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At least 883 records · Page 49Linked to original sources
PubMed2000

Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells.

HFE is a MHC class 1-like protein that is mutated in hereditary hemochromatosis. In order to elucidate the role of HFE protein on cellular iron metabolism, functional studies were carried out in human hepatoma cells (HLF) overexpressing a fusion gene of HFE and green fluorescent protein (GFP). The expression of HFE-GFP was found to be localized on cell membrane and perinuclear compartment by fluorescent microscopy. By co-immunoprecipitation and Western blotting, HFE-GFP protein formed a complex with endogenous transferrin receptor and beta(2)-microglobulin, suggesting that this fusion protein has the function of HFE reported previously. We then examined the (59)Fe uptake and release, and internalization and recycling of (125)I-labeled transferrin in order to elucidate the functional roles of HFE in the cell system. In the transfectants, HFE protein decreased the rate of transferrin receptor-dependent iron ((59)Fe) uptake by the cells, but did not change the rate of iron release, indicating that HFE protein decreased the rate of iron influx. Scatchard analysis of transferrin binding to HFE-transfected cells showed an elevation of the dissociation constant from 1.9 to 4. 3 nM transferrin, indicating that HFE protein decreased the affinity of transferrin receptor for transferrin, while the number of transferrin receptors decreased from 1.5x10(5)/cell to 1. 2x10(5)/cell. In addition, the rate of transferrin recycling, especially return from endosome to surface, was decreased in the HFE-transfected cells by pulse-chase study with (125)I-labeled transferrin. Our results strongly suggest an additional role of HFE on transferrin receptor recycling in addition to the decrease of receptor affinity, resulting in the reduced cellular iron.

Carcinoma, Hepatocellular↗
PubMed2003

Population screening for hemochromatosis: a study in 5370 Spanish blood donors.

BACKGROUND/AIMS: Hereditary hemochromatosis is associated with homozygosity for C282Y mutation in the HFE gene, elevated serum transferrin saturation and excess iron deposits throughout the body. We conducted a population-based study in Spain to asses the prevalence of the HFE mutations and their effect on iron parameters. METHODS: We screened 5370 blood donors for the C282Y and H63D HFE mutations by allele-specific polymerase chain reaction. Serum iron, serum ferritin and transferrin saturation were also measured. RESULTS: We have found eight (five men and three women) blood donors who are C282Y homozygotes (0.15%) and 74 C282Y/H63D compound heterozygotes (1.38%). Four out of the eight C282Y homozygotes, all men, had high serum ferritin and transferrin saturation values. No woman was detected with both iron parameters increased. Only one of the 74 C282Y/H63D compound heterozygotes showed elevated serum ferritin and transferrin saturation values (penetrance 1.35%). Serum ferritin and transferrin saturation were significantly higher in C282Y homozygous men as compared with the rest of the genotypes. CONCLUSIONS: The C282Y/C282Y genotype frequency in Spain is 1 in 1004. The C282Y/C282Y genotype is clearly associated with an increase in iron parameters. Biochemical expression of the disease was found in 80% of the C282Y/C282Y men.

Adult↗
PubMed1999

Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions.

BACKGROUND/AIMS: Liver iron accumulation has been described in patients with chronic active hepatitis (CAH) C, and could play a role in the course of liver disease and negatively influence the response to interferon. The aim of this study was to determine the prevalence and severity of liver iron accumulation in CAH C, to assess its relationship with the HFE C282Y and H63D mutations, and to study its interactions with hepatic histological lesions. METHODS: Two hundred and nine patients (131 men, 78 women, mean age 44.3+/-12.0 years) with CAH C, including 19 patients with cirrhosis (9.1%) were studied. A semiquantitative grading system from 0 to 3 was used for histological assessment of liver iron accumulation on Perls' staining. The HFE C282Y and H63D mutations were screened for by restriction enzyme analysis performed on PCR-amplified products. Histological scores of activity and fibrosis were determined according to a previously validated METAVIR score system. RESULTS: Liver iron accumulation was found in 88/209 patients (42.1%), and was generally mild. The C282Y and H63D allele frequencies were in 23 (11.0%), and 50 (23.9%), respectively. No association was found between the presence of liver iron accumulation and the detection of the C282Y and H63D mutations. A significant relationship was found between the severity of histological activity and liver iron accumulation of macrophagic or mixed (i.e. both macrophagic and hepatocytic) type (p = 0.04). Although the number of cirrhotic patients was small, cirrhosis was more frequently observed in patients with than without liver iron accumulation (17.2% vs. 3.3%, p = 0.004). CONCLUSIONS: Overall, these data suggest that the liver iron accumulation in patients with CAH C is significantly associated with histological activity and cirrhosis, whereas the two missense hemochromatosis gene mutations are not major determinants.

Adult↗
PubMedDate not supplied

Analysis of HFE-codon 63/282 (H63D/C282Y) gene variants in mexican mestizos. Blood donors and patients with hereditary hemochromatosis.

BACKGROUND: The prevalence of hereditary hemochromatosis (HH) (H63D/C282Y) gene variants in Mexico is unknown. METHODS: Using amplification refractory mutation system polymerase chain reaction, an analysis of HFE-codon 63/282 (H63D/C282Y) gene variants was performed in a group of 153 Mexican mestizo blood donors and six individuals with familial iron overload. RESULTS: In normal blood donors, three heterozygotes for the C282Y mutation (2.0%) were found, whereas 18 heterozygotes and one homozygote for the H63D mutation (11.8% and 0.6%, respectively) were identified; there was one compound heterozygote for the C282Y/H63D mutation. These data resulted in allele frequencies of 0.013 (+/-0. 2%, alpha = 0.05) and 0.062 (+/-0.9%, alpha = 0.05), respectively, for these two mutations, results similar to those found in whites. In the six patients with the HH phenotype, two were found to be heterozygous for C282Y and one heterozygous for H63D; three individuals with HH had no gene mutations. Two heterozygous HH individuals were found to have iron overload associated with other conditions: one heterozygous for C282Y infected with HIV, and another heterozygous for H63D with heterozygous beta-thalassemia. CONCLUSIONS: The prevalence of C282Y and H63D HFE gene mutations in Mexican mestizos is similar to that found in other populations. In addition, other gene mutations responsible for HH in the Mexican mestizo population should be investigated, because, in three of six individuals with the HH phenotype, neither of the two mutations was recorded.

Blood Donors↗
PubMedDate not supplied

The hemochromatosis gene affects the age of onset of sporadic Alzheimer's disease.

In the present study we analysed the genotype of HFE, the gene involved in hemochromatosis, in 107 patients with sporadic late-onset AD and in 99 age-matched non-demented controls. We observed that patients carrying the mutant HFE-H63D allele had a mean age at onset of 71.7 +/- 6.0 years versus 76.6 +/- 5.8 years of those who were homozygous for the wild-type allele (p = 0.001). The frequency of the HFE-H63D mutation was highest (0.22) in the patients aged <70 years at the time of disease onset, whereas it was 0.12 in those with disease onset at an age of 70-80 years, and 0.04 in those aged more than 80 years. The APOE genotype did not significantly modify the effect of HFE on age at onset. We conclude that mild disturbances of iron homeostasis associated with a common genetic determinant may interact with other pathogenic mechanisms involved in AD. HFE mutations may anticipate AD clinical presentation in susceptible individuals.

Age of Onset↗
PubMed2002

Morbidity risk in HFE associated hereditary hemochromatosis C282Y heterozygotes.

Hereditary hemochromatosis (HHC) is a late-onset, autosomal recessive disorder leading to a chronic iron overload syndrome, finally causing diabetes, cardiomyopathy and liver disease. HHC is the most common single gene disorder in northern Europeans that occurs with a frequency of approximately 0.5%, and most of these patients carry the C282Y and H63D mutation in the HFE gene on chromosome 6p21.3. The vast majority of HHC patients are homozygous for the C282Y mutation, but HHC phenotypes are observed in other genotypes. Expression of the disease, in those homozygous for the C282Y mutation, is highly variable depending on the various features of the population studied. C282Y heterozygotes have slightly increased iron stores and in absence of other genetic and/or environmental factors do usually not develop the HHC phenotype. It is currently a matter of debate whether C282Y heterozygotes may have an increased risk for morbidity. Different studies investigating the association of C282Y heterozygocity with morbidity have given conflicting results, as is exemplified by extrahepatic cancers, cardiovascular diseases, alcoholic liver disease, and diabetes. However, there are examples of clear and unambiguous disease associations, such as with sporadic pophyria cutanea tarda. It remains to be seen whether a strong correlation between the C282Y heterozygous state and distinct pathological conditions will exist and large-scale genotyping studies will help to identify such potential risk groups in the future.

Australia↗
PubMed2003

Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism.

Iron overload increases oxidative stress and may lead to neurodegenerative disease like Parkinson's disease (PD). We studied the role of mutations in the hemochromatosis gene HFE in PD and other parkinsonism (non-PD PS) in two population-based series. The first series consisted of 137 patients with PD and 47 with non-PD PS, and the second of 60 patients with PD and 25 with non-PD PS. In the first series, PD patients were significantly more often homozygous for the C282Y mutation than controls (P=0.03). Patients with non-PD PS in both series were more often carriers for the C282Y mutation than controls (P=0.009, P=0.006, respectively). Our data are hampered by small numbers, yet suggest that the C282Y mutation increases the risk of PD and non-PD PS. The rarity of this genotype requires a large series of patients to prove our hypothesis.

Aged↗
PubMed2002

Epidemic pathogenic selection: an explanation for hereditary hemochromatosis?

Hereditary hemochromatosis (HH) is a disorder associated with progressive iron overload and deposition in multiple organs. It is the most common inherited single gene disorder in people of Northern and Western European descent. About 80% of individuals of European descent with HH are homozygous for a cysteine-to-tyrosine substitution (C282Y) in the gene now called HFE. The function of HFE protein, a major histocompatibility class I-like transmembrane protein, has not been fully elucidated. Three consequences of the C282Y mutation are lack of expression of HFE on the cellular surface, a lowered iron level in macrophages, and an increased rate of clearance of iron from the intestinal lumen. These changes could confer protection against certain pathogens early in life before iron overload occurs. Furthermore, the C282Y mutation might have been selected for during the European plagues caused by Yersinia spp. and other pathogens because of the conferred resistance to infection, i.e., by epidemic pathogenic selection.

Amino Acid Substitution↗
PubMed2001

High-performance liquid chromatography multiplex detection of two single nucleotide mutations associated with hereditary hemochromatosis.

High-performance liquid chromatography (HPLC) has been applied to the multiplex detection of the two single nucleotide mutations commonly found in hereditary hemochromatosis (HH). HH is associated with a major G to A transition at position 845 (mutation Cys282Tyr) and a minor C to G transition at position 187 (mutation His63Asp) in the cDNA of the HFE gene. Two detection assays were developed based on HPLC analysis of restriction fragment length polymorphism (RFLP) or single nucleotide extension (SNE) products following multiplex PCR amplification. RFLP genotypes the two sites as dsDNA fragments of different lengths generated by restriction enzymes Rsa I/Bcl I. SNE extends primers 5'-adjacent to the sites of interest with a dideoxynucleotide triphosphate (ddNTP) to generate extended ssDNA. The identity of the added ddNTP reveals the identity of the original possible mutation site(s). Application of these methods with HPLC analysis provides simple and reliable genotyping for HH and can be applied to other single nucleotide polymorphism studies.

Chromatography, High Pressure Liquid↗
PubMed1998

Unusual MHC-like molecules: CD1, Fc receptor, the hemochromatosis gene product, and viral homologs.

The MHC fold, with its well-characterized peptide-binding groove, can perform other functions in addition to presentation of antigenic peptides to T cells. Homologs of MHC molecules have diverse roles that include presentation of lipid antigens (by CD1), transport of immunoglobulins (by the neonatal Fc receptor), regulation of iron metabolism (by the hemochromatosis gene product, HFE), and deception of the host immune system (by viral homologs). Recent crystal structures of two of these non-standard MHC-like molecules have allowed comparison of the recognition properties of classical. MHC molecules with those of their unusual homologs.

Animals↗
PubMedDate not supplied

Can defects in transferrin receptor 2 and hereditary hemochromatosis genes account for iron overload in HbH disease?

Iron overload was found to be the major cause of disability in Chinese HbH disease patients although they were not on regular blood transfusion. The transferrin receptor 2 (TFR2) and hereditary hemochromatosis (HFE) genes were examined to see if inheritance of these gene defects may be a possible cause of iron overload in 45 HbH patients. A novel intronic (IVS6 (+6) T-->A) mutation of the TFR2 gene was identified in one patient, and six others were found to carry a known missense mutation (exon 5, I238M) that was also present in one normal control subject. One HbH patient and one normal control carried the H63D mutation of the HFE gene. Since only eight out of 45 iron-overloaded HbH patients carry a defect in the TFR2 or HFE gene in the heterozygote state and their iron loading status was comparable to the matched controls without such defects, it would appear that the accumulation of excess iron in HbH disease is more likely a result of increase dietary absorption secondary to ineffective erythropoiesis.

Alleles↗
PubMedDate not supplied

Hemochromatosis gene (HFE) mutations in South East Asia: a potential for iron overload.

Hereditary hemochromatosis (HH) is an autosomal recessive disease caused by mutations in the HFE gene that mainly affects populations of European descent. Recently a novel mutation (IVS5+1 G-->A) has been described in a Vietnamese patient with HH that was not detected in a European control population. We have developed a novel method to screen for this mutation based on restriction enzyme digestion of a PCR product using a modified forward primer. We have screened 314 Vietnamese people from several ethnic groups and 154 people from Thailand for this mutation and have detected two heterozygotes in the Vietnamese subjects (allele frequency 0.003). Analysis of these heterozygotes indicates that the mutation is on the same haplotype as that found in the original proband. Screening for the widely distributed HFE mutation, H63D, gave an allele frequency of 0.049 in the Vietnamese subjects and 0.032 in the subjects from Thailand. This is the first report of H63D allele frequencies in these populations. We suggest that the presence of the IVS5+1 G-->A and H63D mutations should be considered when investigating iron overload in Vietnamese patients and those of mixed origin as co-inheritance of both mutations is likely to be a risk factor for iron overload.

Gene Frequency↗
PubMedDate not supplied

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

Cysteine↗
PubMed2001

An improved real time PCR method for simultaneous detection of C282Y and H63D mutations in the HFE gene associated with hereditary hemochromatosis.

HFE-linked hereditary hemochromatosis (HH) is one of the most common inherited diseases among individuals of Northern European ancestry. Two sites of point mutations in the HFE gene--C282Y and H63D--are associated with greater than 90% of HH cases. We have developed a sensitive real time PCR (TaqMan) 5'-nuclease assay for single nucleotide polymorphism (SNP) detection using novel DNA chemistry, and successfully applied this method to detect these mutations. Fluorogenic PCR probes, chemically modified with a minor groove binding agent to increase duplex stability, were used in single and multiplex probe closed tube formats. The probes were tested in two commercially available thermocycling fluorimeters (the Light Cycler and the ABI Prism 7700). Comparison of the results obtained from the analysis of 43 samples showed no discrepancies between our 5' nuclease assay and the restriction length polymorphism analysis, which is routinely used in hospitals. The reported real time PCR technology is ideal for the clinical setting as it is sensitive, eliminates the labor and supply costs of post-PCR steps, reduces the risk of crossover contamination, minimizes sources of error, and can be fully automated.

Base Sequence↗
PubMed2003

The enigmatic role of the hemochromatosis protein (HFE) in iron absorption.

The HFE gene, a member of the class-I transplantation antigen gene family, is responsible for hereditary hemochromatosis, one of the most common inherited diseases in individuals of European descent. Patients exhibit predictable changes in iron homeostasis, including elevations in both transferrin saturation and serum ferritin levels. A subset of patients progress to overt clinical sequelae, resulting from iron overload. A hallmark of the disease is increased absorption of iron by the intestine. Although the HFE protein appears to modulate the function of the transferrin receptor in vitro, its precise role in vivo remains obscure. With multiple cell types involved in iron metabolism, the function of HFE is likely to be complex.

Animals↗
PubMed2002

Do some carriers of hemochromatosis gene mutations have higher than normal rates of disease and death?

Some heterozygote carriers of hemochromatosis HFE gene mutations become iron loaded with ensuing increased risk of disease and premature death. Contributing nutritional, behavioral and genetic factors are beginning to be identified. Carriers of HFE gene mutations should be advised to minimize contributing factors, if possible, and to have their iron values tested periodically. If values begin to rise, a schedule of phlebotomies should be considered.

Hemochromatosis↗
PubMed2002

Comprehensive hereditary hemochromatosis genotyping.

Hereditary hemochromatosis (HH) is an iron-overload disease common in populations of Northern European origin. Patients display increased iron absorption leading to excessive iron deposition and potential multiorgan failure. Using polymerase chain reaction sequence-specific primer (PCR-SSP) technology, we have developed an HH diagnosis assay capable of detecting 19 non-synonymous HFE mutations (including a previously unreported mutation, V295A) and several TFR2, SLC11A3 and H ferritin alleles implicated in HH. As part of the validation process, 159 UK renal donors were genotyped to determine HH allele frequencies in the UK population. The alleles nominally identified as HFE*01 (C282Y), HFE*02 (H63D) and HFE*03 (S65C) were found at frequencies of 0.085, 0.173 and 0.009, respectively. All other potential HH-associated alleles were absent, confirming their low prevalence in this population. This assay enables comprehensive routine HH genotyping, producing rapid, accurate and reproducible results at low cost.

DNA Mutational Analysis↗
PubMed2003

HFE, the MHC and hemochromatosis: paradigm for an extended function for MHC class I.

HFE was discovered as the hereditary hemochromatosis (HH) gene. It is located on chromosome 6 (6p21.3), 4Mb telomeric to the HLA-A locus, and its product has a structure similar to MHC class I molecules. HFE encodes two frequent mutations: C282Y and H63D. One of these (C282Y) is present in a large proportion of Caucasian HH patients. HFE has a tissue distribution compatible with a role in iron absorption (intestine), recycling (macrophages) and transport to the fetus (placenta).

Animals↗