Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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After the main hereditary hemochromatosis mutation C282Y in the HFE gene was described, we report here the C282Y frequencies for various European populations. The aim of this meta-analysis is to compile the Y allele frequencies of the C282Y mutation for 53 European populations, representing a total of 9265 unrelated people representing control samples. The most elevated values are observed in residual Celtic populations in Ireland, in the United Kingdom, and in France, in accordance with the initial hypothesis of Simon et al. (Prog. Med. Genet. 4, 135-168, 1980) concerning a Celtic origin of the hereditary hemochromatosis mutation.
Blood Cells Mol Dis
PMID:Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis. 1150 66

The gene responsible for hemochromatosis (HFE) has been identified on the short arm of chromosome 6, 4.5 Mb telomeric to HLA-A. A major mutation C282Y is closely correlated with the disease, as it accounts for 68 to 100\% of the cases of hemochromatosis. Nevertheless, some C282Y homozygotes subjects have no clinical or biological expression of the disease. Moreover, in Northern European populations a large discrepancy is observed between the number of C282Y homozygotes and the number of diagnosed hemochromatosis patients, suggesting incomplete penetrance of the mutation. To localize and identify the modifying genes, we investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients. Genomic DNA from 20 C282Y homozygotes (10 patients and 10 siblings presenting no or minor biological abnormalities) were studied. Five polymorphisms from the HFE gene were determined by PCR restriction. Extended haplotypes of the 6p21.3 region were constructed with 10 microsatellite markers. All the C282Y homozygotes shared the same HFE polymorphism. The haplotypes presented no significant difference between the probands and their unaffected relatives. These studies suggest that neither HFE polymorphism nor genes surrounding HFE are able to modulate HFE expression.
Blood Cells Mol Dis
PMID:Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region. 1150 63

Hereditary haemochromatosis is an autosomal recessive disease which results in iron overload, and it is the most frequently inherited disorder in Caucasian populations. The gene involved (HFE) has recently been identified, and it encodes an MHC class I-like molecule. A 2.7 kb cDNA has been isolated, whereas the HFE gene expression is characterized by an almost ubiquitous mRNA of 4.1 kb in size. The difference between this transcript and the isolated cDNA has not yet been explained. Thus, the 5' end of the HFE gene is still undefined and very little is known about the regulation of its expression. By searching this end, we isolated an antisense transcript originating from the same gene locus. Further investigations (rapid amplification of cDNA ends, RT-PCR experiments and dbEST screening) indicated that this RNA spans exon 1, exon 2, part of intron 1 of the HFE gene and approximately 1 kb upstream of it. This HFE antisense transcript is polyadenylated but displays no open reading frame. A ribonuclease A protection assay definitively demonstrated the biological existence of the HFE antisense RNA, which appears to be expressed in all of the tissues and cell lines tested. Furthermore, in vitro coupled transcription-translation experiments revealed that the HFE expression is decreased by this antisense RNA, indicating that it may play a critical role in the regulation of the HFE gene expression.
Hum Mol Genet 2001 Aug 15
PMID:Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene. 1153 95

The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and DCYTB: Ongoing studies of Friedreich's ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.
Hum Mol Genet 2001 Oct 01
PMID:Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers. 1167 99

The human CD1 proteins belong to a lipid-glycolipid antigen-presenting gene family and are related in structure and function to the MHC class I molecules. Previous mapping and DNA hybridization studies have shown that five linked genes located within a cluster on human chromosome 1q22-23 encode the CD1 protein family. We have analyzed the complete genomic sequence of the human CD1 gene cluster and found that the five active genes are distributed over 175,600 nucleotides and separated by four expanded intervening genomic regions (IGRs) ranging in length between 20 and 68 kb. The IGRs are composed mostly of retroelements including five full-length L1 PA sequences and various pseudogenes. Some L1 sequences have acted as receptors for other subtypes or families of retroelements. Alu molecular clocks that have evolved during primate history are found distributed within the HLA class I duplicated segments (duplicons) but not within the duplicons of CD1. Phylogeny of the alpha3 domain of the class I-like superfamily of proteins shows that the CD1 cluster is well separated from HLA class I by a number of superfamily members including MIC (PERB11), HFE, Zn-alpha2-GP, FcRn, and MR1. Phylogenetically, the human CD1 sequences are interspersed by CD1 sequences from other mammalian species, whereas the human HLA class I sequences cluster together and are separated from the other mammalian sequences. Genomic and phylogenetic analyses support the view that the human CD1 gene copies were duplicated prior to the evolution of primates and the bulk of the HLA class I genes found in humans. In contrast to the HLA class I genomic structure, the human CD1 duplicons are smaller in size, they lack Alu clocks, and they are interrupted by IGRs at least 4 to 14 times longer than the CD1 genes themselves. The IGRs seem to have been created as "buffer zones" to protect the CD1 genes from disruption by transposable elements.
J Mol Evol 2001 Dec
PMID:Genomic and phylogenetic analysis of the human CD1 and HLA class I multicopy genes. 1167 24

Hereditary hemochromatosis (HH) is a genetically heterogeneous disease. The HFE gene resides on chromosome 6 and its mutations account for the majority of HH cases in populations of northern European ancestry. Recently, two new types of hemochromatosis have been identified: Juvenile hemochromatosis (JH or HFE2), which maps to chromosome 1q21, and an adult form defined as HFE 3, which results from mutations of the TFR 2 gene, located at 7q22. We have performed a linkage study in five unrelated families of Greek origin with non-HFE hemochromatosis. Linkage at the chromosome 1q21 JH locus was detected in affected members with the use of polymorphic markers. Comparison of haplotypes between Greek and Italian JH patients revealed the presence of a common haplotype. However, the fact that many other haplotypes carrying the JH defect were observed in the two populations indicates that the respective mutations may have occurred in different genetic backgrounds. We suggest that hemochromatosis patients without HFE mutations should be evaluated for other possible types of hemochromatosis since hemochromatosis type 3 (HFE3) has a clinical appearance similar to HFE 1, and JH may have a late onset in some cases.
Blood Cells Mol Dis
PMID:Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. 1177 58

We have examined transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin for mutations that might modulate the iron burden of individuals harboring the common mutant hemochromatosis HFE genotype C282Y/C282Y or cause hemochromatosis independent of mutations in the HFE gene. In a group of white, Asian, and African-American normal and iron-overloaded individuals, the coding and flanking regions of these genes were completely sequenced. Numerous coding region and promoter polymorphisms were detected. These were further examined for association with differences in iron accumulation as measured by plasma transferrin saturation and ferritin levels, but no such association could be documented.
Blood Cells Mol Dis
PMID:A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. 1178 42

We describe a woman, found as part of a screening study on cases of elevated transferrin saturation values in France, who was heterozygous for the C282Y mutation and at the same time homozygous for the H63D mutation in the HFE gene. Our description includes two other recently described patients presenting the symmetrical genotypic statement (homozygous for the C282Y mutation and heterozygous for the H63D mutation). The C282Y and H63D mutations in the "cis" phase may thus account for some very rare cases.
Blood Cells Mol Dis
PMID:A rare case of a patient heterozygous for the hemochromatosis mutation C282Y and homozygous for H63D. 1178 52

The transferrin receptor (TfR) binds two proteins critical for iron metabolism: transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. Previous results demonstrated that Tf and HFE compete for binding to TfR, suggesting that Tf and HFE bind to the same or an overlapping site on TfR. TfR is a homodimer that binds one Tf per polypeptide chain (2:2, TfR/Tf stoichiometry), whereas both 2:1 and 2:2 TfR/HFE stoichiometries have been observed. In order to more fully characterize the interaction between HFE and TfR, we determined the binding stoichiometry using equilibrium gel-filtration and analytical ultracentrifugation. Both techniques indicate that a 2:2 TfR/HFE complex can form at submicromolar concentrations in solution, consistent with the hypothesis that HFE competes for Tf binding to TfR by blocking the Tf binding site rather than by exerting an allosteric effect. To determine whether the Tf and HFE binding sites on TfR overlap, residues at the HFE binding site on TfR were identified from the 2.8 A resolution HFE-TfR co-crystal structure, then mutated and tested for their effects on HFE and Tf binding. The binding affinities of soluble TfR mutants for HFE and Tf were determined using a surface plasmon resonance assay. Substitutions of five TfR residues at the HFE binding site (L619A, R629A, Y643A, G647A and F650Q) resulted in significant reductions in Tf binding affinity. The findings that both HFE and Tf form 2:2 complexes with TfR and that mutations at the HFE binding site affect Tf binding support a model in which HFE and Tf compete for overlapping binding sites on TfR.
J Mol Biol 2001 Oct 19
PMID:Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. 1180 May 64

Hereditary hemochromatosis is a genetic disease characterized by exaggerated absorption of intestinal iron leading to its accumulation in some organs over the years. Its prevalence is estimated to be 3-5/1000 in Caucasians. A single mutation, C282Y in the HFE gene explains 80-90% of all diagnosed cases in populations of northwestern European ancestry. The importance of another frequent mutation in this gene, H63D, as well as of C282Y/H63D compound heterozygotes, is still a matter of debate. We estimated the prevalence of these mutations in newborns from a genetically well defined French-Canadian population, in Quebec City. We compared genotype and allele frequencies between neonates and referred patients for HFE molecular analysis. We genotyped anonymous-unlinked cord blood samples for C282Y (n = 881) and H63D (n = 870) mutations from neonates. Referred patients (n = 1084) were genotyped in two different laboratories and pooled after verifying the similarity of both groups. No C282Y homozygote was found in neonates (allele frequency = 0.043). However, we identified 163 C282Y homozygotes (15%) among 1084 referred patients leading to a, not surprising, 97-fold enrichment of this genotype. We found a similar proportion of genotypes homozygous for H63D in both groups suggesting a weak association with the disease. However, we found a 5-fold enrichment of compound heterozygotes in the referred group. Fewer C282Y homozygotes were observed in the French-Canadian population than in northwest Europe populations. However, the strong enrichment of homozygotes between the neonates and the referred patients is an argument in favour of screening for this lethal disease.
Hum Mol Genet 2002 Jan 15
PMID:Prevalence of HFE gene C282Y and H63D mutations in a French-Canadian population of neonates and in referred patients. 1180 27


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