Disease relevance of HFE

• CONCLUSIONS: Our data show that duodenal-cytochrome b activity in iron deficiency is stimulated via enhanced protein expression, whereas in HFE hemochromatosis it is up-regulated post-translationally [1].
• These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload [2].
• A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis [3].
• In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation [3].
• Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032) [4].
• The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH [5].

Psychiatry related information on HFE

• Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer's disease patients from Northern Italy [6].
• METHODS: Forty patients with increased serum ferritin, resistant to dietary restriction and normal transferrin saturation, 90 with ultrasonographic evidence of hepatic steatosis, and 60 obligate heterozygotes for hemochromatosis, all negative for alcohol abuse, hepatitis virus infections, and inflammation were studied [7].
• The 23 C282Y homozygotes identified were matched to 2 subjects each of 5 other HFE genotypes with respect to sex, age, and alcohol consumption [8].
• A 14-year-old boy who presented with debilitating lethargy was shown to have an elevated serum ferritin of 572 microg/L and a C282Y homozygous HFE genotype [9].
• We report a single case of a 25-year-old man suffering from juvenile hemochromatosis, with aggressive clinical manifestations, typically characterized by transaminasemia and progressive erectile dysfunction, due to hypogonadotropic hypogonadism [10].

High impact information on HFE

• Mutations in hemojuvelin disrupt its ability to stimulate expression of the iron regulatory peptide hepcidin and result in the severe iron loading disorder juvenile hemochromatosis [11].
• Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly [12].
• Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2) [12].
• Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE [13].
• Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200) [13].

Chemical compound and disease context of HFE

• The iron overload is moderate compared to patients with type 1 hemochromatosis but the deferoxamine test was normal in all patients [14].
• This study, comprising 108 patients with PCT, was intended to define the role of hemochromatosis gene (HFE) mutations in the expression of PCT and to determine the contribution of acquired factors including alcohol, hepatitis C virus (HCV), and estrogen [15].
• Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda [16].
• Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease [17].
• Our studies suggest that HFE expression and its consequent effect on cellular iron homeostasis may modulate doxorubicin-induced oxidative stress and apoptosis in breast cancer cells [18].

Biological context of HFE

• Most cases arise from a founder mutation in HFE (845G-->A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with beta2-microglobulin [19].
• Mechanisms of HFE-induced regulation of iron homeostasis: Insights from the W81A HFE mutation [20].
• In the studies presented here, we demonstrate by immunohistochemistry 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 [2].
• Our results indicate that in this B-lymphoid cell line, the HFE C282Y mutation affects both Tf-dependent and -independent iron uptake and enhances cell sensitivity to oxidative stress [21].
• Transfection of TRVb cells or the derivative line TRVb1 (which stably expresses human TfR1) with HFE resulted in lower ferritin levels and decreased Fe(2+) uptake [22].

Anatomical context of HFE

• We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages [23].
• In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing beta2M, resulted in a decrease in TfR1dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state [24].
• Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum [25].
• HeLa cells expressing fW81AHFE behaved in a similar manner to cells expressing wild-type HFE with respect to decreased intracellular iron levels measured by iron regulatory protein gel-shift assays and ferritin levels [20].
• The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body [2].

Associations of HFE with chemical compounds

• Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake [26].
• Because of similarities in the transport of gallium and iron and the use of (67)Ga scanning in lymphoid malignancies, we examined the effect of HFE expression on (67)Ga uptake [27].
• Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed [7].
• Expression and Polarized Localization of the Hemochromatosis Gene Product HFE in Retinal Pigment Epithelium [28].
• Our findings indicate that the treatment rather than the disease increased the cadmium uptake in homozygous HH [29].

Physical interactions of HFE

• The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding [30].
• Furthermore, at 4 degrees C, the added soluble complex of HFE/beta2m inhibited binding of transferrin to HeLa cell TfR in a concentration-dependent manner [30].
• Co-immunoprecipitation studies of cell lysates from human embryonic kidney cells transfected with wild-type or mutant HLA-H cDNA demonstrate that wild-type HLA-H binds beta2-microglobulin and that the C282Y mutation, but not the H63D mutation, completely abrogates this interaction [31].
• Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells [32].
• We further observed that, unlike TfR1/HFE, Tf does not compete with HFE for binding to TfR2 and that binding is independent of pH (pH 6-7.5) [33].

Enzymatic interactions of HFE

• A single cut-off point of 55% for transferrin saturation and a cut-off point at the 90th percentile for the serum ferritin level were adequate for the detection of hemochromatosis if homozygosity was considered to be present when the results of one or both tests were positive [34].

Regulatory relationships of HFE

• Herein we show that TfR is required for and controls the assembly and the intracellular transport and surface expression of HFE [35].
• HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells [26].
• The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin [36].
• We addressed the question of whether hemojuvelin mutations may influence the phenotype of patients with adult-onset haemochromatosis with or without mutations of the HFE gene [37].
• Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis [38].

Other interactions of HFE

• A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2 [39].
• CONCLUSIONS: Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis [39].
• BACKGROUND & AIMS: An increased duodenal expression of the iron transporters, divalent-metal-transporter-1, and ferroportin is observed in patients with iron deficiency or hereditary hemochromatosis [1].
• Measurement of transferrin saturation was the most sensitive test for hemochromatosis [40].
• These results indicate that the association of HFE with TfR is not essential for its ability to lower intracellular iron stores [20].
• To determine if HFE had a similar effect on Zip14 in another cell line, HeLa cells expressing HFE under the tetracycline-repressible promoter were transfected with Zip14 [41].

Analytical, diagnostic and therapeutic context of HFE

• Western blot analyses show that the HFE protein is associated with beta2M in placental membranes [2].
• We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay [42].
• In order to more fully characterize the interaction between HFE and TfR, we determined the binding stoichiometry using equilibrium gel-filtration and analytical ultracentrifugation [43].
• The binding affinities for TfR of HFE mutants, designed using the HFE crystal structure, were measured using biosensor assays [44].
• RESULTS: RT-PCR showed predominant expression of HFE mRNA in the RPE-eyecup [28].

References