Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HFE is a non-typical MHC class 1-type protein that is mutated in hereditary hemochromatosis. The purpose of this study was to identify possible splice variants of HFE mRNA and investigate the regulation of these isoforms in duodenum and liver of patients with normal and altered iron stores. RT-PCR was performed using HFE specific primers and duodenal RNA obtained from patients with hemochromatosis, iron deficiency, secondary iron overload and normal controls. The reaction products were visualized by Southern blot and identified by DNA sequence analysis. Additional studies were performed on RNA isolated from liver and a range of human tissues. A truncated (soluble) form of HFE protein was identified that lacks the transmembrane domain and occurs as a result of alternative splicing. Soluble HFE was found predominantly in the duodenum, spleen, breast, skin and testicle. In hereditary hemochromatosis full length HFE was the predominant isoform present in the duodenum similar to iron deficiency. Alternate splicing produces soluble HFE that may have a unique function to regulate cellular iron transport.
Blood Cells Mol Dis 1999 Feb
PMID:Alternate splicing produces a soluble form of the hereditary hemochromatosis protein HFE. 1034 14

HFE is a class I major histocompatibility complex (MHC)-related protein that is mutated in patients with the iron storage disease hereditary hemochromatosis. HFE binds tightly to transferrin receptor (TfR), the receptor that mediates uptake of iron-loaded transferrin. The binding affinities for TfR of HFE mutants, designed using the HFE crystal structure, were measured using biosensor assays. The results allow localization of the TfR binding site on HFE to the C-terminal portion of the alpha1 domain helix and an adjacent loop, a region distinct from the ligand binding sites on class I MHC and related proteins. A biosensor-derived pH-dependent affinity profile for the HFE-TfR interaction is discussed in terms of HFE's hypothesized role in intracellular trafficking.
J Mol Biol 1999 Jun 18
PMID:The transferrin receptor binding site on HFE, the class I MHC-related protein mutated in hereditary hemochromatosis. 1036 85

Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochromatosis ( HFE ) gene. This population screening approach, utilizing a combined heteroduplex and single-strand conformation polymorphism (HEX-SSCP) method, revealed three previously described and four novel missense mutations. Novel variants V53M and V59M were identified in exon 2, Q127H in exon 3 and R330M in exon 5. The exon 5 variant was identified in one of 13 patients referred for a molecular diagnosis of hereditary haemochromatosis (HH), who tested negative for the known C282Y and H63D mutations. Mutation Q127H was detected in exon 3 of the HFE gene together with mutation H63D in an apparently severely affected patient previously shown to carry the protoporphyrinogen oxidase ( PPOX ) gene mutation R59W, which accounts for dominantly inherited variegate porphyria (VP) in >80% of affected South Africans. The mutant allele frequency of the C282Y mutation was found to be significantly lower in 73 apparently unrelated VP patients with the R59W mutation than in 102 controls drawn from the same population ( P = 0.005). The population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supports previous data on the involvement of this gene in the porphyria phenotype.
Hum Mol Genet 1999 Aug
PMID:Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. 1040 Oct

Recently a candidate gene for hereditary hemo-chromatosis, HFE, was identified. The finding raises the possibility for genetic testing to provide earlier detection and more complete genotypic evaluation of hemochromatosis affected individuals. We determined the frequency of the HFE polymorphisms, C282Y and H63D, in a randomly selected multi-ethnic control population for establishment of a hemochromatosis genetic testing program. Prevalence was determined by PCR amplification and restriction enzyme digestion of HFE in 100 Caucasians, 100 Hispanics, and 56 African Americans. Heterozygosity for C282Y was detected in 8% of Caucasians, 3% of Hispanics, and 2% of African Americans. Homozygosity for C282Y was detected in 1% of Caucasians. Heterozygosity for H63D was detected in 24% of Caucasians, 15% Hispanics, and 3.5% of African Americans. Homozygosity for H63D was present in 4% of Caucasians and 1% of Hispanics. One Hispanic case was double heterozygous for C282Y and H63D. These results indicate the highest prevalence of C282Y and H63D in the Caucasian population. Additionally, we demonstrate C282Y and H63D polymorphisms in our Hispanic and African American populations, groups in which prevalence rates remain less defined. Our results support the need for thorough interpretation of genetic results for hereditary hemochromatosis in various ethnic populations.
Int J Mol Med 1999 Oct
PMID:Prevalence of the C282Y and H63D polymorphisms in a multi-ethnic control population. 1049 80

Diverse hereditary disorders associated with iron accumulation cause widespread organ damage. New insights into cellular pathways of iron transport have emerged from the identification of molecules implicated in heritable defects of iron metabolism. Unravelling the genetic basis of rare variants of haemochromatosis should provide vital functional information to further our mechanistic understanding of iron homeostasis.
Mol Med Today 1999 Oct
PMID:Inherited disorders of iron storage and transport. 1049 11

Sequencing of HFE exons 2, 3, 4, and 5, and of portions of introns 2, 4, and 5 revealed novel mutations in four of twenty hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for previously undescribed mutations: exon 2, nt 314T-->C (314C; I105T), and exon 2, nt 277G-->(277C; G93R), respectively; these probands were also heterozygous for H63D and C282Y, respectively. Probands 3 and 4 were heterozygous for a previously described but uncommon HFE mutation: exon 2, nt 193A-->T (193T; S65C). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda, and Proband 4 had hereditary stomatocytosis. Each of these four 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 our probands. The I105T and G93R mutations were linked to haplotypes bearing HLA-A3,-B7 and HLA-A2,-B62, respectively. The S65C mutation was linked to a haplotype characterized by HLA-32. Sixteen other probands did not have an uncommon HFE exon mutation. In 176 normal control subjects, two were heterozygous for S65C, but I105T and G93R were not detected. Nine of twenty probands were heterozygous and two probands were homozygous for a previously described base-pair change at intron 2, nt 3671T-->C. One proband without a detectable missense mutation had a previously described intron 5 allele (nt 6700G-->A). Heterozygosity for a previously described base-pair change in intron 4 (nt 5636T-->C) was detected in all persons we studied who also had the S65C mutation. One proband was heterozygous for a previously undescribed base-pair change at intron 5 (nt 5807A-->G). We conclude that uncommon HFE exon and intron mutations may be discovered among hemochromatosis patients who have "atypical" HFE genotypes.
Blood Cells Mol Dis
PMID:Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. 1057 40

Two amino acid variants in the HFE gene, C282Y and H63D, have been reported in most cases of hereditary hemochromatosis. A recently discovered novel amino acid variant of HFE, namely S65C, has been implicated to be responsible for a mild form of iron overload. We determined genotypes of the HFE S65C variant in 230 voluntary blood donors with a transferrin saturation >45%, who did not carry the HFE C282Y variant. The control group consisted of 248 first time blood donors who had a transferrin saturation < 45%. We also determined genotypes of the HFE H63D variant in the two groups. For the HFE S65C variant, the frequency of the HFE C65 allele was 1. 7% and 2.2% in the high and low transferrin saturation groups, respectively (p = 0.65). In contrast, for the HFE H63D variant, the frequency of the HFE D63 allele was 24.8% and 14.7% in the high and low transferrin saturation groups, respectively (p = 0.0009). This study demonstrates no association of the HFE C65 allele with the phenotype of high transferrin saturation. The results do not support the use of DNA genotyping for the HFE S65C mutation in population screening studies for hemochromatosis.
Blood Cells Mol Dis
PMID:HFE S65C variant is not associated with increased transferrin saturation in voluntary blood donors. 1066 Apr 84

The effect of five different transferrin variants (TFv1, TFv2, TFv3, TFv4, and TFv5) on the hemoglobin level, mean corpuscular volume (MCV), ferritin level, percent transferrin saturation (%TS), and the unsaturated iron binding capacity (UIBC) was investigated in subjects with defined HFE haplotypes, 919 persons undergoing health screening and 113 patients with clinical hemochromatosis. The most common variant is TFv4; the population distribution of this variant was also studied. None of the variants were found to have an effect on any of the parameters of iron metabolism that were investigated. Moreover, the frequency of these variants in patients with clinically significant hemochromatosis was no different from that in the general population. We conclude that these polymorphisms in transferrin do not play a role in the expression of hemochromatosis, nor do they produce any other significant changes in iron metabolism.
Blood Cells Mol Dis
PMID:The effect of transferrin polymorphisms on iron metabolism. 1066 Apr 86

In 1996 two mutations in Hfe, the gene affected in hereditary hemochromatosis, were identified as C282Y (c.845G. A) and H63D (c.187C. G). Immunohistochemical studies have localized the protein product of Hfe to the deep crypts of the duodenum, the maximum site of iron absorption. To date, there are no published data on the cellular location and regulation of Hfe in patients with hemochromatosis who are homozygous for C282Y. The aim of this study was to identify the cellular localization of Hfe in genotyped individuals and to study possible regulation of this protein by the mutations described in the Hfe gene locus and iron deficiency. Duodenal biopsy specimens and serum for iron, ferritin, and transferrin saturation were taken from controls (n = 10) and patients with hereditary hemochromatosis (n = 10) and iron deficiency anemia (n = 10). All participants were genotyped for C282Y and H63D mutations. Expression of Hfe in the duodenum was demonstrated by immunohistochemistry. Hfe was expressed in the deep crypts of the duodenum in all three groups in a perinuclear fashion. Hfe staining was weaker in the hemochromatosis and iron deficiency patients (mean transferrin saturation 69.6%, SD 23% and 15%, SD 11%, respectively) when compared to controls (mean transferrin saturation 33.1%, SD 15%). There was no difference in the intensity of Hfe staining within the hemochromatosis group who were iron overloaded when compared to their iron-depleted counterparts. In summary, Hfe is expressed strongly in the deep crypts of the small intestine of normal subjects. Homozygosity for C282Y and conditions of iron deficiency result in a downregulation of Hfe. Furthermore, Hfe is not regulated by therapeutic iron depletion in patients with hemochromatosis who are homozygous for the C282Y mutation.
Blood Cells Mol Dis 2000 Feb
PMID:Immunohistochemistry of the Hfe protein in patients with hereditary hemochromatosis, iron deficiency anemia, and normal controls. 1077 70

We report the clinical, biochemical, and genetic characteristics of 13 hemochromatosis patients from Saguenay-Lac-Saint-Jean in whom the first symptoms appeared before age 30. Although the mean age at onset of the first symptoms was 21. 5 years, their mean age at diagnosis was 23.8 years; the diagnosis was particularly delayed among women. Seventy-seven percent of the patients had hypogonadotrophic hypogonadism and 69% heart failure and/or cardiac arrhythmias. Genetic analysis of the HFE gene revealed heterozygosity for the C282Y mutation in 2 patients and for the S65C mutation in 2 others and homozygosity for the H63D mutation in 1 patient. The remaining 8 patients had no identified mutation in the HFE gene, although sequencing of all seven codons and intron-exon junctions was performed (5 patients). All 13 patients fulfill the clinical criteria of juvenile hemochromatosis and represent the largest cluster thus far reported.
Blood Cells Mol Dis 2000 Feb
PMID:Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint-Jean (Quebec, canada). 1077 71


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