Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent research in iron metabolism has revealed the existence of iron-responding elements in the 5'UTR of the mRNA of ferritin. Binding of these structures with iron-regulatory proteins regulates ferritin synthesis within the cell, according to the intracellular iron level. Several mutations of the iron-responding elements located at the 5'UTR of the L-ferritin subunit, which lead to the hereditary hyperferritinaemia cataract syndrome, an autosomal dominant hereditary disease, have been described. Patients with congenital bilateral nuclear cataract present high serum ferritin (360-2264 micrograms/l) in the absence of iron overload. The purpose of our study was to look for this syndrome in Switzerland and in particular in the Geneva population. About 3000 cases of cataract operated on during a 4-year period (1995-1998) in the University Clinic of Ophthalmology were screened. We found 135 patients operated on before the age of 51 years. However, only 19 had bilateral nuclear cataract. 15 patients agreed to undergo iron screening. In 2 of them, a slight elevation of ferritin (267 micrograms/l in a female, 416 micrograms/l in a male) was found in the absence of iron overload. In both cases there is a positive family history of cataract. DNA sequencing analysis in these patients showed a normal nucleotide sequence of the whole iron-responding elements region. One of them (male) was found to present the codon 63 mutation at HFE gene in the heterozygous state. Our local study indicates that hereditary hyperferritinaemia cataract syndrome is extremely rare in Switzerland. However, similar studies should be carried out in other regions of the country. Iron status evaluation and ferritin level monitoring should become routine examinations in all new cases presenting with bilateral nuclear cataract before the age of 50 years.
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PMID:Hereditary hyperferritinaemia cataract syndrome: does it exist in Switzerland? 1074 72

Early diagnosis and treatment of hemochromatosis is essential to prevent organ damage. Screening strategies to detect early hemochromatosis include testing for iron overload and/or genetic testing. Voluntary blood donors numbering 5,211 were screened with unbound iron-binding capacity (UIBC), transferrin saturation (TS), and genetic testing for the C282Y mutation of the HFE gene. The study found 16 C282Y homozygotes (1 in 327), 69 compound heterozygotes, 371 simple heterozygotes, and 4,755 normals. There were 5 men and 11 women homozygotes with a mean age of 42, range 28 to 57. Mean UIBC (24 +/- 7 microL) and TS (48% +/- 17%) in homozygotes were significantly different from compound heterozygotes, simple heterozygotes, and normals (ANOVA). Only 3 homozygotes had an elevated serum ferritin. Family studies found an additional 4 iron-loaded homozygotes. Optimal thresholds were < or =28 micromol/L for UIBC and > or =46% for TS. Receiver operating characteristic (ROC) curve analysis showed an area under the curve for UIBC of 0.93 (0. 85-1.0, 95% confidence interval), and for TS of 0.83 (0.7-0.95). Screening with UIBC to preselect those for genotyping is a cost-efficient strategy for population screening for hemochromatosis.
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PMID:Population screening for hemochromatosis: a comparison of unbound iron-binding capacity, transferrin saturation, and C282Y genotyping in 5,211 voluntary blood donors. 1079 97

Genetic hemochromatosis is an autosomal recessive disease, characterized by an increased iron absorption, leading to progressive iron overload. The fully expressed phenotype comprises fatigue, skin pigmentation, liver disease with hepatomegaly, cirrhosis and hepatocellular carcinoma, and diabetes. Arthralgias are frequent, cardiopathy or impotence may occur. This presentation is now unfrequent with earlier diagnosis, and patients are often asymptomatic--with only biochemical expression--or pauci-symptomatic (mild fatigue, arthralgias or increased transaminases). Transferrin saturation is always increased. Serum ferritin is proportional to iron burden. Diagnosis is now easy, since most patients are homozygote for the C282Y mutation of the HFE gene. Liver biopsy can be useful to quantify iron overload and assess liver fibrosis. The disease can be lethal due to liver disease, carcinoma or heart disease, but life expectancy goes to normal if patients are treated before the occurrence of cirrhosis. Treatment relies on regular venesections. Familial screening is essential.
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PMID:[Diagnosis and treatment of genetic hemochromatosis]. 1086 97

The identification of the HFE gene involved in hemochromatosis allows genetic tests based on mutation analysis to be performed. However, discrepancies in the correlation between HFE genotypes and iron-loading status have arisen. We investigated 708 patients with various signs or symptoms suggesting a putative iron overload that, nevertheless, did not reach the current criteria for hemochromatosis diagnosis. Most of the patients (91.4%) included in our study displayed one of three classical iron marker values above the threshold defined for iron overloading. HFE mutation analysis allowed us to identify 45.7% of carrier chromosomes in the studied group of patients that showed higher frequencies of HFE mutations compared with controls. In addition, the frequencies of compound C282Y/H63D heterozygous, H63D/H63D homozygous, and C282Y heterozygous genotypes were higher than those in HH probands and controls; they accounted for 16, 5.6, and 22.5% of the patients, respectively. All genotypic groups had a significantly higher value of serum ferritin concentration compared to the normal value; only the C282Y homozygotes and compound heterozygotes with H63D had a transferrin saturation significantly higher than the normal value. On the whole the H63D homozygous and compound heterozygous patients constitute an intermediate phenotypic group between HH and controls. Some of them may reach the critical overloading defined for HH diagnosis along with a potential risk of developing complications, whereas others only show a partial phenotypic expression.
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PMID:Relation between HFE mutations and mild iron-overload expression. 1087 Aug 47

Hereditary hemochromatosis (HC) is one of the most common single-gene hereditary diseases. A phenotypic hallmark of HC is low iron in reticuloendothelial cells in spite of body iron overload. Most patients with HC have the same mutation, a change of cysteine at position 282 to tyrosine (C282Y) in the HFE protein. The role of HFE in iron metabolism and the basis for the phenotypic abnormalities of HC are not understood. To clarify the role of HFE in the phenotypic expression of HC, we studied monocytes-macrophages from subjects carrying the C282Y mutation in the HFE protein and clinically expressing HC and transfected them with wild-type HFE by using an attenuated Salmonella typhimurium strain as a gene carrier. The Salmonella system allowed us to deliver genes of interest specifically to monocytes-macrophages with high transduction efficiency. The accumulation of (55)Fe delivered by (55)Fe-Tf was significantly lower in macrophages from patients with HC than from controls expressing wild-type HFE. Transfection of HC macrophages with the HFE gene resulted in a high level of expression of HFE protein at the cell surface. The accumulation of (55)Fe delivered by (55)Fe-Tf was raised by 40% to 60%, and this was reflected by an increase in the (55)Fe-ferritin pool within the HFE-transfected cells. These results suggest that the iron-deficient phenotype of HC macrophages is a direct effect of the HFE mutation, and they demonstrate a role for HFE in the accumulation of iron in these cells.
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PMID:Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. 1091 Sep 32

Gene variations of HFE, a HLA-class I like molecule, are highly associated with hereditary haemochromatosis (HH). Functional as well as molecular studies of the HFE protein have indicated that the molecule is involved in iron metabolism and that the HFE gene variations observed among HH patients affect its interaction with the transferrin receptor (TfR). In the present study, we have therefore analysed the relationship between the HFE gene variants, C282Y and H63D, and body iron status among 85 German HH patients. In addition, two TfR gene polymorphism, TfR-Hin6I and TfR-BanI, were typed that have been reported to define ethnically distinct haplotypes. As controls we used 251/159 healthy German blood donors. Seventy-eight (92%) patients were C292Y homozygous, the H63D mutation was present in five (6%) patients with none of the patients being H63D homozygous. Serum transferrin, transferrin saturation and liver iron content were determined prior to therapeutic intervention. Among C282Y homozygous patients serum ferritin levels (2294 +/- 3174 vs. 463 +/- 224 microg L-1, P < 0.0001) and transferrin saturation (86 +/- 18% vs. 62 +/- 25%, P = 0.048) were elevated significantly compared with C282Y and/or H63D heterozygous patients. In addition, the liver iron content (291 +/- 165 vs. 138 +/- 95 micromol g-1, P = 0.028) and liver iron index (6.4 +/- 2.8 vs. 3.2 +/- 2.3, P = 0.019) were increased among C282Y homozygotes compared with C282Y heterozygotes. In contrast, no difference was observed between patients and controls regarding the distribution of TfR-Hin6I and TfR-BanI alleles. These data indicate that the iron intake is higher among C282Y homozygous patients compared with C282Y heterozygous or C282Y/H63D compound heterozygous individuals and supports the functional role of the HFE protein in iron metabolism whereas the TfR gene variants seem to have no influence on iron uptake.
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PMID:Iron-overload and genotypic expression of HFE mutations H63D/C282Y and transferrin receptor Hin6I and BanI polymorphism in german patients with hereditary haemochromatosis. 1094 80

Amplification of the region of the HFE gene that contains the c.845G-->A (C282Y) mutation is usually performed using one amplimer that binds to a sequence in intron 3 and another that binds to a sequence in intron 4. Previously, a mutation that interferes with efficient binding to the intron 4 site has been described. We now find that another common mutation in intron 3, IVS3 -48c-->g, prevents binding of the amplimer to that site. This polymorphism occurs at a gene frequency of 0.128 in the African-American population and at a frequency of only 0.006 in the European population. DNA samples heterozygous for the IVS3 -48c-->g polymorphism and C282Y were undistinguishable from samples homozygous for the C282Y mutation when they were examined by allele-specific oligonucleotide hybridization (ASOH) and showed only a weak normal band when examined by electrophoresis following restriction endonuclease digestion. Although the polymorphism occurs in a DNA sequence almost identical to the intron 3 splice donor site, we found no evidence of alternative splice forms. Moreover, serum iron, transferrin saturation, and serum ferritin levels were normal in subjects heterozygous for the polymorphism. It appears, therefore, that the main importance of this polymorphism is that it may lead to misdiagnosis of heterozygotes for the C282Y mutation as homozygotes. We therefore recommend exonic amplimers that avoid sites that contain polymorphisms and that can be multiplexed for detection of the c.187C-->G (H63D) and c.845G-->A (C282Y) mutations.
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PMID:A common intron 3 mutation (IVS3 -48c-->g) leads to misdiagnosis of the c.845G-->A (C282Y) HFE gene mutation. 1095 Sep 43

The widespread use of the genotype assay that identifies the common C282Y mutation in the HFE gene has allowed an earlier diagnosis to be made in many subjects. A significant number of these patients may have no evidence of phenotypic disease and have a normal serum ferritin level. This phenomenon is more common when the genotype assay is used to screen populations rather than higher-risk groups such as family members of a proband with hereditary hemochromatosis. Moreover, patients with significant iron overload may be wild type for the C282Y mutation and have no other demonstrable mutation of the HFE gene. The HFE genotype assay has recently been found to give a false-positive C282Y homozygous result in half of the subjects in one population screening study due to the presence of a single nucleotide polymorphism (SNP) that interfered with primer binding in the PCR assay. The problem may be overcome by using alternate primers. A number of other groups have confirmed the finding but in a much smaller number of subjects, whereas others found that their assays were not affected by the SNP. The use of the HFE genotype assay as the sole diagnostic criterion for hereditary hemochromatosis is not recommended. The genotype assay should be used as an adjunct to the established methods of demonstrating iron overload and be viewed as a predictor of either the presence of iron overload or the subsequent development of iron overload during an individual's lifetime.
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PMID:Pitfalls in the genetic diagnosis of hereditary hemochromatosis. 1095 53

We describe a case of homozygosity due to the substitution of aspartic acid with histidine at position 63 of the protein encoded by the gene (known as HFE) associated with hereditary hemochromatosis. Liver biopsy did not disclose stainable iron accumulation; serum ferritin was elevated (639 ng/mL), while the transferrin saturation index was within the normal range (38.1%). As the patient was affected by chronic hepatitis C virus, the high serum ferritin could be attributed to this disease, a frequent occurrence. We also describe a case of heterozygosity for both the substitution of tyrosine with cysteine at position 282 and the substitution of histidine to aspartic acid at position 63 (so-called "compound heterozygosity"). The patient had the typical biochemical abnormalities of iron overload: transferrin saturation index of 53.1% and elevated serum ferritin (658 ng/mL). The removal of > 5 g of iron by phlebotomies did not precipitate iron deficiency. Although the patient refused to undergo liver biopsy, clinical evidence alone enabled a diagnosis of hemochromatosis. These two cases concord with the present scientific orientation, i.e.: 1) homozygosity for the major mutation is associated with the phenotypical (clinical) picture of hemochromatosis, but compound heterozygosity also determines significant iron metabolism abnormalities; 2) homozygosity for the minor mutation does not appear to determine important phenotypical abnormalities.
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PMID:[Significance of "minor" genetic mutations in hereditary hemochromatosis: 2 case reports]. 1105 64

In the last four years there has been a major change in the approach to diagnosis of the iron overload disorder hereditary haemochromatosis (HH) following the discovery of the gene that is mutated in HH called HFE. In the first part of this review we will give a concise overview of the disease. Also the current literature on the role of HFE in iron absorption and transport at a molecular level and how mutations in HFE may lead to the break down in the regulation of iron homeostasis is reviewed. The second part of the review focuses on the molecular aspects of iron storage. Different chemical forms of storage iron deposits such as ferrihydrite and geotite are present in the iron storage proteins ferritin and haemosiderin. The type of iron storage deposits is thought to be an important factor in determining the degree of iron toxicity and tissue damage in patients with iron overload. Variations in the form of iron deposits in different types of iron overload disease e.g. HH or beta-thalessemia, the site of iron deposition and the clinical treatment used will be discussed.
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PMID:The new iron age. 1107 17


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