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1.
A. -M. Neghina A. Anghel I. Sporea A. Popescu R. Neghina A. Collins K. Thorstensen 《Journal of applied genetics》2009,50(2):173-176
The present study aimed at assessing the frequency ofHFE mutations (C282Y, H63D and S65C) in western Romanian patients with liver disease of diverse aetiologies suspected of iron
overload. A total of 21 patients, all Romanian residents hospitalized with clinical suspicion of iron overload and liver disease,
were assayed for C282Y, H63D and S65C mutations, serum ferritin and viral hepatitis markers. Overall, 9 out of the 21 patients
(42.86%) were found to harbour mutations in theHFE gene: 4 homozygotes C282Y (19.0%), 1 compound heterozygote C282Y/H63D (4.8%), 1 single heterozygote C282Y (4.8%), 2 single
heterozygotes H63D (9.5%), 1 single heterozygote S65C (4.8%), and 12 wild-type cases (57.1%). Among the subgroup of 10 patients
with the most prominent signs of iron overload (hyperferritinaemia and/or hepatocyte iron score ≥ 1), without hepatocellular
carcinoma, theHFE genotypes were conclusive in 5 cases (50%). They had significantly increased ferritin levels compared to wild-type cases
(P = 0.029). The inclusion of iron studies during routine clinical visits, coupled with the availability ofHFE genotyping for family and population studies, should facilitate the early detection of hereditary haemochromatosis in Romania. 相似文献
2.
Graça Porto Helena Alves Pedro Rodrigues José M Cabeda Cristina Portal Anunciação Ruivo Benvindo Justiça Roger Wolff Maria De Sousa 《Immunogenetics》1998,47(5):404-410
The present study is an analysis of the frequencies of HFE mutations in patients with different forms of iron overload compared with the frequencies found in healthy subjects from
the same region. The frequencies of HLA-A and -B antigens and HLA haplotypes were also analyzed in the same subjects. The study population included: 71 healthy individuals; 39 genetically
and clinically well-characterized patients with genetic hemochromatosis (HH); and 25 patients with non-classical forms of
iron overload (NCH), excluding secondary hemochromatosis. All subjects were HLA-typed and HFE-genotyped by the oligonucleotide ligation assay (OLA). The gene frequencies found for the C282Y and H63D mutations of HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 and 0.04 in HH patients, and 0.08 and 0.48 in NCH patients.
An expected significant association between HH and HLA-A3 was observed, which was found to be in linkage disequilibrium with
the C282Y mutation. A new association was seen, however, between HLA-A29 and NCH, in linkage disequilibrium with the H63D
mutation. Again as expected, the HLA-B antigen B7 was associated with HH in linkage disequilibrium with HLA-A3. In addition,
the HLA-B antigen B44 was found to be associated with NCH but not in linkage disequilibrium with either A29 or the H63D mutation.
In conclusion, a new association of the HFE H63D mutation with forms of hemochromatosis other than HH and a new association between the HLA phenotype A29 and the HFE H63D mutation were found in the same patients. These findings reinforce evidence for the involvement of the major histocompatibility
class I in iron metabolism, supporting the notion of a physiological role for the immunological system in the regulation of
iron load.
Received: 11 June 1997 / Revised: 29 October 1997 相似文献
3.
Haemochromatosis is predominantly associated with the HFE p.C282Y homozygous genotype, which is present in approximately 1 in 200 people of Northern European origin. However, not
all p.C282Y homozygotes develop clinical features of haemochromatosis, and not all p.C282Y homozygotes even present abnormal
iron parameters justifying venesection therapy. This situation was not apparent from initial genotype/phenotype correlation
studies as there was a selection bias of patients. Only those patients with a significant iron burden were included in these
early studies. It is now largely accepted that the p.C282Y/p.C282Y genotype is necessary for the development of HFE haemochromatosis. However, this genotype provides few clues as to why certain symptoms are associated with the disease. Expression
of iron overload in people with this genotype depends on the complex interplay of environmental factors and modifier genes.
In this review, we restrict our discussion to work done in humans giving examples of animal models where this has helped clarify
our understanding. We discuss penetrance, explaining that this concept normally does not apply to autosomal recessive disorders,
and discuss the usefulness of different biochemical markers in ascertaining iron burden. Hepcidin, a peptide synthesized primarily
by the liver, has been identified as the central regulator in iron homeostasis. Consequently, understanding its regulation
is the key. We conclude that the main goal now is to identify important modifiers that have a significant and unambiguous
effect on iron storage. 相似文献
4.
Haemochromatosis (HC) is an inherited disorder of iron metabolism. The 85–90% of Hereditary hemochromatosis cases are caused by mutations in HFE gene (HC type 1). The remaining 10–15% of HC cases are caused by mutations in other non-HFE genes (HJV, HAMP, TRF2, SLC40A1, BMP6). The study of patients for the diagnosis of HC has an important laboratory approached: analysis of biochemical parameters and genetic studies. To confirm a case, it is necessary to carry out a genetic study of the C282Y and H63D mutations. The presence of C282Y mutation in homozygosis is compatible with the diagnosis of HC type 1. Due to the incomplete penetrance of this mutation and the variable phenotypic expression, the severe forms of the disease are relatively rare. The study of variants in non-HFE genes allows more detailed study of both non-classic HC cases and those with more severe clinical expression. The genotype characterization of a patient not always justified the phenotype expression of the symptoms in this disease. All laboratory clinicians must consider recommendation provide by the experts in the Materia. 相似文献
5.
In Caucasians, 4–35% of hemochromatosis patients carry at least one chromosome without a common HFE mutation (i.e. C282Y, H63D and S65C). Several studies have now shown that iron overload phenotypes in such patients can be associated with uncommon HFE mutations. We previously supported implication of the C282Y/Q283P compound heterozygous genotype in hemochromatosis phenotypes and, based on molecular dynamics simulations, proposed that the Q283P substitution prevents normal folding of the HFE 3-domain. In the current work, we have used HeLa cells carrying wild-type or Q283P-mutant HFE cDNA under the control of a tetracycline-sensitive promoter to functionally characterise the Q283P mutation. Experiments using cells over-expressing wild-type HFE confirm the existence of 2microglobulin(2m)/HFE and HFE/transferrin receptor 1 (TfR1) interactions, as well as the capacity of HFE to reduce transferrin-mediated iron uptake. In contrast, neither 2m/HFE nor HFE/TfR1 complex formation was detected in cells over-expressing the mutated form of HFE. Moreover, the 283P HFE protein was found to have a very limited effect on the major cellular iron uptake pathway. Combined, our results indicate that the Q283P mutation leads to structural and functional consequences similar to those described for the main hereditary hemochromatosis mutation. As a consequence, our study has implications for the screening of hemochromatosis patients that have one or two copies of HFE which lack the main mutations. It also highlights that protein structure prediction methods could be more generally used to better interpret relationships between rare genotypes and molecular diagnosis of a human inherited disorder. 相似文献
6.
In liver hepatocytes, the HFE gene regulates cellular and systemic iron homeostasis by modulating cellular iron-uptake and producing the iron-hormone hepcidin in response to systemic iron elevation. However, the mechanism of iron-sensing in hepatocytes remain enigmatic. Therefore, to study the effect of iron on HFE and hepcidin (HAMP) expressions under distinct extracellular and intracellular iron-loading, we examined the effect of holotransferrin treatment (1, 2, 5 and 8 g/L for 6 h) on intracellular iron levels, and mRNA expressions of HFE and HAMP in wild-type HepG2 and previously characterized iron-loaded recombinant-TfR1 HepG2 cells. Gene expression was analyzed by real-time PCR and intracellular iron was measured by ferrozine assay. Data showed that in the wild-type cells, where intracellular iron content remained unchanged, HFE expression remained unaltered at low holotransferrin treatments but was upregulated upon 5 g/L (p?<?0.04) and 8 g/L (p?=?0.05) treatments. HAMP expression showed alternating elevations and increased upon 1 g/L (p?<?0.05) and 5 g/L (p?<?0.05). However, in the recombinant cells that showed higher intracellular iron levels than wild-type cells, HFE and HAMP expressions were elevated only at low 1 g/L treatment (p?<?0.03) and were repressed at 2 g/L treatment (p?<?0.03). Under holotransferrin-untreated conditions, the iron-loaded recombinant cells showed higher expressions of HFE (p?<?0.03) and HAMP (p?=?0.05) than wild-type cells. HFE mRNA was independently elevated by extracellular and intracellular iron-excess. Thus, it may be involved in sensing both, extracellular and intracellular iron. Repression of HAMP expression under simultaneous intracellular and extracellular iron-loading resembles non-hereditary iron-excess pathologies. 相似文献
7.
Paul Clark Laurence J Britton Lawrie W Powell 《The Clinical biochemist. Reviews / Australian Association of Clinical Biochemists》2010,31(1):3-8
Hereditary haemochromatosis (HH) is a common genetic disorder of iron metabolism in individuals of Northern European ancestry which leads to inappropriate iron absorption from the intestine and iron overload in susceptible individuals. Iron overload is suggested by elevations in serum ferritin and transferrin saturation. The majority of patients with clinically significant iron overload are homozygous for the C282Y mutation of the HFE gene, however only a minority of C282Y homozygotes fully express the disease clinically. Those with a high serum ferritin (>1000 μg/L) and additional hepatic insults from cofactors are more likely to develop cirrhosis and its complications. The mainstay of treatment is venesection. Those without cirrhosis who undergo appropriate venesection have a normal life expectancy. Family screening is recommended for all first degree relatives of an individual with the disease.HH refers to a group of inherited disorders that result in progressive iron overload. Mutations of the HFE gene are responsible for the majority of cases of HH,1 although disease expression is highly variable.2 The ready availability of testing for the two clinically relevant mutations: C282Y and H63D, has substantially altered the approach to suspected iron overload in clinical practice. A number of rare but important forms of non-HFE related HH have also been described.3 The other main causes of iron overload are outlined in the HH HFE related HH (C282Y/C282Y, C282Y/H63D) Non-HFE related HH Juvenile Haemochromatosis Hemojuvelin related Hepcidin related Transferrin receptor-2 related HH Ferroportin related HH Secondary Iron Overload Iron loading anaemia Thalassaemia major Sideroblastic anaemia Chronic haemolytic anaemia Parenteral iron overload (multiple transfusions) Others Metabolic syndrome Chronic liver disease Hepatitis C Alcoholic liver disease Non-alcoholic steatohepatitis Porphyria cutanea tarda African Iron Overload Acaeruloplasminaemia Atransferrinaemia Neonatal iron overload