Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Hereditary Hemochromatosis (HFE) is one of the most common inherited disorders with an estimated frequency of homozygous patients of 0.002-0.0045. The disease is characterized by increased intestinal iron absorption and progressive iron overload. Affected subjects show clinical symptoms of parenchymal organ damage after the third-fourth decade of life and have a 200 fold increased risk of developing hepatocellular carcinoma. Early diagnosis and treatment prevent complications and may normalize life expectancy of patients. The biochemical and genetic defects leading to progressive iron accumulation are still unknown, but the HFE gene is tightly linked to HLA complex on the short arm of chromosome 6. Utilizing HLA serotypes and the study of several polymorphic markers of 6p21, a linkage analysis of the disease locus was performed in a series of Italian hemochromatosis families. The data obtained by linkage analysis and the study of a family with a double recombinant allowed us to better define the HFE gene location with respect to HLA-class I A and F loci.
Hum Mol Genet 1993 May
PMID:Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F. 851 96

The haemochromatosis gene (HFE) is linked to both HLA-A and D6S105 on the short arm of chromosome 6 but these markers are separated by approximately 2 Mb of DNA. Most chromosomes carrying HFE have a common haplotype which extends from HLA-A to D6S105 and includes HLA-F. To localise the gene more precisely we have examined 10 microsatellite markers extending over a genetic distance of approximately 5 cM from D6S265 (within 100 kb of HLA-A on the centromeric side) to D6S299 (telomeric). The order of markers is D6S265, HLA-F, D6S258, D6S306, CS3, D6S105, D6S464, CS5, D6S461 and D6S299. We confirm that haemochromatosis appears to originate from a founder mutation which has multiplied in the population through successive generations. This mutation is associated with the haplotype D6S306-5, CS3-3, D6S105-8, D6S464-9 and CS5-4 which is found on approximately 70% of HFE chromosomes. We have applied a new and powerful, likelihood analysis for linkage disequilibrium. The maximum value of lambda (proportion of total possible association between a marker and disease) is 0.74 for marker CS5 (allele 4). A multipoint analysis also gives a maximum likelihood near marker CS5. We conclude that the HFE gene is likely to be located telomeric of D6S105 and close to CS5.
Hum Mol Genet 1995 Oct
PMID:New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105. 859 9

Selective hybridization of small intestine and liver cDNA libraries was carried out using yeast artificial chromosomes (YACs) surrounding D6S105, the microsatellite that appears to be close to the gene for hereditary hemochromatosis (HFE). Of 14 candidate probes hybridizing with these YACs, only one, designated. LD5-1, detected abnormalities in southern blots of patients with hemochromatosis. Two different abnormalities. were detected in 3 of 55 patients with hemochromatosis with the LD5-1 probe, and one of these was detected in one of 44 normal subjects. The gene that hybridizes with this probe is located about 300-400 kb centromeric of D6S105. It is transcribed into mRNA that is about 8.5 kb in length in many tissues, including peripheral blood leukocytes. The available sequence indicates tha it codes for a zinc finger protein. We propose that there is a reasonable probability that LD5-1 hybridizes with the gene for hereditary hemochromatosis.
Blood Cells Mol Dis 1995
PMID:A strategy for cloning the hereditary hemochromatosis gene. 867 73

Two mutations have been described on the gene considered to be responsible for genetic hemochromatosis, the HLA-H or HFE gene. The C282Y mutation is a disease-causing mutation in most cases of genetic hemochromatosis, but involvment of the H63D substitution in the pathogenesis of the disease is unclear. Compound heterozygotes for both substitutions could help to determine whether or not the second mutation is a worsening factor when associate in trans with the C282Y mutant. We found twenty nine compound heterozygotes during DNA analysis of patients referred to our laboratory for the screening of those mutations. Clinical and biological data were obtainable for 23 of them. Compound heterozygotes could be divided into two groups: subjects with or without iron overload. Five (22%) individuals had normal ferritin levels, whereas 18 had elevated ferritin concentrations (78%). Among those 18 patients, 7 (30% of the total) had clinical and biological criteria of genetic hemochromatosis. Eleven had iron overload without all the criteria of genetic hemochromatosis. Such a high proportion of genetic hemochromatosis is not found in heterozygotes for the C282Y mutation alone neither in our series nor in the literature. Compound heterozygotes for the C282Y and the H63D mutations may have a higher risk of iron overload or genetic hemochromatosis than single heterozygotes for the C282Y mutation. We propose a schematic theoretical representation that could explain this fact at the protein level. Further fundamental studies on the protein, and clinical follow up of compound heterozygotes could help to ascertain this hypothesis.
Blood Cells Mol Dis 1997 Aug
PMID:Compound heterozygotes for hemochromatosis gene mutations: may they help to understand the pathophysiology of the disease? 941 Apr 70

This report assesses the degree of iron overload in a cohort of patients in relationship to the presence or absence of the recently described 845 G-->A (C282Y) and 187 C-->G (H63D) mutations in the HFE (HLA-H) gene. Sixty-one patients with hereditary hemochromatosis diagnosed either with liver biopsy or on clinical grounds were included in this analysis. Forty-one patients were homozygous for C282Y, the genotype considered to be characteristic of hereditary hemochromatosis. At the time of this analysis, 37 of these 41 patients had achieved a state of iron depletion and mobilizable iron was calculated: 19 had less than 4 grams. Twenty-five of these 41 patients had liver biopsies; 4 of these patients had a hepatic iron index less than 1.9. Of the 4 patients with a normal hepatic iron index, 3 had a quantitative hepatic iron of greater than 50 micromol/g dry weight, and one had an inadequate biopsy sample. These findings support our suspicion that individuals may have hereditary hemochromatosis and homozygous C282Y despite relatively low body iron stores. Five patients were compound heterozygotes for C282Y and H63D. Four of these patients underwent liver biopsy; two had a hepatic iron index greater than 1.9. a third patient had a hepatic iron index of 1.3 but a quantitative hepatic iron of 90.6 micromol/g dry weight. All patients were phlebotomized to a state of iron depletion and only one of these patients had a mobilizable iron greater than 4 grams. Three patients were homozygous for H63D; these patients had either a hepatic iron index >1.9 or greater than 4 grams of mobilizable iron. Patients with homozygous H63D and significant iron overload are not well described. Seven patients were heterozygous for either C282Y or H63D; 4 had significant iron overload but three did not. Five patients had no HFE mutations; one of these patients unequivocally has iron overload with a hepatic iron index of 4.4 We conclude that: (1) Identification of HFE mutations will be clinically useful in identifying patients with hereditary hemochromatosis, (2) Patient genotyping will help confirm a diagnosis of hereditary hemochromatosis in some patients with relatively low body iron stores, (3) Significant iron loading can occur in the absence of homozygous C282Y, adding to the evidence that genes other than HFE may be involved in iron loading, and (4) Homozygous H63D can be associated with significant iron overload.
Blood Cells Mol Dis 1997 Aug
PMID:Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases. 941 Apr 75

Hereditary hemochromatosis mutation 845A (C282Y) in the HFE gene was recently described, and the C282Y frequencies were reported for various world populations. The aim of this study was to determine the Y allele frequencies of the C282Y mutation for five French populations. The most elevated value (= 5.6%) was obtained for Bretons, in accordance to the hypothesis indicating a Celtic origin of the hereditary hemochromatosis mutation.
Blood Cells Mol Dis 1998 Jun
PMID:Frequency of the C282Y mutation of hemochromatosis in five French populations. 964 97

Nramp2 is a gene encoding a transmembrane protein that is important in metal transport, in particular iron. Mutations in nramp2 have been shown to be associated with microcytic anemia in mk/mk mice and defective iron transport in Belgrade rats. Nramp2 contains a classical iron responsive element in the 3' untranslated region that confers iron dependent mRNA stabilization. In this report, we describe a splice variant form of human nramp2 that has the carboxyl terminal 18 amino acids substituted with 25 novel amino acids and has a new 3' untranslated region lacking a classical iron-responsive element. This splice form of nramp2, nramp2 non-IRE, was found to be derived from splicing of an additional exon into the terminal coding exon. The nramp2 gene is comprised of 17 exons and spans more than 36 kb. It contains an additional 5' exon and intron (exon and intron 1) and an additional 3' exon (exon 17) and intron (intron 16) as compared to nramp1, a homologous gene. The additional exons and introns account for much of the difference in length between nramp2 (> 36 kb) and nramp1 (12 kb). The exon-intron borders of nramp2 exons 3-15 are homologous to nramp1 exons 2-14. The nramp2 5' regulatory region contains two CCAAT boxes but lacks a TATA box. The 5' regulatory region of nramp2 also contains five potential metal response elements (MRE's) that are similar to the MRE's found in the metallothionein-IIA gene, three potential SP1 binding sites and a single gamma-interferon regulatory element. Five single nucleotide mutations or polymorphisms were identified within the nramp2 gene. One of these, 1303C-->A, occurs in the coding region of nramp2 and results in an amino acid change from leucine to isolecine. A polymorphism, 1254T/C, also occurs in the coding region of nramp2 but does not cause an amino acid change. The other 3 polymorphisms are within introns (IVS2 + 11A/G, IVS4 + 44C/A, and IVS6 + 538G/Gdel). In addition, a polymorphic microsatellite TATATCTATATATC (TA)6-7 (CA)10-11 CCCCCTATA (TATC)3 (TCTG)5 TCCG (TCTA)6 was identified in intron 3. Analysis of cDNA derived by direct amplification of reversed transcribed RNA or cDNA clones isolated from a library provide evidence of skipping of exons 10 and 12 of nramp2. Deletion of either of these exons would result in a sequence that remains in frame yet would generate a protein that would lack transmembrane spanning region 7 or 8 respectively. The deletion of a single transmembrane domain would have severe topological consequences. The coding region of the nramp2 gene of hemochromatosis patients with or without mutations in the hemochromatosis gene, HFE, were examined and found to be normal. One hemochromatosis patient, with a normal HFE genotype, was heterozygous for the 1303C-->A mutation. Furthermore, in an examination of hemochromatosis patients with mutant HFE and normal HFE genes, we did not observe a linkage disequilibrium of either group with a particular nramp2 haplotype. These data suggest that mutations in nramp2 are not commonly associated with hemochromatosis.
Blood Cells Mol Dis 1998 Jun
PMID:The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. 964

Sixty patients diagnosed with hereditary hemochromatosis with grade 3 or 4 hepatic iron overload and 18 patients diagnosed with hereditary hemochromatosis who had less than grade 3 hepatic iron overload were examined for the HFE gene mutations, 845A (C282Y) and 187G (H63D). Control samples were obtained from 109 randomly selected individuals. Fifty-six of 60 unrelated hereditary hemochromatosis patients (93%) with grade 3 or 4 hepatic iron deposition were homozygous for the C282Y mutation. Fourteen of the 18 hereditary hemochromatosis patients with <3+ iron deposition (76%) were homozygous for the C282Y mutation. Three of 8 patients who were heterozygous for the C282Y mutation were also heterozygous for the H63D mutation. Thirty-one of 109 control individuals were heterozygous for the C282Y mutation and 27 were heterozygous for the H63D mutation. Our finding that 93% of hereditary hemochromatosis patients who fulfil standard diagnostic criteria are homozygous for the C282Y mutation provides clear evidence that this mutation is strongly associated with hereditary hemochromatosis. The allele frequency of 14% for the C282Y mutation in our control population is the highest reported and supports the hypothesis of a Celtic origin for the hereditary hemochromatosis gene.
Blood Cells Mol Dis 1998 Dec
PMID:Hemochromatosis in Ireland and HFE. 985 96

The C282Y mutation in the HFE gene is the main mutation causing hemochromatosis, and C282Y frequencies have been reported for various European populations. The aim of this review is to compile the Y allele frequencies of the C282Y mutation for twenty European populations. The most elevated value (6.88%) is observed in residual Celtic populations in UK and France, in accordance to the hypothesis of Simon et al. concerning a Celtic origin of the hereditary hemochromatosis mutation.
Blood Cells Mol Dis 1998 Dec
PMID:Celtic origin of the C282Y mutation of hemochromatosis. 985 97

The Cys282-->Tyr mutation in the HFE gene is carried by the majority of hereditary hemochromatosis patient chromosomes, yet some patients do not seem to harbor any mutation in this gene. This suggests a possibility that these patients may have a mutation in other genes in the same pathway as HFE. We analyzed the cDNA sequences of transferrin receptor (TFR), which was recently shown to interact with HFE, in twenty-one hereditary hemochromatosis patients including sixteen individuals who did not carry a Cys282-->Tyr mutation. A nucleotide substitution (424A-->G), which resulted in the Ser142-->Gly amino acid substitution, was the only amino acid polymorphism detected in the open reading frame of the TFR gene in these patients. This amino acid substitution was a rather common polymorphism in the general population (49%) and its frequency did not significantly differ in the hereditary hemochromatosis (HH) patients regardless of the HFE genotype. Thus, amino acid changes in the TFR gene do not appear to play a role in HH even when the patients do not have a HFE mutation. However, this study does not rule out the possibility of the involvement of mutations in non-coding regions.
Blood Cells Mol Dis 1998 Sep
PMID:Transferrin receptor mutation analysis in hereditary hemochromatosis patients. 1008 90


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