]

  19. Drakesmith, H., Sweetland, E., Schimanski, L., Edwards, J., Cowley, D., Ashraf, M., Bastin, J., Townsend, A. R. M. The hemochromatosis protein HFE inhibits iron export from macrophages. Proc. Nat. Acad. Sci. 99: 15602-15607, 2002. [PubMed: 12429850, images, related citations] [Full Text]

  20. El Kahloun, A., Chauvel, B., Mauvieux, V., Dorval, I., Jouanolle, A.-M., Gicquel, I., Le Gall, J.-Y., David, V. Localization of seven new genes around the HLA-A locus. Hum. Molec. Genet. 2: 55-60, 1993. [PubMed: 8490624, related citations] [Full Text]

  21. European Haemochromatosis Consortium. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. (Letter) Nature Genet. 23: 271 only, 1999. [PubMed: 10545942, related citations] [Full Text]

  22. Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13: 399-408, 1996. [PubMed: 8696333, related citations] [Full Text]

  23. Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., Schatzman, R. C. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc. Nat. Acad. Sci. 95: 1472-1477, 1998. [PubMed: 9465039, images, related citations] [Full Text]

  24. Feder, J. N., Tsuchihashi, Z., Irrinki, A., Lee, V. K., Mapa, F. A., Morikang, E., Prass, C. E., Starnes, S. M., Wolff, R. K., Parkkila, S., Sly, W. S., Schatzman, R. C. The hemochromatosis founder mutation in HLA-H disrupts beta-2-microglobulin interaction and cell surface expression. J. Biol. Chem. 272: 14025-14028, 1997. [PubMed: 9162021, related citations] [Full Text]

  25. Gao, J., Zhao, N., Knutson, M. D., Enns, C. A. The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells. J. Biol. Chem. 283: 21462-21468, 2008. [PubMed: 18524764, images, related citations] [Full Text]

  26. Goei, V. L., Parimoo, S., Capossela, A., Chu, T. W., Gruen, J. R. Isolation of novel non-HLA gene fragments from the hemochromatosis region (6p21.3) by cDNA hybridization selection. Am. J. Hum. Genet. 54: 244-251, 1994. [PubMed: 8304341, related citations]

  27. Gomez, P. S., Parks, S., Ries, R., Tran, T. C., Gomez, P. F., Press, R. D. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results (Letter) Nature Genet. 23: 272 only, 1999. [PubMed: 10545944, related citations] [Full Text]

  28. Hamosh, A. Personal Communication. Baltimore, Md. 8/10/2023.

  29. Hashimoto, K., Hirai, M., Kurosawa, Y. A gene outside the human MHC related to classical HLA class I genes. Science 269: 693-695, 1995. [PubMed: 7624800, related citations] [Full Text]

  30. Hashimoto, K., Hirai, M., Kurosawa, Y. Identification of a mouse homolog for the human hereditary haemochromatosis candidate gene. Biochem. Biophys. Res. Commun. 230: 35-39, 1997. [PubMed: 9020055, related citations] [Full Text]

  31. Hill, W. G., Robertson, A. Linkage disequilibrium in finite populations. Theor. Appl. Genet. 38: 226-231, 1968. [PubMed: 24442307, related citations] [Full Text]

  32. Jazwinska, E. C., Cullen, L. M., Busfield, F., Pyper, W. R., Webb, S. I., Powell, L. W., Morris, C. P., Walsh T. P. Haemochromatosis and HLA-H. (Letter) Nature Genet. 14: 249-251, 1996. [PubMed: 8896549, related citations] [Full Text]

  33. Jeffrey, G. P., Chakrabarti, S., Hegele, R. A., Adams, P. C. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis. (Letter) Nature Genet. 22: 325-326, 1999. [PubMed: 10431233, related citations] [Full Text]

  34. Jenkitkasemwong, S., Wang, C.-Y., Coffey, R., Zhang, W., Chan, A., Biel, T., Kim, J.-S., Hojyo, S., Fukada, T., Knutson, M. D. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22: 138-150, 2015. [PubMed: 26028554, images, related citations] [Full Text]

  35. Jouanolle, A. M., Fergelot, P., Gandon, G., Yaouanq, J., Le Gall, J. Y., David, V. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations. Hum. Genet. 100: 544-547, 1997. [PubMed: 9341868, related citations] [Full Text]

  36. Jouanolle, A. M., Gandon, G., Jezequel, P., Blayau, M., Campion, M. L., Yaouanq, J., Mosser, J., Fergelot, P., Chauvel, B., Bouric, P., Carn, G., Andrieux, N., Gicquel, I., Le Gall, J.-Y., David, V. Haemochromatosis and HLA-H. (Letter) Nature Genet. 14: 251-252, 1996. [PubMed: 8896550, related citations] [Full Text]

  37. Ka, C., Le Gac, G., Dupradeau, F.-Y., Rochette, J., Ferec, C. The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein. Hum. Genet. 117: 467-475, 2005. [PubMed: 15965644, related citations] [Full Text]

  38. Le Gac, G., Dupradeau, F.-Y., Mura, C., Jacolot, S., Scotet, V., Esnault, G., Mercier, A.-Y., Rochette, J., Ferec, C. Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect. Blood Cells Molec. Dis. 30: 231-237, 2003. [PubMed: 12737937, related citations] [Full Text]

  39. Lebron, J. A., Bennett, M. J., Vaughn, D. E., Chirino, A. J., Snow, P. M., Mintier, G. A., Feder, J. N., Bjorkman, P. J. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93: 111-123, 1998. [PubMed: 9546397, related citations] [Full Text]

  40. Levy, J. E., Montross, L. K., Cohen, D. E., Fleming, M. D., Andrews, N. C. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94: 9-11, 1999. [PubMed: 10381492, related citations]

  41. Livesey, K. J., Wimhurst, V. L. C., Carter, K., Worwood, M., Cadet, E., Rochette, J., Roberts, A. G., Pointon, J. J., Merryweather-Clarke, A. T., Bassett, M. L., Jouanolle, A.-M., Mosser, A., David, V., Poulton, J., Robson, K. J. H. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J. Med. Genet. 41: 6-10, 2004. [PubMed: 14729817, related citations] [Full Text]

  42. Lucotte, G. Celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Molec. Dis. 24: 433-438, 1998. [PubMed: 9851897, related citations] [Full Text]

  43. McCune, C. A., Al-Jader, L. N., May, A., Hayes, S. L., Jackson, H. A., Worwood, M. Hereditary haemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum. Genet. 111: 538-543, 2002. [PubMed: 12436244, related citations] [Full Text]

  44. Mehrany, K., Drage, L. A., Brandhagen, D. J., Pittelkow, M. R. Association of porphyria cutanea tarda with hereditary hemochromatosis. J. Am. Acad. Derm. 51: 205-211, 2004. [PubMed: 15280838, related citations] [Full Text]

  45. Mercier, B., Mura, C., Ferec, C. Putting a hold on 'HLA-H'. (Letter) Nature Genet. 15: 234 only, 1997. [PubMed: 9054932, related citations] [Full Text]

  46. Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum. Molec. Genet. 12: 2241-2247, 2003. [PubMed: 12915468, related citations] [Full Text]

  47. Merryweather-Clarke, A. T., Pointon, J. J., Shearman, J. D., Robson, K. J. H. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34: 275-278, 1997. [PubMed: 9138148, related citations] [Full Text]

  48. Moczulski, D. K., Grzeszczak, W., Gawlik, B. Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care 24: 1187-1191, 2001. [PubMed: 11423500, related citations] [Full Text]

  49. Mura, C., Nousbaum, J.-B., Verger, P., Moalic, M.-T., Raguenes, O., Mercier, A.-Y., Ferec, C. Phenotype-genotype correlation in haemochromatosis subjects. Hum. Genet. 101: 271-276, 1997. [PubMed: 9439654, related citations] [Full Text]

  50. Mura, C., Raguenes, O., Ferec, C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93: 2502-2505, 1999. [PubMed: 10194428, related citations]

  51. Nairz, M., Theurl, I., Schroll, A., Theurl, M., Fritsche, G., Lindner, E., Seifert, M., Crouch, M.-L. V., Hantke, K., Akira, S., Fang, F. C., Weiss, G. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar typhimurium infection via induction of lipocalin-2. Blood 114: 3642-3651, 2009. [PubMed: 19700664, images, related citations] [Full Text]

  52. Noll, W. W., Belloni, D. R., Stenzel, T. T., Grody, W. W. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. (Letter) Nature Genet. 23: 271-272, 1999. [PubMed: 10545943, related citations] [Full Text]

  53. Oliva, R., Novials, A., Sanchez, M., Villa, M., Ingelmo, M., Recasens, M., Ascaso, C., Bruguera, M., Gomis, R. The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2. Endocrine 24: 111-114, 2004. [PubMed: 15347835, related citations] [Full Text]

  54. Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R. E., Sly, W. S. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc. Nat. Acad. Sci. 94: 13198-13202, 1997. [PubMed: 9371823, images, related citations] [Full Text]

  55. Parkkila, S., Waheed, A., Britton, R. S., Feder, J. N., Tsuchihashi, Z., Schatzman, R. C., Bacon, B. R., Sly, W. S. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc. Nat. Acad. Sci. 94: 2534-2539, 1997. [PubMed: 9122230, images, related citations] [Full Text]

  56. Peterlin, B., Petrovic, M. G., Makuc, J., Hawlina, M., Petrovic, D. A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes. J. Hum. Genet. 48: 646-649, 2003. [PubMed: 14618419, related citations] [Full Text]

  57. Poullis, A., Moodie, S. J., Maxwell, J. D. Clinical haemochromatosis in HFE mutation carriers. Lancet 360: 411-412, 2002. [PubMed: 12241803, related citations] [Full Text]

  58. Rhodes, D. A., Raha-Chowdhury, R., Cox, T. M., Trowsdale, J. Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J. Med. Genet. 34: 761-764, 1997. [PubMed: 9321765, related citations] [Full Text]

  59. Rienhoff, H. Y., Jr. Iron-overload-related disease in HFE hereditary hemochromatosis. (Letter) New Eng. J. Med. 358: 2294 only, 2008. [PubMed: 18504828, related citations]

  60. Roberts, A. G., Whatley, S. D., Morgan, R. R., Worwood, M., Elder, G. H. Increased frequency of the haemochromatosis cys282tyr mutation in sporadic porphyria cutanea tarda. Lancet 349: 321-323, 1997. [PubMed: 9024376, related citations] [Full Text]

  61. Robson, K. J. H., Lehmann, D. J., Wimhurst, V. L. C., Livesey, K. J., Combrinck, M., Merryweather-Clarke, A. T., Warden, D. R., Smith, A. D. Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. J. Med. Genet. 41: 261-265, 2004. [PubMed: 15060098, related citations] [Full Text]

  62. Rohrlich, P. S., Fazilleau, N., Ginhoux, F., Firat, H., Michel, F., Cochet, M., Laham, N., Roth, M. P., Pascolo, S., Nato, F., Coppin, H., Charneau, P., Danos, O., Acuto, O., Ehrlich, R., Kanellopoulos, J., Lemonnier, F. A. Direct recognition by alpha-beta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Nat. Acad. Sci. 102: 12855-12860, 2005. [PubMed: 16123136, images, related citations] [Full Text]

  63. Roth, M.-P., Giraldo, P., Hariti, G., Poloni, E. S., Sanchez-Mazas, A., De Stefano, G. F., Dugoujon, J.-M., Coppin, H. Absence of the hemochromatosis gene Cys282Tyr mutation in three ethnic groups from Algeria (Mzab), Ethiopia, and Senegal. Immunogenetics 46: 222-225, 1997. [PubMed: 9211748, related citations] [Full Text]

  64. Roy, C. N., Custodio, A. O., de Graaf, J., Schneider, S., Akpan, I., Montross, L. K., Sanchez, M., Gaudino, A., Hentze, M. W., Andrews, N. C., Muckenthaler, M. U. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nature Genet. 36: 481-485, 2004. [PubMed: 15098034, related citations] [Full Text]

  65. Roy, C. N., Penny, D. M., Feder, J. N., Enns, C. A. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chem. 274: 9022-9028, 1999. [PubMed: 10085150, related citations] [Full Text]

  66. Ryan, E., O'Keane, C., Crowe, J. Hemochromatosis in Ireland and HFE. Blood Cells Mol. Dis. 24: 428-432, 1998. [PubMed: 9851896, related citations] [Full Text]

  67. Saric, M., Zamurovic, L., Keckarevic-Markovic, M., Keckarevic, D., Stevanovic, M., Savic-Pavicevic, D., Jovic, J., Romac, S. Frequency of the hemochromatosis gene mutations in the population of Serbia and Montenegro. (Letter) Clin. Genet. 70: 170-172, 2006. [PubMed: 16879202, related citations] [Full Text]

  68. The UK Haemochromatosis Consortium. A simple genetic test identifies 90% of UK patients with haemochromatosis. Gut 41: 841-844, 1997. [PubMed: 9462220, related citations] [Full Text]

  69. Thenie, A. C., Gicquel, I. M., Hardy, S., Ferran, H., Fergelot, P., Le Gall, J.-Y., Mosser, J. Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene. Hum. Molec. Genet. 10: 1859-1866, 2001. [PubMed: 11532995, related citations] [Full Text]

  70. Tomatsu, S., Orii, K. O., Fleming, R. E., Holden, C. C., Waheed, A., Britton, R. S., Gutierrez, M. A., Velez-Castrillon, S., Bacon, B. R., Sly, W. S. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc. Nat. Acad. Sci. 100: 15788-15793, 2003. [PubMed: 14673107, images, related citations] [Full Text]

  71. Totaro, A., Rommens, J. M., Grifa, A., Lunardi, C., Carella, M., Huizenga, J. J., Roetto, A., Camaschella, C., De Sandre, G., Gasparini, P. Hereditary hemochromatosis: generation of a transcription map within a refined and extended map of the HLA class I region. Genomics 31: 319-326, 1996. [PubMed: 8838313, related citations] [Full Text]

  72. Waalen, J., Beutler, E. Iron-overload-related disease in HFE hereditary hemochromatosis. (Letter) New Eng. J. Med. 358: 2293-2294, 2008. [PubMed: 18499578, related citations] [Full Text]

  73. Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., Sly, W. S. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta-2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc. Nat. Acad. Sci. 94: 12384-12389, 1997. [PubMed: 9356458, images, related citations] [Full Text]

  74. Wallace, D. F., Subramaniam, V. N. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet. Med. 18: 618-626, 2016. [PubMed: 26633544, related citations] [Full Text]

  75. Walsh, C. H., Malins, J. M. Proliferative retinopathy in a patient with diabetes mellitus and idiopathic haemochromatosis. Brit. Med. J. 2: 16-17, 1978. [PubMed: 678784, related citations] [Full Text]

  76. Yaouanq, J., Perichon, M., Chorney, M., Pontarotti, P., Le Treut, A., El Kahloun, A., Mauvieux, V., Blayau, M., Jouanolle, A. M., Chauvel, B., Moirand, R., Nouel, O., Le Gall, J. Y., Feingold, J., David, V. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE). Am. J. Hum. Genet. 54: 252-263, 1994. [PubMed: 8304342, related citations]

  77. Zhou, X. Y., Tomatsu, S., Fleming, R. E., Parkkila, S., Waheed, A., Jiang, J., Fei, Y., Brunt, E. M., Ruddy, D. A., Prass, C. E., Schatzman, R. C., O'Neill, R., Britton, R. S., Bacon, B. R., Sly, W. S. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Nat. Acad. Sci. 95: 2492-2497, 1998. [PubMed: 9482913, images, related citations] [Full Text]

  78. Zoller, H., Theurl, I., Koch, R. O., McKie, A. T., Vogel, W., Weiss, G. Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology 125: 746-754, 2003. [PubMed: 12949720, related citations] [Full Text]


Ada Hamosh - updated : 10/23/2018
Patricia A. Hartz - updated : 6/9/2016
Paul J. Converse - updated : 7/1/2011
Creation Date:
Carol A. Bocchini : 10/19/2010
alopez : 03/12/2024
carol : 08/10/2023
carol : 05/19/2022
carol : 01/15/2020
alopez : 10/23/2018
carol : 05/02/2018
carol : 10/21/2016
joanna : 07/01/2016
mgross : 6/9/2016
mgross : 6/9/2016
carol : 10/15/2013
carol : 4/12/2013
alopez : 9/1/2011
terry : 7/19/2011
terry : 7/19/2011
mgross : 7/7/2011
terry : 7/1/2011
terry : 1/13/2011
carol : 10/21/2010

* 613609

HOMEOSTATIC IRON REGULATOR; HFE


Alternative titles; symbols

HFE GENE
HLAH


HGNC Approved Gene Symbol: HFE

SNOMEDCT: 1186847009;  


Cytogenetic location: 6p22.2     Genomic coordinates (GRCh38): 6:26,087,429-26,098,343 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6p22.2 Hemochromatosis, type 1 235200 Autosomal recessive 3

TEXT

Cloning and Expression

El Kahloun et al. (1993) used a yeast artificial chromosome with a 320-kb insert of genomic DNA that included the major histocompatibility complex class I HLA-A gene (142800) to screen a human duodenal mucosa cDNA library. They isolated 7 cDNA clones that corresponded to 7 new non-class I structural genes. Since these genes were located within the hemochromatosis (HFE1; 235200) candidate gene region, they referred to the genes as HCG (hemochromatosis candidate gene) I-VII. El Kahloun et al. (1993) concluded that HCG I, III, V, and VI are probably single-copy genes situated 180, 155, 140, and 230 kb, respectively, centromeric to HLA-A. There were several copies of the other 3 genes. Each of the genes was associated with a CpG/HTF island.

Using cDNA hybridization selection with a 320-kb YAC containing the HLA-A gene to screen a human duodenal cDNA library, Goei et al. (1994) isolated and characterized 10 novel gene fragments. Also in search of the HFE gene, Yaouanq et al. (1994) identified a zone of linkage disequilibrium which suggested that the HFE gene may reside within a 400-kb expanse of DNA between the locus they referred to as i97 and HLA-F (143110). Totaro et al. (1996) generated a detailed 1.2-Mb physical and transcription map of 6p spanning the HLA class I region from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes were detected and integrated into the map. Thirteen cDNA fragments showed no similarity with known sequences, and could be candidates for hemochromatosis.

By linkage disequilibrium and full haplotype analysis of hereditary hemochromatosis patients, Feder et al. (1996) identified a 250-kb region more than 3 Mb telomeric of the MHC on chromosome 6 that is identical by descent in 85% of patient chromosomes. Within this region, they identified a gene, which they termed HLA-H, that encodes a predicted 343-amino acid protein related to the MHC class I gene family. The protein comprises a signal sequence, peptide-binding regions (alpha-1 and alpha-2 domains), a transmembrane region, and a small cytoplasmic portion. One of the most conserved structural features of MHC class I molecules in HLA-H are the 4 cysteine residues that form disulfide bridges in the alpha-2 and alpha-3 domains. Northern blot analysis detected a 4-kb major mRNA transcript in all tissues tested, except brain.

Searching for new human MHC class I related genes, Hashimoto et al. (1995) identified MHC-related protein-1 (MR1; 600764) and a second gene, MR2. The HLA-H gene (HFE) reported by Feder et al. (1996) as a candidate gene for hereditary hemochromatosis turned out to be identical to the MR2 gene of Hashimoto et al. (1995). Hashimoto et al. (1997) isolated the murine homolog of this gene. It was found to be similar to its human counterpart with an overall predicted amino acid sequence similarity of approximately 66% and expression in various tissues as in human. An extra 8 amino acid residues between the alpha-1 and the alpha-2 domains in the mouse molecule compared to the human counterpart could be explained by the creation of the additional coding sequence from the intron.

Thenie et al. (2001) isolated an antisense transcript originating from the HFE gene locus. The RNA spans exon 1, exon 2, part of intron 1 of the HFE gene, and 1 kb upstream of it. The antisense transcript is polyadenylated, but displays no open reading frame, and appears to be expressed at low levels in all tissues and cell lines tested. In vitro coupled transcription-translation experiments revealed that HFE expression is decreased by this antisense RNA, suggesting that it may play a role in the regulation of HFE gene expression.


Nomenclature

Mercier et al. (1997) urged strongly that the symbol HFE be used for the hemochromatosis gene rather than 'HLA-H' as used by Feder et al. (1996). The designation HLA-H was used also for a presumed pseudogene in the HLA class I region; see 142800. Similarly, Bodmer et al. (1997) argued that 'HLA-H' is an undesirable designation and pointed to the accepted authority of the WHO Nomenclature Committee for Factors of the HLA System in determining symbols of genes in this region.


Biochemical Features

Crystal Structure

Lebron et al. (1998) determined the 2.6-angstrom crystal structure of the HFE protein.


Gene Structure

Feder et al. (1996) determined that the HFE gene contains 7 exons spanning 12 kb.


Mapping

By fluorescence in situ hybridization analysis, Hashimoto et al. (1995) mapped the HFE gene to chromosome 6p22.

The HFE gene maps within the MHC region on chromosome 6p21.3 (Feder et al., 1996).

Hashimoto et al. (1997) showed that whereas the human gene is located telomeric to the MHC region on 6p, the mouse homolog was translocated from the site telomeric to MHC on chromosome 17 to chromosome 13 along with other genes.


Gene Function

Parkkila et al. (1997) generated an antibody to a C-terminal peptide and used it for immunolocalization of the HLA-H protein in the gastrointestinal tract of Finnish and American subjects presumed not to have hereditary hemochromatosis. Although staining for the HLA-H protein was seen in some epithelial cells in every segment of the alimentary canal, its cellular and subcellular expression in the small intestine was distinct from that in other segments. In contrast to the stomach and colon, where staining is polarized and restricted to the basal lateral surfaces, and in contrast to the epithelial cells of the esophagus and submucosal leukocytes, which showed nonpolarized staining around the entire plasma membrane, the staining in the small intestine was mainly intracellular and perinuclear, limited to cells in deep crypts. Parkkila et al. (1997) concluded that the unique subcellular localization in the crypts of the small intestine in proximity to the presumed sites of iron absorption supported the implication of this protein in the molecular basis of hemochromatosis.

By immunohistochemistry, Parkkila et al. (1997) demonstrated that the HFE protein is expressed in human placenta in the apical plasma membrane of the syncytiotrophoblasts, where the transferrin-bound iron is normally transported to the fetus via receptor-mediated endocytosis. Western blot analyses showed that the HFE protein is associated with beta-2-microglobulin (B2M; 109700) in placental membranes. Unexpectedly, the transferrin receptor (TFR; 190010) was also found to be associated with the HFE protein/B2M complex. These studies placed the normal HFE protein at the site of contact with the maternal circulation where its association with transferrin receptor raised the possibility that the HFE protein plays some role in determining maternal/fetal iron homeostasis.

Feder et al. (1998) demonstrated that the HFE protein forms stable complexes with the transferrin receptor. Studies on cell-associated transferrin at 37 degrees C suggested that overexpression of HFE protein decreases the affinity of TFR for transferrin. Feder et al. (1998) demonstrated that the mutant H63D (613609.0002) HFE protein found in patients with hemochromatosis formed stable complexes with TFR, but that overexpression of H63D did not decrease the affinity of TFR for transferrin. In contrast, the mutant C282Y (613609.0001) HFE protein only associated with TFR to a small degree. The results established a molecular link between the HFE protein and the transferrin receptor, raising the possibility that alterations in this regulatory mechanism of iron transport may play a role in the pathogenesis of hereditary hemochromatosis.

By analyzing the crystal structure of the HFE protein, Lebron et al. (1998) identified a patch of histidines that could be involved in pH-dependent interactions. Soluble TFR and HFE bound tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TFR:HFE stoichiometry (2:1) differed from TFR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TFR, consistent with the demonstration that HFE, transferrin, and TFR form a ternary complex. Lebron et al. (1998) used the crystal structure to reveal the locations of hemochromatosis mutations.

At the cell surface, HFE complexes with TFRC, increasing the dissociation constant of transferrin (TF) for its receptor 10-fold. HFE does not remain at the cell surface, but traffics with TFRC to transferrin-positive internal compartments. Using a HeLa cell line in which the expression of HFE is controlled by tetracycline, Roy et al. (1999) showed that the expression of HFE reduced uptake of radioactive iron from TF by 33%, but did not affect the endocytic or exocytic rates of TFRC cycling. Therefore, HFE appears to reduce cellular acquisition of iron from TF within endocytic compartments. HFE specifically reduces iron uptake from TF, as non-TF-mediated iron uptake from Fe-nitrilotriacetic acid was not altered. These results explained the decreased ferritin levels seen in the HeLa cell system, and demonstrated the specific control of HFE over the TF-mediated pathway of iron uptake. These results also have implications for the understanding of cellular iron homeostasis in organs such as the liver, pancreas, heart, and spleen that are iron loaded in persons with hereditary hemochromatosis lacking functional HFE.

The HFE protein normally binds to TFR in competition with transferrin and, in vitro, reduces cellular iron by reducing iron uptake. However, in vivo, HFE is strongly expressed by liver macrophages and intestinal crypt cells, which behave as though they are relatively iron-deficient in HH. These observations suggest, paradoxically, that expression of wildtype HFE may lead to iron accumulation in these specialized cell types. Drakesmith et al. (2002) showed that wildtype HFE protein raises cellular iron by inhibiting iron efflux from the monocyte/macrophage cell line, and extended these results to macrophages derived from healthy individuals and HH patients. They found that the HH-associated mutant H63D (H41D of the mature protein) lost the ability to inhibit iron release despite binding to TFR as well as wildtype HFE. They also showed that the ability of HFE to block iron release is not competitively inhibited by transferrin. They concluded that HFE has 2 mutually exclusive functions: binding to TFR in competition with transferrin and inhibition of iron release.

Zoller et al. (2003) studied the mRNA and protein expression and activity of cytochrome b reductase-1 (CYBRD1; 605745) in duodenal biopsies of patients with iron deficiency anemia, hereditary hemochromatosis, and controls. They found that CYBRD1 activity in iron deficiency is stimulated via enhanced protein expression, whereas in hemochromatosis due to mutations in the HFE gene it is upregulated posttranslationally. Hemochromatosis patients with no mutations in HFE did not have increased CYBRD1 activity. Zoller et al. (2003) concluded that there are different kinetics of intestinal iron uptake between iron deficiency and hemochromatosis due to mutations in HFE, and that duodenal iron accumulation in hereditary hemochromatosis due to mutations in HFE and hereditary hemochromatosis due to mutations in other genes is pathophysiologically different.

Drakesmith et al. (2005) found that the Nef protein of human immunodeficiency virus-1 (HIV-1) downregulated macrophage-expressed HFE. Iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wildtype HFE. The effect was lost with Nef-deleted HIV-1 or with infected macrophages from hemochromatosis patients expressing mutant HFE. Iron accumulation in HIV-1-infected wildtype macrophages was paralleled by increased cellular HIV-1 Gag protein expression.

Like classic class Ia MHC molecules, HFE has a peptide-binding groove, but the HFE groove has no ligand. Rohrlich et al. (2005) studied the interactions of human and mouse HFE with T lymphocytes and found that the mouse alpha/beta TCR recognized human HFE, leading to Zap70 (176947) phosphorylation. Cytotoxic T lymphocytes from mice lacking Hfe were able to recognize murine Hfe. Rohrlich et al. (2005) proposed that the immune system may be involved in control of iron metabolism.

Gao et al. (2008) found that expression of HFE decreased uptake of both TF-bound iron and non-TF-bound iron in human HepG2 hepatoma cells. Knockdown of ZIP14 (SLC39A14; 608736) in HepG2 cells abolished the inhibitory effect of HFE on uptake of non-TF-bound iron. HFE appeared to reduce the stability of ZIP14 protein and had no effect on ZIP14 mRNA.


Molecular Genetics

In patients with hereditary hemochromatosis (HFE1; 235200), Feder et al. (1996) identified 2 mutations in the HFE gene (C282Y, 613609.0001 and H63D, 613609.0002). The C282Y mutation was detected in 85% of all HFE chromosomes, indicating that in their population 83% of hemochromatosis cases are related to C282Y homozygosity.

By sequence analysis of exons 2, 3, 4, and 5, and portions of introns 2, 4, and 5 of the HFE gene, Barton et al. (1999) identified novel mutations in 4 of 20 hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for the previously undescribed mutations ile105-to-thr (I105T; 613609.0009) and gly93-to-arg (G93R; 613609.0010). Probands 3 and 4 were heterozygous for the previously described but uncommon HFE mutation ser65-to-cys (S65C; 613609.0003). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda (see 176100), and proband 4 had hereditary stomatocytosis (185000). Each of these 4 probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in these probands. In 176 normal control subjects, 2 were heterozygous for S65C, but I105T and G93R were not detected.

Wallace and Subramaniam (2016) reviewed 161 variants previously associated with any form of hereditary hemochromatosis and found that 43 were represented among next-generation sequence public databases including ESP, 1000 Genomes Project, and ExAC. The frequency of the C282Y mutation in HFE (613609.0001) matched previous estimates from similar populations. Of the non-HFE forms of iron overload, TFR2 (604720)-, HFE2 (608374)-, and HAMP (606464)-related forms were extremely rare, with pathogenic allele frequencies in the range of 0.00007 to 0.0005. However, SLC40A1 (604653) variants were identified in several populations (pathogenic allele frequency 0.0004), being most prevalent among Africans.


Animal Model

To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, Zhou et al. (1998) studied the effects of a targeted disruption of the murine homolog of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates, and hepatic iron concentration was 8-fold higher than that of wildtype littermates. Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different from that in littermates. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. The study showed that HFE protein is involved in the regulation of iron homeostasis and that mutations in the gene are responsible for hereditary hemochromatosis. Beutler (1998) emphasized the pathologic and clinical importance of the knockout mouse model for hemochromatosis.

The puzzling linkage between genetic hemochromatosis and the histocompatibility loci became even more puzzling when the gene involved, HFE, was identified. Indeed, within the well-defined, mainly peptide-binding, MHC-class I family of molecules, HFE seems to perform an unusual but essential function. Understanding of HFE function in iron homeostasis was only partial; an even more open question was its possible role in the immune system. To advance knowledge in both of these areas, Bahram et al. (1999) studied deletion of the HFE alpha-1 and alpha-2 putative ligand-binding domains in vivo. HFE-deficient mice were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion developed iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allowed a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. However, extensive phenotyping of primary and secondary lymphoid organs including the gut provided no compelling evidence for an obvious immune-linked function for HFE.

Inflammation influences iron balance in the whole organism. A common clinical manifestation of these changes is anemia of chronic disease (ACD; also called anemia of inflammation). Inflammation reduces duodenal iron absorption and increases macrophage iron retention, resulting in low serum iron concentrations (hyposideremia). Despite the protection hyposideremia provides against proliferating microorganisms, this 'iron withholding' reduces the iron available to maturing red blood cells and eventually contributes to the development of anemia. Hepcidin antimicrobial peptide (HAMP; 606464) is a hepatic defensin-like peptide hormone that inhibits duodenal iron absorption and macrophage iron release. HAMP is part of the type II acute phase response and is thought to have a crucial regulatory role in sequestering iron in the context of ACD. Roy et al. (2004) reported that mice with deficiencies in the hemochromatosis gene product, Hfe, mounted a general inflammatory response after injection of lipopolysaccharide but lacked appropriate Hamp expression and did not develop hyposideremia. These data suggested a previously unidentified role for Hfe in innate immunity and ACD.

Nairz et al. (2009) found that mice lacking 1 or both Hfe alleles were protected from Salmonella typhimurium septicemia, displaying reduced bacterial replication and prolonged host survival. Increased resistance was associated with enhanced production of the enterochelin-binding protein Lcn2 (600181), which reduced iron availability for Salmonella. Macrophages lacking both Hfe and Lcn2 were unable to efficiently control S. typhimurium or to withhold iron from the bacterium. Salmonella lacking enterochelin overcame protection in Hfe -/- mice, as did wildtype bacteria in Hfe -/- Lcn2 -/- double-knockout mice. Nairz et al. (2009) concluded that loss of HFE confers host resistance to systemic Salmonella infection by inducing the iron-capturing peptide LCN2, thereby providing an evolutionary advantage that may account for the high prevalence of genetic hemochromatosis.

Jenkitkasemwong et al. (2015) found that loss of Slc39a14 prevented hepatic iron overload in the Hfe -/- and Hfe2 (HJV; 608374) -/- mouse models of hemochromatosis. However, loss of Slc39a14 did not prevent iron accumulation in other tissues and cells of Hfe -/- or Hfe2 -/- mice, but instead resulted in altered patterns of iron accumulation compared with single-knockout or wildtype mice. Jenkitkasemwong et al. (2015) concluded that SLC39A14 is required for development of hepatic iron overload in hereditary hemochromatosis.


ALLELIC VARIANTS 11 Selected Examples):

.0001   RECLASSIFIED - HFE POLYMORPHISM

HFE, CYS282TYR
SNP: rs1800562, gnomAD: rs1800562, ClinVar: RCV000000019, RCV000178096, RCV000210820, RCV000308358, RCV000414811, RCV001248830, RCV001270034, RCV001731264, RCV002280089, RCV002512585, RCV003224084, RCV003390626, RCV003493406

This variant has been reclassified as a polymorphism because the C282Y variant is present in the gnomad database (v2.1.1) in 9,544 of 282,608 alleles and in 276 homozygotes, with an allele frequency of 0.03377 (Hamosh, 2023).

Drakesmith et al. (2002) used a numbering system beginning from the first amino acid of the mature protein, omitting the 22 amino acids of the signal sequence, so that C282 of the immature protein is C260 of the mature protein.

Hemochromatosis, Type 1

In patients with hemochromatosis (HFE1; 235200), Feder et al. (1996) identified an 845G-A transition in the HFE gene (which they referred to as HLA-H or 'cDNA 24'), resulting in a cys282-to-tyr (C282Y) substitution. This missense mutation occurs in a highly conserved residue involved in the intramolecular disulfide bridging of MHC class I proteins, and could therefore disrupt the structure and function of this protein. Using an allele-specific oligonucleotide-ligation assay on their group of 178 patients, they detected the C282Y mutation in 85% of all HFE chromosomes. In contrast, only 10 of the 310 control chromosomes (3.2%) carried the mutation, a carrier frequency of 10/155 = 6.4%. One hundred forty-eight of 178 HH patients were homozygous for this mutation, 9 were heterozygous, and 21 carried only the normal allele. These numbers were extremely discrepant from Hardy-Weinberg equilibrium. The findings corroborated heterogeneity among the hemochromatosis patients, with 83% of cases related to C282Y homozygosity.

Jazwinska et al. (1996) provided convincing evidence that the C282Y mutation in homozygous form in the HFE gene is the cause of hemochromatosis. In studies in Australia, patients properly characterized at the genotypic and phenotypic level all showed homozygosity for the C282Y substitution. Irrespective of haplotype, all HH heterozygotes were cys/tyr heterozygotes, and all homozygous normal controls were cys/cys homozygotes. The presence of a single mutation in all patients contrasted with the data of Feder et al. (1996), who reported a lower frequency of the mutation. Jazwinska et al. (1996) suggested that different clinical criteria for the diagnosis of HH may account for the difference, or that HH may not be as homogeneous as previously believed. They noted that a key question is why there is a variation in severity of iron loading in HH that is haplotype-related when the mutation is identical in all haplotypes tested. Jazwinska et al. (1996) hypothesized that the HFE locus is the primary HH locus, but that there are likely to be other 6p-linked modifying genes that would explain both the HLA-linked haplotype variation in expression of the disorder and the large region of linkage disequilibrium present in all populations and spanning at least 4.5 Mb distal of D6S265.

Jouanolle et al. (1996) commented on the significance of the C282Y mutation on the basis of a group of 65 unrelated affected individuals who had been under study in France for more than 10 years and identified by stringent criteria. Homozygosity for the C282Y mutation was found in 59 of 65 patients (90.8%); 3 of the patients were compound heterozygotes for the C282Y mutation and the H63D mutation (613609.0002); 1 was homozygous for the H63D mutation; and 2 were heterozygous for H63D. These results corresponded to an allelic frequency of 93.1% for the C282Y and 5.4% for the H63D mutations, respectively. Of note, the C282Y mutation was never observed in the family-based controls, whereas it was present in 5.8% of the general Breton population. This corresponds to a theoretical frequency of about 1 per 1,000 for the disease, which is slightly lower than generally estimated. In contrast, the H63D allelic frequency was nearly the same in both control groups (15% and 16.5% in the family-based and general population controls, respectively). While the experience of Jouanolle et al. (1996) appeared to indicate a close relationship of C282Y to hemochromatosis, the implication of the H63D variant was not clear.

Beutler et al. (1996) reported mutation analysis of 147 patients with hereditary hemochromatosis and 193 controls; 121 (82.3%) HH patients were homozygous for the C282Y mutation and 10 (6.8%) were heterozygous. All of the C282Y homozygous patients were also homozygous for the wildtype nucleotide 187C (see H63D; 613609.0002), and all C282Y heterozygotes had at least 1 copy of 187C. Thus, the 2 nucleotides, 845 and 187, were in complete linkage disequilibrium; nucleotide 187 was a C on all chromosomes with the 845A (C282Y) mutation. Eight of the 10 heterozygotes for 845A were heterozygous for 187G (H63D).

Among 132 unrelated hemochromatosis patients in Brittany, Jouanolle et al. (1997) found that 92% were homozygous for the C282Y mutation and that all 264 chromosomes except 5 carried either the C282Y mutation or the H63D mutation. The UK Haemochromatosis Consortium (1997) genotyped 115 unrelated hereditary hemochromatosis patients and found that 105 (91%) were homozygous for the C282Y mutation. One of 101 controls was also found to be homozygous but was subsequently found to have evidence of iron overload. Compound heterozygosity for the C282Y and H63D mutations was found in 3 patients who had mild disease and in 4 controls who had no signs of iron overload. Five patients lacked either mutation, 2 of whom had atypical, early-onset disease.

Feder et al. (1997) confirmed the prediction that the C282Y mutation would disrupt a critical disulfide bond in the alpha-3 loop of the HFE protein and abrogate binding of the mutant HFE protein to beta-2-microglobulin (B2M; 109700), as well as its transport to and presentation on the cell surface. In vitro, the C282Y mutant HFE protein failed to associate with endogenous B2M in human embryonic kidney cells stably transfected with the mutant cDNA. Waheed et al. (1997) found that whereas the wildtype and H63D HFE proteins associate with beta-2 microglobulin and are expressed on the cell surface of COS-7 cells, these capabilities are lost by the C282Y HFE protein. They presented biochemical and immunofluorescence data indicating that the C282Y mutant protein is retained in the endoplasmic reticulum and middle Golgi compartments, fails to undergo late Golgi processing, and is subject to accelerated degradation. The block in intracellular transport, accelerated turnover, and failure of the C282Y protein to be presented normally on the cell surface provides a possible basis for impaired function of this mutant protein in hereditary hemochromatosis.

In 478 hemochromatosis probands in Brittany selected from their iron status markers, primarily serum iron, serum ferritin, and transferrin saturation, Mura et al. (1997) investigated the relationships between the hemochromatosis phenotype and genotypes at the HLA-H locus and surrounding markers. They found that the C282Y substitution is unambiguously associated with the hemochromatosis phenotype; 81.2% of all patients were homozygous. The subgroup of heterozygous individuals showed lower values for serum ferritin, transferrin saturation, and iron removed by phlebotomy than did the subgroup of hemochromatosis patients homozygous for C282Y. In the subgroup not homozygous for C282Y, no other mutation in the HLA-H gene was found; hence, the genotype remained unclear. The authors suggested additional nongenetic cause, other mutations, or another gene as explanations for the results in these patients.

Rhodes et al. (1997) reported haplotype and mutation analysis in a 3-generation family. Three sibs with overt hemochromatosis, 1 male and 2 females aged 50 to 53 years, showed homozygosity for the C282Y mutation. However, homozygosity for the mutation was detected in an asymptomatic and biochemically normal 50-year-old male sib of the affected individuals. Rhodes et al. (1997) concluded that this finding caused them to question the possibility of population and presymptomatic screening by genetic testing for hemochromatosis.

Roth et al. (1997) found no instance of the C282Y substitution in the HFE gene of individuals originating from Algeria, Ethiopia, or Senegal, whereas it is highly prevalent in populations of European ancestry. The geographic distribution supported the previously suggested Celtic origin of hemochromatosis. In contrast, the H63D substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the central Ethiopians and Algerians genotyped for this study. Thus, the H63D substitution must have occurred earlier than the C282Y substitution.

Merryweather-Clarke et al. (1997) reported the prevalence of the C282Y and H63D mutations in 2,978 people from 42 different populations worldwide. The authors found the highest frequency of C282Y in northern European populations, consistent with the theory of a north European origin for the mutation. In this report, C282Y was seen rarely in the African, Asian, and Australasian chromosomes studied, while H63D was more widely distributed.

Although hemochromatosis is common in Caucasians, affecting more than 1 in 300 individuals of northern European origin, the disorder has not been recognized in other populations. Cullen et al. (1998) used PCR and restriction-enzyme digestion to analyze the frequency of the C282Y and H63D mutations in HLA-typed samples of non-Caucasian populations, comprising Australian Aboriginal, Chinese, and Pacific Islanders. They found that the C282Y mutation was present in these populations (allele frequency 0.32%), and that it was always seen in conjunction with HLA haplotypes common in Caucasians, suggesting that C282Y may have been introduced into these populations by Caucasian admixture. They found the H63D mutation at an allele frequency of 2.68% in the 2 populations analyzed (Australian Aboriginal and Chinese). In the Australian Aboriginal samples, H63D was found to be associated with HLA haplotypes common in Caucasians, again suggesting that it was introduced by recent admixture. In the Chinese samples analyzed, on the other hand, H63D was present in association with a wide variety of HLA haplotypes, showing that this mutation is widespread and likely to predate the more genetically restricted C282Y mutation.

In European populations, Lucotte (1998) found the frequency of the C282Y mutation to be 6.88% in Celtics, 6.46% in Nordics, 5.95% in Anglo-Saxons, 2.53% in southern Europeans, and 1.76% in Russians. They believed these findings supported the suggestion concerning the Celtic origin of the mutation. Celtic origin of the mutation was also supported by the finding of Ryan et al. (1998) of a 14% carrier frequency of the C282Y allele in Ireland, the highest frequency reported to the time of report.

Jeffrey et al. (1999) identified a single nucleotide polymorphism (5569G-A; 613609.0004) in intron 4 of the HFE gene that caused overestimation of C282Y homozygote prevalence in hemochromatosis.

Beutler et al. (2002) screened 41,038 individuals attending a health appraisal clinic in the U.S. for the C282Y and H63D (613609.0002) HFE mutations, and analyzed laboratory data on signs and symptoms of hemochromatosis as elicited by questionnaire. The most common symptoms of hemochromatosis were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls; there was no measurable loss of such individuals from the population during aging. However, there was a significantly increased prevalence of a history of hepatitis or 'liver trouble' among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only 1 of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of hemochromatosis. Beutler et al. (2002) concluded that the penetrance of hereditary hemochromatosis is much lower than generally thought. They estimated that less than 1% of homozygotes develop frank clinical hemochromatosis.

Poullis et al. (2002) concluded that Beutler et al. (2002) underestimated the penetrance of the C282Y HFE mutation. The immigration of Hispanic and Asian populations into southern California may have influenced the frequency.

Within South Wales, McCune et al. (2002) performed a systematic review of patients with HH over a 2-year period which revealed that only 1.2% of adult C282Y homozygotes had been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% had more than 4 grams of iron (the diagnostic threshold for iron overload). McCune et al. (2002) stated that screening the general UK population by genetic testing could identify thousands of individuals homozygous for the C282Y mutation, but the majority would not express a phenotype leading to a diagnosis of HH and would likely remain healthy. They concluded that until the cofactors determining disease expression were more fully understood, the benefits of such screening, both to the individual and to the community, would likely be outweighed by the costs.

Andersen et al. (2004) undertook to determine the progression rate of iron overload in hereditary hemochromatosis in individuals in the general population, and to answer the question of how frequently asymptomatic C282Y homozygotes identified in the population need to be screened for manifestations of hemochromatosis in later years. As a function of biologic age, transferrin saturation and ferritin levels increase slightly in male and female C282Y homozygotes. None of the C282Y homozygotes developed clinically overt hemochromatosis. The authors concluded that most such homozygotes need to be screened for manifestation of hemochromatosis every 10 to 20 years.

Saric et al. (2006) estimated the frequency of the C282Y mutation to be 1.6% in the population of Serbia and Montenegro. The authors noted that the frequency of C282Y decreases going from northwest to southeast Europe, consistent with a Viking or Celtic origin.

Livesey et al. (2004) analyzed the presence of the common mtDNA 16189T-C variant, which appears to be a risk factor for type 2 diabetes (125853), in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. The frequency of the 16189 variant was found to be elevated in individuals with hemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic. They concluded that iron loading in C282Y homozygotes with hemochromatosis was exacerbated by the presence of the 16189 variant.

Allen et al. (2008) reported on a study of HFE mutations in 31,192 persons of northern European descent between ages 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1,438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), they obtained clinical and biochemical data, including 2 sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. The proportion of C282Y homozygotes with documented iron overload-related disease was 28.4% for men and 1.2% for women. Only 1 non-C282Y homozygote (a compound heterozygote with his63 to asp) had documented iron overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1,000 micrograms per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wildtype gene. Waalen and Beutler (2008) and Rienhoff (2008) commented that the study by Allen et al. (2008) may have overestimated the clinical prevalence and penetrance of iron-overload disease in C282Y homozygotes.

Levy et al. (1999) produced 2 mutations in the murine Hfe gene. The first mutation deleted a large portion of the coding sequence, generating a null allele. The second mutation introduced the C282Y change into the Hfe gene but otherwise left the gene intact. Homozygosity for either mutation resulted in postnatal iron loading. The effects of the null mutation were more severe than the effects of the C282Y mutation. The mice heterozygous for either mutation accumulated more iron than normal controls. Although liver iron stores were greatly increased, splenic iron was decreased. Levy et al. (1999) concluded that the C282Y mutation does not result in a null allele.

Hemochromatosis, Juvenile

Merryweather-Clarke et al. (2003) reported an individual with a juvenile hemochromatosis (602390) phenotype who was heterozygous for the C282Y mutation in the HFE gene as well as a 4-bp HAMP frameshift mutation (606464.0003). In another family, they found the C282Y mutation in HFE together with a G71D mutation in HAMP (606464.0004). There was a correlation between severity of iron overload, heterozygosity for a G71D HAMP mutation, and heterozygosity or homozygosity for the HFE C282Y mutation.

Porphyria Cutanea Tarda

Roberts et al. (1997) analyzed 41 patients with sporadic porphyria cutanea tarda and 101 controls for the presence of the C282Y and H63D mutations. They identified the C282Y mutation in 18 (44%) patients compared to 11 (11%) controls (relative risk = 6.2; p = 0.00003); 7 patients were homozygotes. In 12 patients, the C282Y mutation was associated with markers of the HLA-A3-containing ancestral hemochromatosis haplotype. There was no difference in the frequency of the H63D mutation between the 2 groups. Roberts et al. (1997) concluded that inheritance of one or more hemochromatosis genes is an important susceptibility factor for sporadic porphyria cutanea tarda. They noted that some C282Y homozygotes present late in life with porphyria cutanea tarda, indicating that not all homozygotes present clinically with hemochromatosis.

Among 8 patients with porphyria cutanea tarda, Mehrany et al. (2004) found that 6 had mutations in the HFE gene: 3 were homozygous for C282Y, 1 was compound heterozygous for C282Y and H63D, and 2 were heterozygous for C282Y. Mehrany et al. (2004) noted that early detection and treatment of hereditary hemochromatosis limits progression of PCT and improves life expectancy.

Porphyria Variegata

De Villiers et al. (1999) found that the mutant allele frequency of the C282Y mutation was significantly lower in 73 apparently unrelated variegate porphyria (176200) patients with the arg59-to-trp mutation in the PPOX gene (600923.0003) than in 102 controls drawn from the same population (P = 0.005). The authors concluded that the population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supported previous data on involvement of the HFE gene in the porphyria phenotype. Iron overload is a well-established precipitating or aggravating factor in porphyria variegata.

Transferrin Serum Level Quantitative Trait Locus 2

In a genomewide association study of Australians of European descent, Benyamin et al. (2009) found that the C282Y variant (rs1800562) was associated with serum iron (p = 3.5 x 10(-11)), serum transferrin (see TFQTL2, 614193) (p = 1.1 x 10(-10)), transferrin saturation (p = 4.3 x 10(-15)), and serum ferritin (see FTH1, 134770) (p = 4.5 x 10(-5)). C282Y explained 9.5%, 9.1%, 13.2%, and 3.7% of the variation in means of serum iron, serum transferrin, transferrin saturation, and serum ferritin levels, respectively. Three SNPs in the TF gene plus the HFE C282Y mutation explained about 40% of genetic variation in serum transferrin (p = 7.8 x 10(-25)).

Microvascular Complications of Diabetes 7, Susceptibility to

Walsh and Malins (1978) reported an association between diabetic retinopathy (MVCD7; 603933) and idiopathic hemochromatosis. Peterlin et al. (2003) searched for a relationship between the C282Y and H63D gene mutations and the development of proliferative diabetic retinopathy in Caucasians with type 2 diabetes (125853). A significantly higher frequency of C282Y heterozygosity was found in patients with proliferative diabetic retinopathy compared to subjects without it, whereas no association was demonstrated with H63D. Logistic regression analysis revealed that the C282Y mutation was a significant independent risk factor for the development of PDR (odds ratio = 6.1; p = 0.027).

Oliva et al. (2004) analyzed the C282Y HFE polymorphism in 225 Spanish patients with type 2 diabetes and detected a younger age of onset and longer duration of disease in patients carrying at least 1 C282Y allele. They also found an increased prevalence of retinopathy (p = 0.014) and of nephropathy (p = 0.04) in individuals carrying at least 1 C282Y allele; the increased prevalence of retinopathy, but not nephropathy, in C282Y carriers was related to increased duration of disease. Multivariate logistic regression analysis confirmed that the prevalence of nephropathy was higher in the group of patients carrying at least 1 Y allele.

Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses.

Alzheimer Disease

Robson et al. (2004) noted that there is evidence that iron may play a role in the pathology of Alzheimer disease (104300). Thus, genetic factors that contribute to iron deposition resulting in tissue damage might exacerbate AD. The authors examined the interaction between the C2 variant of the TF gene (190000.0004) and the C282Y allele of the HFE gene, the most common basis of hemochromatosis, as risk factors for developing AD. The results showed that each of the 2 variants was associated with an increased risk of AD only in the presence of the other. Neither allele alone had any effect. Carriers of both variants were at 5 times greater risk of AD compared with all others. Furthermore, carriers of these 2 alleles plus APOE4 (see 107741) were at still higher risk of AD: of the 14 carriers of the 3 variants identified in this study, 12 had AD and 2 had mild cognitive impairment. Robson et al. (2004) concluded that their results indicated that the combination of TF*C2 and HFE C282Y may lead to an excess of redoxactive iron and the induction of oxidative stress in neurons, which is exacerbated in carriers of APOE4. They noted that 4% of northern Europeans carry the 2 iron-related variants and that iron overload is a treatable condition.


.0002   RECLASSIFIED - HFE POLYMORPHISM

HFE, HIS63ASP
SNP: rs1799945, gnomAD: rs1799945, ClinVar: RCV000000026, RCV000175607, RCV000394716, RCV000763144, RCV000844708, RCV000991133, RCV001248831, RCV001731265, RCV002227011, RCV002272003

This variant has been reclassified as a polymorphism because the H63D variant is present in the gnomad database (v2.1.1) in 30,592 of 282,855 alleles and in 2,023 homozygotes, with an allele frequency of 0.1082 (Hamosh, 2023).

Drakesmith et al. (2002) used a numbering system beginning with the first amino acid of the mature HFE protein, omitting the 22 amino acids of the signal sequence, so that H63 of the immature protein is H41 in the mature protein.

Hemochromatosis, Type 1

In 9 patients with hemochromatosis (HFE1; 235200) who were heterozygous for the C282Y mutation (613609.0001), Feder et al. (1996) identified a C-to-G transversion in exon 2 of the HFE gene, resulting in a his63-to-asp substitution (H63D). This variant was present in 8 of the 9 (89%) nonancestral chromosomes, representing a significant enrichment over the 17% frequency observed in control chromosomes. One patient was homozygous for the H63D variant.

An analysis of the H63D mutation in 13 families by Jouanolle et al. (1996) did not support a relationship to HFE. The mutation was present in 3 of 26 heterozygous parents of probands and in each case it was present on the normal chromosome; the analysis of these individuals did not support a compound heterozygous contribution to HFE.

In a study of 115 unrelated patients with hereditary hemochromatosis, the UK Haemochromatosis Consortium (1997) found 1 patient who was homozygous for the H63D mutation. However, 3 homozygotes with no evidence of iron overloading were found among 101 control samples derived from healthy blood donors. In addition, compound heterozygosity for the H63D and C232Y mutations was found in 3 patients and 4 controls.

Beutler (1997), commenting on the conclusion of Carella et al. (1997) that H63D is a polymorphic change, assembled evidence supporting the likelihood that it is a hemochromatosis-causing mutation with reduced penetrance. He suggested that most of the heterozygotes with mild disease manifestations reported before discovery of the HFE gene will prove, in fact, to be compound heterozygotes for C282Y (613609.0001) and H63D.

Aguilar-Martinez et al. (2001) investigated the phenotypic consequences of H63D homozygosity in 56 French homozygotes identified from a series of blood samples submitted for HFE genotyping in response to a confirmed (12) or suspected (38) clinical diagnosis of hemochromatosis or a family history of hemochromatosis (6). Of these, 50 (89%) had evidence of iron overload. In 16 individuals (32%) this appeared to be a phenomenon secondary to dysmetabolic iron overload syndrome, porphyria cutanea tarda, alcohol use, or hepatitis. In the remaining 34 (68%) individuals a secondary cause of iron overload was not identified: 12 had a phenotypic diagnosis of hemochromatosis and the remaining 22 had ill-defined, variable degrees of iron overload with no apparent cause. Extended genetic analysis failed to demonstrate any association between phenotype and other HFE mutations/polymorphisms or the TFR2 Y250X mutation (604720.0001)/TFR2 polymorphisms. The authors commented that, in this selected population, H63D homozygosity was associated with extremely variable phenotypes. They suggested that factors such as age and sex may be important nongenetic phenotypic modifiers.

Cardoso et al. (2002) analyzed linkage disequilibrium between HLA alleles and HFE mutations in a Portuguese population. The results confirmed linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. Extensions of these studies showed significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a coselection of H63D and the HLA-A29 allele itself. Insight into the biologic significance of this association was given by the finding of significantly higher CD8+ T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.

To examine whether the HFE H63D mutation is pathogenic, Tomatsu et al. (2003) generated knockin mice homozygous for H67D (corresponding to human H63D), mice homozygous for C294Y (corresponding to human C282Y), and mice compound heterozygous for both mutations. The biochemical and histopathologic severity of hepatic iron loading was significantly increased in all 3 groups compared to control mice, but was less in H67D homozygotes than in compound heterozygotes, and was highest in C294Y homozygotes. Only the C294Y homozygous mice showed a significant increase in transferrin saturation compared to controls. Tomatsu et al. (2003) concluded that the H67D allele, when homozygous or combined with a more severe mutation, leads to partial loss of Hfe function in mice and to increased hepatic iron loading.

Microvascular Complications of Diabetes 7, Susceptibility to

Moczulski et al. (2001) analyzed the H63D polymorphism in 563 Polish patients with type 2 diabetes (125853) and 196 controls and observed an increased frequency of the 63D allele (odds ratio, 1.8) among patients with diabetic nephropathy (MVCD7; 612635).

In a study of 225 Spanish patients with type 2 diabetes, Oliva et al. (2004) found that the prevalence of nephropathy was higher in the group of patients carrying the homozygous D/D genotype compared to the group carrying the wildtype or heterozygous D genotypes.

Davis et al. (2008) analyzed H63D and C282Y HFE genotype data for 1,245 Australian patients with type 2 diabetes from the longitudinal observational Fremantle Diabetes Study and found no independent positive associations between HFE gene status and either microvascular or macrovascular complications in cross-sectional and longitudinal analyses.


.0003   HEMOCHROMATOSIS, TYPE 1

HFE, SER65CYS
SNP: rs1800730, gnomAD: rs1800730, ClinVar: RCV000000028, RCV000290779, RCV000764641, RCV000998547, RCV001328435, RCV003224085, RCV003924786

Mura et al. (1999) reported on the analysis of the cys282-to-tyr (C282Y; 613609.0001), his63-to-asp (H63D; 613609.0002), and ser65-to-cys (S65C) mutations of the HFE gene in a series of 711 probands with hereditary hemochromatosis (235200) and 410 controls. The results confirmed that the C282Y substitution is the main mutation involved in HH, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, the screening showed that the S65C substitution, which results from a 193A-T transversion, was significantly enriched in probands with at least 1 chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggested that the S65C substitution is associated with a mild form of hemochromatosis.

Barton et al. (1999) identified the S65C mutation in 2 patients. One was also heterozygous for C282Y, i.e., was a compound heterozygote, and had porphyria cutanea tarda (see 176100). The other patient had hereditary stomatocytosis (185000). Iron overload due to the HFE mutations probably precipitated or exacerbated the porphyria cutanea tarda in the first patient. In the second patient, iron overload from the hereditary stomatocytosis undoubtedly exacerbated the iron overload due to the HFE mutation.


.0004   HFE INTRONIC POLYMORPHISM

HFE, 5569G-A
SNP: rs1800758, gnomAD: rs1800758, ClinVar: RCV000000031, RCV001618204

In a population screening study of 5,211 voluntary blood donors, Jeffrey et al. (1999) identified 31 putative 5474A (613609.0001) homozygotes. When they validated the assay by genomic DNA sequence analysis, only 16 individuals were confirmed to be 5474A homozygotes and the remaining 15 were heterozygous for this mutation. Each of the 5474A heterozygotes was also heterozygous for a previously unrecognized 5569G-A single nucleotide polymorphism located in the binding region of the antisense primer. Jeffrey et al. (1999) developed a new antisense primer that excluded the site of this newly found polymorphism and confirmed the 15 putative homozygotes to be 5474A heterozygotes using restriction endonuclease digestion. Hill and Robertson's maximum likelihood estimate of linkage disequilibrium D (Hill and Robertson, 1968) was 0.71 (P less than 0.005), confirming the presence of moderate to strong linkage disequilibrium between the 2 variant sites. It was considered unlikely that the 5569A polymorphism has functional significance, because it is within intron 4 and does not disrupt a splice site consensus sequence. Moreover, all 5474A/5569A compound heterozygotes had a transferrin saturation in the normal range. In their population survey, Jeffrey et al. (1999) found that 21% of 113 normal patients, corresponding to an allele frequency of 0.106, had the polymorphism. In their sample, the prevalence of hemochromatosis was reduced from 1 in 168 to 1 in 327 by the use of new primers. These results had major public health implications regarding the use of population screening for hemochromatosis. Individuals previously considered to be nonexpressing 5474A homozygotes on the basis of PCR-based restriction endonuclease digestion assay using the original Feder et al. (1996) primers require confirmatory testing.

The European Haemochromatosis Consortium (1999), representing 11 laboratories, retyped 944 samples for the C282Y mutation (613609.0001) by a primer external to the 5569G-A polymorphism or by sequencing. Five hundred seventy-five previously diagnosed C282Y homozygotes were confirmed using the new primer, as well as 192 C282Y wildtype homozygotes, including 10 carrying the polymorphism in homozygosity, and 177 heterozygotes. Of the heterozygotes, 28 were C282Y/5569G-A compound heterozygotes which had been reported correctly using the original Feder reverse primer. The European Haemochromatosis Consortium (1999) did not observe nonamplification of the polymorphic allele, demonstrating that the validity of their previous publications was not compromised by findings reported by Jeffrey et al. (1999). Noll et al. (1999) confirmed the observations of the European Haemochromatosis Consortium (1999). Gomez et al. (1999) reevaluated 221 putative C282Y homozygotes; 219 were confirmed and 2 were found to be 5569A/282Y compound heterozygotes without clinical evidence of iron overload. There was a significantly higher prevalence of the 5569A allele in a group of healthy controls (33 of 314, or 10.5%) than in the putative HFE C282Y homozygous group (2 of 442, or 0.45%), suggesting that the polymorphism is very common, but is not found on the same founder chromosome as the C282Y mutation.


.0005   HFE POLYMORPHISM

HFE, VAL53MET
SNP: rs28934889, gnomAD: rs28934889, ClinVar: RCV000000032, RCV001336845

In a mutation analysis of the HFE gene using DNA samples from members of 4 different ethnic groups in South Africa, de Villiers et al. (1999) identified a 157G-A transition in exon 2 of the HFE gene, resulting in a val53-to-met (V53M) substitution. The mutation was detected only in South African Black and Bushman (Khoisan) populations. The mutation created a new NlaIII site and abolished an MaeII site.


.0006   HFE POLYMORPHISM

HFE, VAL59MET
SNP: rs111033557, gnomAD: rs111033557, ClinVar: RCV000000033, RCV000987659, RCV003234881

In a mutation analysis of the HFE gene using DNA samples from members of 4 different ethnic groups in South Africa, de Villiers et al. (1999) identified a 175G-A transition in exon 2 of the HFE gene, resulting in a val59-to-met (V59M) substitution in a South African Caucasian. The mutation created an NlaIII site.


.0007   HEMOCHROMATOSIS, TYPE 1

HFE, GLN127HIS
SNP: rs28934595, ClinVar: RCV000000034

In an 11-year-old girl with hemochromatosis (235200) and variegate porphyria (176200), de Villiers et al. (1999) identified compound heterozygosity for mutations in the HFE gene: a 381A-C transversion in exon 3 resulting in a gln127-to-his (Q127H) substitution, and a his63-to-asp (613609.0002) substitution. The severely affected patient carried the R59W mutation (600923.0003) in the PPOX gene, which accounts for dominantly inherited variegate porphyria in more than 80% of affected South Africans. Iron overload is a well-established precipitating or exacerbating factor in porphyria variegata.


.0008   HEMOCHROMATOSIS, TYPE 1

HFE, ARG330MET
SNP: rs111033558, ClinVar: RCV000000035

Among 13 Caucasian South African patients referred for a molecular diagnosis of hereditary hemochromatosis (235200), de Villiers et al. (1999) identified a 989G-T transversion in exon 5 of the HFE gene, resulting in an arg330-to-met (R330M) substitution.


.0009   HEMOCHROMATOSIS, TYPE 1

HFE, ILE105THR
SNP: rs28934596, gnomAD: rs28934596, ClinVar: RCV000000029, RCV001322296

In a patient with hemochromatosis (235200), Barton et al. (1999) identified compound heterozygosity for a 314T-C transition in exon 2 of the HFE gene, resulting in an ile105-to-thr (I105T) substitution, and the H63D mutation (613609.0002).


.0010   HEMOCHROMATOSIS, TYPE 1

HFE, GLY93ARG
SNP: rs28934597, gnomAD: rs28934597, ClinVar: RCV000000030

In a patient with hemochromatosis (235200), Barton et al. (1999) identified compound heterozygosity for a 277G-C transversion in exon 2 of the HFE gene, resulting in a gly93-to-arg (G93R) substitution, and the C282Y mutation (613609.0001).


.0011   HEMOCHROMATOSIS, TYPE 1

HFE, GLN283PRO
SNP: rs111033563, gnomAD: rs111033563, ClinVar: RCV000000036, RCV001050090, RCV003884332

In affected members of a French family with hemochromatosis (235200), Le Gac et al. (2003) identified compound heterozygosity for 2 mutations in the HFE gene: an 848A-C transversion in exon 4, resulting in a gln283-to-pro (Q283P) substitution within the alpha-3 domain, and a C282Y (613609.0001) substitution. Molecular modeling studies predicted a destabilizing effect for the Q283P substitution on the tertiary structure of the protein.

By performing immunoprecipitation studies in HeLa cells, Ka et al. (2005) found that the Q283P mutation prevented the normal interaction between HFE protein and beta-2-microglobulin (B2M; 109700) and between HFE protein and transferrin receptor (TFRC; 190010). Further studies showed that the Q283P mutation decreased the capacity of HFE to reduce transferrin-mediated iron uptake. Ka et al. (2005) noted that the Q283P mutation is adjacent to the disulfide bridge formed by cys225 and cys282, and concluded that the Q283P protein is retained in the endoplasmic reticulum and middle Golgi compartments, similar to the C282Y mutant protein. The results indicated that the Q283P mutation leads to structural and functional consequences similar to those described for the more common C282Y mutation.


REFERENCES

  1. Aguilar-Martinez, P., Bismuth, M., Picot, M. C., Thelcide, C., Pageaux, G.-P., Blanc, F., Blanc, P., Schved, J.-F., Larrey, D. Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause? Gut 48: 836-842, 2001. [PubMed: 11358905] [Full Text: https://doi.org/10.1136/gut.48.6.836]

  2. Allen, K. J., Gurrin, L. C., Constantine, C. C., Osborne, N. J., Delatycki, M. B., Nicoll, A. J., McLaren, C. E., Bahlo, M., Nisselle, A. E., Vulpe, C. D., Anderson, G. J., Southey, M. C., Giles, G. G., English, D. R., Hopper, J. L., Olynyk, J. K., Powell, L. W., Gertig, D. M. Iron-overload-related disease in HFE hereditary hemochromatosis. New Eng. J. Med. 358: 221-230, 2008. [PubMed: 18199861] [Full Text: https://doi.org/10.1056/NEJMoa073286]

  3. Andersen, R. V., Tybjaerg-Hansen, A., Appleyard, M., Birgens, H., Nordestgaard, B. G. Hemochromatosis mutations in the general population: iron overload progression rate. Blood 103: 2914-2919, 2004. [PubMed: 15070663] [Full Text: https://doi.org/10.1182/blood-2003-10-3564]

  4. Bahram, S., Gilfillan, S., Kuhn, L. C., Moret, R., Schulze, J. B., Lebeau, A., Schumann, K. Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism. Proc. Nat. Acad. Sci. 96: 13312-13317, 1999. [PubMed: 10557317] [Full Text: https://doi.org/10.1073/pnas.96.23.13312]

  5. Barton, J. C., Rothenberg, B. E., Bertoli, L. F., Acton, R. T. Diagnosis of hemochromatosis in family members of probands: a comparison of phenotyping and HFE genotyping. Genet. Med. 1: 89-93, 1999. [PubMed: 11336458] [Full Text: https://doi.org/10.1097/00125817-199903000-00005]

  6. Barton, J. C., Sawada-Hirai, R., Rothenberg, B. E., Acton, R. T. Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Molec. Dis. 25: 147-155, 1999. [PubMed: 10575540] [Full Text: https://doi.org/10.1006/bcmd.1999.0240]

  7. Benyamin, B., McRae, A. F., Zhu, G., Gordon, S., Henders, A. K., Palotie, A., Peltonen, L., Martin, N. G., Montgomery, G. W., Whitfield, J. B., Visscher, P. M. Variants in TF and HFE explain about 40% of genetic variation in serum-transferrin levels. Am. J. Hum. Genet. 84: 60-65, 2009. [PubMed: 19084217] [Full Text: https://doi.org/10.1016/j.ajhg.2008.11.011]

  8. Beutler, E., Felitti, V. J., Koziol, J. A., Ho, N. J., Gelbart, T. Penetrance of 845G-A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359: 211-218, 2002. [PubMed: 11812557] [Full Text: https://doi.org/10.1016/S0140-6736(02)07447-0]

  9. Beutler, E., Gelbart, T., West, C., Lee, P., Adams, M., Blackstone, R., Pockros, P., Kosty, M., Venditti, C. P., Phatak, P. D., Seese, N. K., Chorney, K. A., Ten Elshof, A. E., Gerhard, G. S., Chorney, M. Mutation analysis in hereditary hemochromatosis. Blood Cells Molec. Dis. 22: 187-194, 1996. [PubMed: 8931958] [Full Text: https://doi.org/10.1006/bcmd.1996.0027]

  10. Beutler, E. The significance of the 187G (H63D) mutation in hemochromatosis. (Letter) Am. J. Hum. Genet. 61: 762-764, 1997. [PubMed: 9326341]

  11. Beutler, E. Targeted disruption of the HFE gene. Proc. Nat. Acad. Sci. 95: 2033-2034, 1998. [PubMed: 9482831] [Full Text: https://doi.org/10.1073/pnas.95.5.2033]

  12. Bodmer, J. G., Parham, P., Albert, E. D., Marsh, S. G. E. Putting a hold on 'HLA-H'. (Letter) Nature Genet. 15: 234-235, 1997. [PubMed: 9054933] [Full Text: https://doi.org/10.1038/ng0397-234c]

  13. Cardoso, C. S., Alves, H., Mascarenhas, M., Goncalves, R., Oliveira, P., Rodrigues, P., Cruz, E., de Sousa, M., Porto, G. Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium? Immunogenetics 53: 1002-1008, 2002. [PubMed: 11904676] [Full Text: https://doi.org/10.1007/s00251-001-0414-8]

  14. Carella, M., D'Ambrosio, L., Totaro, A., Grifa, A., Valentino, M. A., Piperno, A., Girelli, D., Roetto, A., Franco, B., Gasparini, P., Camaschella, C. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am. J. Hum. Genet. 60: 828-832, 1997. [PubMed: 9106528]

  15. Cullen, L. M., Gao, X., Easteal, S., Jazwinska, E. C. The hemochromatosis 845 G-to-A and 187 C-to-G mutations: prevalence in non-Caucasian populations. Am. J. Hum. Genet. 62: 1403-1407, 1998. [PubMed: 9585606] [Full Text: https://doi.org/10.1086/301878]

  16. Davis, T. M. E., Beilby, J., Davis, W. A., Olynyk, J. K., Jeffrey, G. P., Rossi, E., Boyder, C., Bruce, D. G. Prevalence, characteristics, and prognostic significance of HFE gene mutations in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care 31: 1795-1801, 2008. [PubMed: 18566337] [Full Text: https://doi.org/10.2337/dc08-0248]

  17. de Villiers, J. N. P., Hillermann, R., Loubser, L., Kotze, M. J. Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum. Molec. Genet. 8: 1517-1522, 1999. Note: Erratum: Hum. Molec. Genet. 8: 1817 only, 1999. [PubMed: 10401000] [Full Text: https://doi.org/10.1093/hmg/8.8.1517]

  18. Drakesmith, H., Chen, N., Ledermann, H., Screaton, G., Townsend, A., Xu, X.-N. HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis. Proc. Nat. Acad. Sci. 102: 11017-11022, 2005. [PubMed: 16043695] [Full Text: https://doi.org/10.1073/pnas.0504823102]

  19. Drakesmith, H., Sweetland, E., Schimanski, L., Edwards, J., Cowley, D., Ashraf, M., Bastin, J., Townsend, A. R. M. The hemochromatosis protein HFE inhibits iron export from macrophages. Proc. Nat. Acad. Sci. 99: 15602-15607, 2002. [PubMed: 12429850] [Full Text: https://doi.org/10.1073/pnas.242614699]

  20. El Kahloun, A., Chauvel, B., Mauvieux, V., Dorval, I., Jouanolle, A.-M., Gicquel, I., Le Gall, J.-Y., David, V. Localization of seven new genes around the HLA-A locus. Hum. Molec. Genet. 2: 55-60, 1993. [PubMed: 8490624] [Full Text: https://doi.org/10.1093/hmg/2.1.55]

  21. European Haemochromatosis Consortium. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. (Letter) Nature Genet. 23: 271 only, 1999. [PubMed: 10545942] [Full Text: https://doi.org/10.1038/15452]

  22. Feder, J. N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D. A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M. C., Fullan, A., Hinton, L. M., Jones, N. L., and 21 others. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13: 399-408, 1996. [PubMed: 8696333] [Full Text: https://doi.org/10.1038/ng0896-399]

  23. Feder, J. N., Penny, D. M., Irrinki, A., Lee, V. K., Lebron, J. A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P. J., Schatzman, R. C. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc. Nat. Acad. Sci. 95: 1472-1477, 1998. [PubMed: 9465039] [Full Text: https://doi.org/10.1073/pnas.95.4.1472]

  24. Feder, J. N., Tsuchihashi, Z., Irrinki, A., Lee, V. K., Mapa, F. A., Morikang, E., Prass, C. E., Starnes, S. M., Wolff, R. K., Parkkila, S., Sly, W. S., Schatzman, R. C. The hemochromatosis founder mutation in HLA-H disrupts beta-2-microglobulin interaction and cell surface expression. J. Biol. Chem. 272: 14025-14028, 1997. [PubMed: 9162021] [Full Text: https://doi.org/10.1074/jbc.272.22.14025]

  25. Gao, J., Zhao, N., Knutson, M. D., Enns, C. A. The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells. J. Biol. Chem. 283: 21462-21468, 2008. [PubMed: 18524764] [Full Text: https://doi.org/10.1074/jbc.M803150200]

  26. Goei, V. L., Parimoo, S., Capossela, A., Chu, T. W., Gruen, J. R. Isolation of novel non-HLA gene fragments from the hemochromatosis region (6p21.3) by cDNA hybridization selection. Am. J. Hum. Genet. 54: 244-251, 1994. [PubMed: 8304341]

  27. Gomez, P. S., Parks, S., Ries, R., Tran, T. C., Gomez, P. F., Press, R. D. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results (Letter) Nature Genet. 23: 272 only, 1999. [PubMed: 10545944] [Full Text: https://doi.org/10.1038/15723]

  28. Hamosh, A. Personal Communication. Baltimore, Md. 8/10/2023.

  29. Hashimoto, K., Hirai, M., Kurosawa, Y. A gene outside the human MHC related to classical HLA class I genes. Science 269: 693-695, 1995. [PubMed: 7624800] [Full Text: https://doi.org/10.1126/science.7624800]

  30. Hashimoto, K., Hirai, M., Kurosawa, Y. Identification of a mouse homolog for the human hereditary haemochromatosis candidate gene. Biochem. Biophys. Res. Commun. 230: 35-39, 1997. [PubMed: 9020055] [Full Text: https://doi.org/10.1006/bbrc.1996.5889]

  31. Hill, W. G., Robertson, A. Linkage disequilibrium in finite populations. Theor. Appl. Genet. 38: 226-231, 1968. [PubMed: 24442307] [Full Text: https://doi.org/10.1007/BF01245622]

  32. Jazwinska, E. C., Cullen, L. M., Busfield, F., Pyper, W. R., Webb, S. I., Powell, L. W., Morris, C. P., Walsh T. P. Haemochromatosis and HLA-H. (Letter) Nature Genet. 14: 249-251, 1996. [PubMed: 8896549] [Full Text: https://doi.org/10.1038/ng1196-249]

  33. Jeffrey, G. P., Chakrabarti, S., Hegele, R. A., Adams, P. C. Polymorphism in intron 4 of HFE may cause overestimation of C282Y homozygote prevalence in haemochromatosis. (Letter) Nature Genet. 22: 325-326, 1999. [PubMed: 10431233] [Full Text: https://doi.org/10.1038/11892]

  34. Jenkitkasemwong, S., Wang, C.-Y., Coffey, R., Zhang, W., Chan, A., Biel, T., Kim, J.-S., Hojyo, S., Fukada, T., Knutson, M. D. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22: 138-150, 2015. [PubMed: 26028554] [Full Text: https://doi.org/10.1016/j.cmet.2015.05.002]

  35. Jouanolle, A. M., Fergelot, P., Gandon, G., Yaouanq, J., Le Gall, J. Y., David, V. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations. Hum. Genet. 100: 544-547, 1997. [PubMed: 9341868] [Full Text: https://doi.org/10.1007/s004390050549]

  36. Jouanolle, A. M., Gandon, G., Jezequel, P., Blayau, M., Campion, M. L., Yaouanq, J., Mosser, J., Fergelot, P., Chauvel, B., Bouric, P., Carn, G., Andrieux, N., Gicquel, I., Le Gall, J.-Y., David, V. Haemochromatosis and HLA-H. (Letter) Nature Genet. 14: 251-252, 1996. [PubMed: 8896550] [Full Text: https://doi.org/10.1038/ng1196-251]

  37. Ka, C., Le Gac, G., Dupradeau, F.-Y., Rochette, J., Ferec, C. The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein. Hum. Genet. 117: 467-475, 2005. [PubMed: 15965644] [Full Text: https://doi.org/10.1007/s00439-005-1307-y]

  38. Le Gac, G., Dupradeau, F.-Y., Mura, C., Jacolot, S., Scotet, V., Esnault, G., Mercier, A.-Y., Rochette, J., Ferec, C. Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect. Blood Cells Molec. Dis. 30: 231-237, 2003. [PubMed: 12737937] [Full Text: https://doi.org/10.1016/s1079-9796(03)00036-6]

  39. Lebron, J. A., Bennett, M. J., Vaughn, D. E., Chirino, A. J., Snow, P. M., Mintier, G. A., Feder, J. N., Bjorkman, P. J. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 93: 111-123, 1998. [PubMed: 9546397] [Full Text: https://doi.org/10.1016/s0092-8674(00)81151-4]

  40. Levy, J. E., Montross, L. K., Cohen, D. E., Fleming, M. D., Andrews, N. C. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94: 9-11, 1999. [PubMed: 10381492]

  41. Livesey, K. J., Wimhurst, V. L. C., Carter, K., Worwood, M., Cadet, E., Rochette, J., Roberts, A. G., Pointon, J. J., Merryweather-Clarke, A. T., Bassett, M. L., Jouanolle, A.-M., Mosser, A., David, V., Poulton, J., Robson, K. J. H. The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading. J. Med. Genet. 41: 6-10, 2004. [PubMed: 14729817] [Full Text: https://doi.org/10.1136/jmg.2003.008805]

  42. Lucotte, G. Celtic origin of the C282Y mutation of hemochromatosis. Blood Cells Molec. Dis. 24: 433-438, 1998. [PubMed: 9851897] [Full Text: https://doi.org/10.1006/bcmd.1998.0212]

  43. McCune, C. A., Al-Jader, L. N., May, A., Hayes, S. L., Jackson, H. A., Worwood, M. Hereditary haemochromatosis: only 1% of adult HFE C282Y homozygotes in South Wales have a clinical diagnosis of iron overload. Hum. Genet. 111: 538-543, 2002. [PubMed: 12436244] [Full Text: https://doi.org/10.1007/s00439-002-0824-1]

  44. Mehrany, K., Drage, L. A., Brandhagen, D. J., Pittelkow, M. R. Association of porphyria cutanea tarda with hereditary hemochromatosis. J. Am. Acad. Derm. 51: 205-211, 2004. [PubMed: 15280838] [Full Text: https://doi.org/10.1016/j.jaad.2003.08.015]

  45. Mercier, B., Mura, C., Ferec, C. Putting a hold on 'HLA-H'. (Letter) Nature Genet. 15: 234 only, 1997. [PubMed: 9054932] [Full Text: https://doi.org/10.1038/ng0397-234b]

  46. Merryweather-Clarke, A. T., Cadet, E., Bomford, A., Capron, D., Viprakasi, V., Miller, A., McHugh, P. J. Chapman, R. W., Pointon, J. J., Wimhurst, V. L. C., Livesey, K. J., Tanphaichitr, V., Rochette, J., Robson, K. J. H. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum. Molec. Genet. 12: 2241-2247, 2003. [PubMed: 12915468] [Full Text: https://doi.org/10.1093/hmg/ddg225]

  47. Merryweather-Clarke, A. T., Pointon, J. J., Shearman, J. D., Robson, K. J. H. Global prevalence of putative haemochromatosis mutations. J. Med. Genet. 34: 275-278, 1997. [PubMed: 9138148] [Full Text: https://doi.org/10.1136/jmg.34.4.275]

  48. Moczulski, D. K., Grzeszczak, W., Gawlik, B. Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care 24: 1187-1191, 2001. [PubMed: 11423500] [Full Text: https://doi.org/10.2337/diacare.24.7.1187]

  49. Mura, C., Nousbaum, J.-B., Verger, P., Moalic, M.-T., Raguenes, O., Mercier, A.-Y., Ferec, C. Phenotype-genotype correlation in haemochromatosis subjects. Hum. Genet. 101: 271-276, 1997. [PubMed: 9439654] [Full Text: https://doi.org/10.1007/s004390050628]

  50. Mura, C., Raguenes, O., Ferec, C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93: 2502-2505, 1999. [PubMed: 10194428]

  51. Nairz, M., Theurl, I., Schroll, A., Theurl, M., Fritsche, G., Lindner, E., Seifert, M., Crouch, M.-L. V., Hantke, K., Akira, S., Fang, F. C., Weiss, G. Absence of functional Hfe protects mice from invasive Salmonella enterica serovar typhimurium infection via induction of lipocalin-2. Blood 114: 3642-3651, 2009. [PubMed: 19700664] [Full Text: https://doi.org/10.1182/blood-2009-05-223354]

  52. Noll, W. W., Belloni, D. R., Stenzel, T. T., Grody, W. W. Polymorphism in intron 4 of HFE does not compromise haemochromatosis mutation results. (Letter) Nature Genet. 23: 271-272, 1999. [PubMed: 10545943] [Full Text: https://doi.org/10.1038/15722]

  53. Oliva, R., Novials, A., Sanchez, M., Villa, M., Ingelmo, M., Recasens, M., Ascaso, C., Bruguera, M., Gomis, R. The HFE gene is associated to an earlier age of onset and to the presence of diabetic nephropathy in diabetes mellitus type 2. Endocrine 24: 111-114, 2004. [PubMed: 15347835] [Full Text: https://doi.org/10.1385/ENDO:24:2:111]

  54. Parkkila, S., Waheed, A., Britton, R. S., Bacon, B. R., Zhou, X. Y., Tomatsu, S., Fleming, R. E., Sly, W. S. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc. Nat. Acad. Sci. 94: 13198-13202, 1997. [PubMed: 9371823] [Full Text: https://doi.org/10.1073/pnas.94.24.13198]

  55. Parkkila, S., Waheed, A., Britton, R. S., Feder, J. N., Tsuchihashi, Z., Schatzman, R. C., Bacon, B. R., Sly, W. S. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc. Nat. Acad. Sci. 94: 2534-2539, 1997. [PubMed: 9122230] [Full Text: https://doi.org/10.1073/pnas.94.6.2534]

  56. Peterlin, B., Petrovic, M. G., Makuc, J., Hawlina, M., Petrovic, D. A hemochromatosis-causing mutation C282Y is a risk factor for proliferative diabetic retinopathy in Caucasians with type 2 diabetes. J. Hum. Genet. 48: 646-649, 2003. [PubMed: 14618419] [Full Text: https://doi.org/10.1007/s10038-003-0094-3]

  57. Poullis, A., Moodie, S. J., Maxwell, J. D. Clinical haemochromatosis in HFE mutation carriers. Lancet 360: 411-412, 2002. [PubMed: 12241803] [Full Text: https://doi.org/10.1016/s0140-6736(02)09581-8]

  58. Rhodes, D. A., Raha-Chowdhury, R., Cox, T. M., Trowsdale, J. Homozygosity for the predominant Cys282Tyr mutation and absence of disease expression in hereditary haemochromatosis. J. Med. Genet. 34: 761-764, 1997. [PubMed: 9321765] [Full Text: https://doi.org/10.1136/jmg.34.9.761]

  59. Rienhoff, H. Y., Jr. Iron-overload-related disease in HFE hereditary hemochromatosis. (Letter) New Eng. J. Med. 358: 2294 only, 2008. [PubMed: 18504828]

  60. Roberts, A. G., Whatley, S. D., Morgan, R. R., Worwood, M., Elder, G. H. Increased frequency of the haemochromatosis cys282tyr mutation in sporadic porphyria cutanea tarda. Lancet 349: 321-323, 1997. [PubMed: 9024376] [Full Text: https://doi.org/10.1016/S0140-6736(96)09436-6]

  61. Robson, K. J. H., Lehmann, D. J., Wimhurst, V. L. C., Livesey, K. J., Combrinck, M., Merryweather-Clarke, A. T., Warden, D. R., Smith, A. D. Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. J. Med. Genet. 41: 261-265, 2004. [PubMed: 15060098] [Full Text: https://doi.org/10.1136/jmg.2003.015552]

  62. Rohrlich, P. S., Fazilleau, N., Ginhoux, F., Firat, H., Michel, F., Cochet, M., Laham, N., Roth, M. P., Pascolo, S., Nato, F., Coppin, H., Charneau, P., Danos, O., Acuto, O., Ehrlich, R., Kanellopoulos, J., Lemonnier, F. A. Direct recognition by alpha-beta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Proc. Nat. Acad. Sci. 102: 12855-12860, 2005. [PubMed: 16123136] [Full Text: https://doi.org/10.1073/pnas.0502309102]

  63. Roth, M.-P., Giraldo, P., Hariti, G., Poloni, E. S., Sanchez-Mazas, A., De Stefano, G. F., Dugoujon, J.-M., Coppin, H. Absence of the hemochromatosis gene Cys282Tyr mutation in three ethnic groups from Algeria (Mzab), Ethiopia, and Senegal. Immunogenetics 46: 222-225, 1997. [PubMed: 9211748] [Full Text: https://doi.org/10.1007/s002510050265]

  64. Roy, C. N., Custodio, A. O., de Graaf, J., Schneider, S., Akpan, I., Montross, L. K., Sanchez, M., Gaudino, A., Hentze, M. W., Andrews, N. C., Muckenthaler, M. U. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nature Genet. 36: 481-485, 2004. [PubMed: 15098034] [Full Text: https://doi.org/10.1038/ng1350]

  65. Roy, C. N., Penny, D. M., Feder, J. N., Enns, C. A. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J. Biol. Chem. 274: 9022-9028, 1999. [PubMed: 10085150] [Full Text: https://doi.org/10.1074/jbc.274.13.9022]

  66. Ryan, E., O'Keane, C., Crowe, J. Hemochromatosis in Ireland and HFE. Blood Cells Mol. Dis. 24: 428-432, 1998. [PubMed: 9851896] [Full Text: https://doi.org/10.1006/bcmd.1998.0211]

  67. Saric, M., Zamurovic, L., Keckarevic-Markovic, M., Keckarevic, D., Stevanovic, M., Savic-Pavicevic, D., Jovic, J., Romac, S. Frequency of the hemochromatosis gene mutations in the population of Serbia and Montenegro. (Letter) Clin. Genet. 70: 170-172, 2006. [PubMed: 16879202] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00655.x]

  68. The UK Haemochromatosis Consortium. A simple genetic test identifies 90% of UK patients with haemochromatosis. Gut 41: 841-844, 1997. [PubMed: 9462220] [Full Text: https://doi.org/10.1136/gut.41.6.841]

  69. Thenie, A. C., Gicquel, I. M., Hardy, S., Ferran, H., Fergelot, P., Le Gall, J.-Y., Mosser, J. Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene. Hum. Molec. Genet. 10: 1859-1866, 2001. [PubMed: 11532995] [Full Text: https://doi.org/10.1093/hmg/10.17.1859]

  70. Tomatsu, S., Orii, K. O., Fleming, R. E., Holden, C. C., Waheed, A., Britton, R. S., Gutierrez, M. A., Velez-Castrillon, S., Bacon, B. R., Sly, W. S. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc. Nat. Acad. Sci. 100: 15788-15793, 2003. [PubMed: 14673107] [Full Text: https://doi.org/10.1073/pnas.2237037100]

  71. Totaro, A., Rommens, J. M., Grifa, A., Lunardi, C., Carella, M., Huizenga, J. J., Roetto, A., Camaschella, C., De Sandre, G., Gasparini, P. Hereditary hemochromatosis: generation of a transcription map within a refined and extended map of the HLA class I region. Genomics 31: 319-326, 1996. [PubMed: 8838313] [Full Text: https://doi.org/10.1006/geno.1996.0054]

  72. Waalen, J., Beutler, E. Iron-overload-related disease in HFE hereditary hemochromatosis. (Letter) New Eng. J. Med. 358: 2293-2294, 2008. [PubMed: 18499578] [Full Text: https://doi.org/10.1056/NEJMc080330]

  73. Waheed, A., Parkkila, S., Zhou, X. Y., Tomatsu, S., Tsuchihashi, Z., Feder, J. N., Schatzman, R. C., Britton, R. S., Bacon, B. R., Sly, W. S. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta-2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc. Nat. Acad. Sci. 94: 12384-12389, 1997. [PubMed: 9356458] [Full Text: https://doi.org/10.1073/pnas.94.23.12384]

  74. Wallace, D. F., Subramaniam, V. N. The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data. Genet. Med. 18: 618-626, 2016. [PubMed: 26633544] [Full Text: https://doi.org/10.1038/gim.2015.140]

  75. Walsh, C. H., Malins, J. M. Proliferative retinopathy in a patient with diabetes mellitus and idiopathic haemochromatosis. Brit. Med. J. 2: 16-17, 1978. [PubMed: 678784] [Full Text: https://doi.org/10.1136/bmj.2.6129.16-a]

  76. Yaouanq, J., Perichon, M., Chorney, M., Pontarotti, P., Le Treut, A., El Kahloun, A., Mauvieux, V., Blayau, M., Jouanolle, A. M., Chauvel, B., Moirand, R., Nouel, O., Le Gall, J. Y., Feingold, J., David, V. Anonymous marker loci within 400 kb of HLA-A generate haplotypes in linkage disequilibrium with the hemochromatosis gene (HFE). Am. J. Hum. Genet. 54: 252-263, 1994. [PubMed: 8304342]

  77. Zhou, X. Y., Tomatsu, S., Fleming, R. E., Parkkila, S., Waheed, A., Jiang, J., Fei, Y., Brunt, E. M., Ruddy, D. A., Prass, C. E., Schatzman, R. C., O'Neill, R., Britton, R. S., Bacon, B. R., Sly, W. S. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc. Nat. Acad. Sci. 95: 2492-2497, 1998. [PubMed: 9482913] [Full Text: https://doi.org/10.1073/pnas.95.5.2492]

  78. Zoller, H., Theurl, I., Koch, R. O., McKie, A. T., Vogel, W., Weiss, G. Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology 125: 746-754, 2003. [PubMed: 12949720] [Full Text: https://doi.org/10.1016/s0016-5085(03)01063-1]


Contributors:
Ada Hamosh - updated : 10/23/2018
Patricia A. Hartz - updated : 6/9/2016
Paul J. Converse - updated : 7/1/2011

Creation Date:
Carol A. Bocchini : 10/19/2010

Edit History:
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