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)

The most common form of hereditary haemochromatosis is an adult-onset condition usually associated with the HFE C282Y/C282Y genotype. The phenotypic expression of this genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors. The aim of the present study was to determine if mutations in the recently identified HJV gene were associated with more severe iron overload phenotypes in C282Y homozygous patients. From a cohort of 310 C282Y homozygous patients, we found nine (six males and three females) with an additional HJV missense mutation in the heterozygous state (S105L, E302K, N372D, R335Q or the previously described L101P and G320V). The iron indices of eight patients appeared to be more severe than those observed in C282Y homozygous patients of identical sex and similar age ranges. The mean serum ferritin concentration of the six males with an HJV mutation was significantly higher than that of C282Y homozygous males without an additional mutation [2350.3 (sigma=1429.9) versus 1227.2 (sigma=1130.1) microg/l; P=0.0233, Student's t-test]. We have recently reported that mutations in the gene that encodes hepcidin (HAMP) could explain one part of the C282Y/C282Y-related phenotypic heterogeneity by accentuating the iron burden. Our new data reveal that mutations in the HJV gene could be associated with a similar effect. Taken together, these results emphasize that a search for modifier genes could enable us to more precisely distinguish those C282Y homozygous patients with a higher risk to develop a severe iron overload and, consequently, clinical complications.
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PMID:The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. 1525 10

The classification of hereditary abnormalities of iron metabolism was recently expanded and diversified. Genetic hemochromatosis now corresponds to six diseases, namely classical hemochromatosis HFE 1; juvenile hemochromatosis HFE 2 due to mutations in an unidentified gene on chromosome 1; hemochromatosis HFE 3 due to mutations in the transferrin receptor 2 (TfR2); hemochromatosis HFE 4 caused by a mutation in the H subunit of ferritin; and hemochromatosis HFE 6 whose gene is hepcidine (HAMP). Systemic iron overload is also associated with aceruloplasminemia, atransferrinemia and the "Gracile" syndrome caused by mutations in BCS1L. The genes responsible for neonatal and African forms of iron overload are unknown. Other genetic diseases are due to localized iron overload: Friedreich's ataxia results from the expansion of triple nucleotide repeats within the frataxin (FRDA) gene; two forms of X-linked sideroblastic anemia are due to mutations within the delta aminolevulinate synthetase (ALAS 2) or ABC-7 genes; Hallervorden-Spatz syndrome is caused by a pantothenate kinase 2 gene (PANK-2) defect; neuroferritinopathies; and hyperferritinemia--cataract syndrome due to a mutation within the L-ferritin gene. In addition to this wide range of genetic abnormalities, two other features characterize these iron disorders: 1) most are transmitted by an autosomal recessive mechanism, but some, including hemochromatosis type 4, have dominant transmission; and 2) most correspond to cytosolic iron accumulation while some, like Friedreich's ataxia, are disorders of mitochondrial metabolism.
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PMID:[Genetics of hereditary iron overload]. 1550 16

Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.3); type 2 (juvenile haemochromatosis) is autosomal recessive, of high penetrance with causative mutations identified in the HFE2 gene on chromosome 1 (q21) and the HAMP gene on chromosome 19 (q13); type 3 is also autosomal recessive with mutations in the TfR2 gene on chromosome 3 (7q22); type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene. In type 4, iron accumulates in both parenchymal and reticuloendothelial cells and the transferrin saturation may be normal. There are also inherited neurodegenerative conditions associated with iron accumulation. The current research challenges include understanding the central role of the HAMP gene (hepcidin) in controlling iron absorption and the reasons for the variable penetrance in HFE type 1.
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PMID:Inherited iron loading: genetic testing in diagnosis and management. 1560 11

The number of new genes implicated in iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause hyperferritinemia associated or not with iron overload. Correct assignment of the specific disorder of iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum transferrin saturation (TfSat)), the presence or not of visceral iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or juvenile) hemochromatosis characterized by elevated TfSat, and hereditary hyperferritinemias where TfSat is normal (or only slightly modified). Adult genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin. Hereditary hyperferritinemias are linked to mutations of three genes: the L-ferritin gene responsible for the hereditary hyperferritinemia cataract syndrome (without iron overload), the ferroportin gene leading to a dominant form of iron overload, and the ceruloplasmin (CP) gene corresponding to an iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in iron metabolism.
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PMID:The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. 1584 97

We evaluated and treated four white adults (one man, three women) who had iron overload associated with daily ingestion of iron supplements for 7, 15, 35, and 61 years, respectively. We performed HFE mutation analysis to detect C282Y, H63D, and S65C in each patient; in two patients, HFE exons were sequenced. In two patients, direct sequencing was performed to detect coding region mutations of TFR2, HAMP, FPN1, HJV, and ALAS2. Patients 1-4 ingested 153, 547, 1,341, and 4,898 g of inorganic iron as supplements. Patient 1 had hemochromatosis, HFE C282Y homozygosity, and beta-thalassemia minor. Patient 2 had spherocytosis and no HFE coding region mutations. Patient 3 had no anemia, a normal HFE genotype, and no coding region mutations in HAMP, FPN1, HJV, or ALAS2; she was heterozygous for the TFR2 coding region mutation V583I (nt 1,747 G-->A, exon 15). Patient 4 had no anemia and no coding region mutations in HFE, TFR2, HAMP, FPN1, HJV, or ALAS2. Iron removed by phlebotomy was 32.4, 10.4, 15.2, and 4.0 g, respectively. There was a positive correlation of log(10) serum ferritin and the quantity of iron removed by phlebotomy (P = 0.0371). Estimated absorption of iron from supplements in patients 1-4 was 20.9%, 1.9%, 1.1%, and 0.08%. We conclude that the clinical phenotypes and hemochromatosis genotypes of adults who develop iron overload after ingesting iron supplements over long periods are heterogeneous. Therapeutic phlebotomy is feasible and effective, and would prevent complications of iron overload.
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PMID:Iron overload and prolonged ingestion of iron supplements: clinical features and mutation analysis of hemochromatosis-associated genes in four cases. 1683 33

Since the discovery of HFE gene in 1996, considerable progress has been made concerning the iron-metabolism and its major abnormalities. Five types of hereditary hemochromatosis are actually known: type 1 (HFE gene), type 2A (HJV gene), type 2B (HAMP gene), type 3 (TfR2 gene), type 4 (SLC40A1 gene). The HFE C282Y +/+ mutation is responsible for the most frequent type of hemochromatosis in France. Various secondary causes can lead to iron-overload: associated genetic diseases, exogenous iron intake, thalassaemia and refractory anaemia, hepatic siderosis, alcoholic hepatitis, cutaneous porphyria and cirrhosis. The deleterious consequences of iron-overload are due to the interactions of the environmental factors. The role of HFE heterozygote mutations is still discussed. In clinical practice, the interpretation of a serum ferritin increase is a frequent problem that needs a careful evaluation based on the tranferrin saturation measurement. Significant increase of both these factors is in favour of an HFE C282Y +/+ hemochromatosis, after exclusion of a hepatocellular insufficiency or a refractory anaemia. Nevertheless, high ferritin is not always a marker of iron-overload. Thus, there are many disorders increasing the serum ferritin levels without iron overload : cytolysis (hepatic...), inflammatory or infectious syndromes, high alcohol intake, neoplasia... Looking for HFE mutations help to separate type 1 hemochromatosis from other conditions mainly hepatic siderosis (metabolic disorders). The identification of rare types of hemochromatosis (types 2-4) is only required in particular cases. The evaluation of the iron overload is now based on hepatic MRI determination rather than liver biopsy. Repeated phlebotomies remain the essential way to decrease the iron overload in HFE hemochromatosis and to prevent the occurrence of severe and irreversible complications (cirrhosis, arthropathies, cardiac failure, and diabetes). Because of the link established between the amount of iron-overload and the occurrence of complications and the mortality over-risk in HFE C282Y +/+ hemochromatosis, venesections must be started when serum ferritin is higher than 300 microg/l in man and 200 microg/l in woman, whatever the clinical manifestations are and obviously before the symptomatic phase of the disease.
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PMID:[Hereditary and acquired iron overload]. 1737 75

There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25-29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25-29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
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PMID:Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS study initial screening. 1772 83

Most cases of genetic hemochromatosis (GH) are associated with the HFE C282Y/C282Y (p.Cys282Tyr/p.Cys282Tyr) genotype in white populations. The symptoms expressed by C282Y homozygotes are extremely variable. Only a few suffer from an overt disease. Several studies have suggested that, in addition to environmental factors, a genetic component could explain a substantial part of this phenotypic variation, although very few genetic factors have been identified so far. In the present study, we tested the association between common variants in candidate genes and hemochromatosis penetrance, in a large sample of C282Y homozygotes, using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. We focused on two biologically relevant gene categories: genes involved in non-HFE GH (TFR2, HAMP, and SLC40A1) and genes involved in the regulation of hepcidin expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway (BMP2, BMP4, HJV, SMAD1, SMAD4, and SMAD5) and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common single-nucleotide polymorphism (SNP) in the BMP2 genic region (P=4.42x10-5). Mean ferritin level, adjusted for age and sex, is 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. Our results further suggest an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV, with a small additive effect of a SNP in BMP4. This first reported association between common variants in the BMP pathway and iron burden suggests that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. Our results also highlight the BMP regulation pathway as a good candidate for identification of new modifier genes.
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PMID:Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. 1784 4

We characterized HFE C282Y homozygotes aged 25-29 years in the HEmochromatosis and IRon Overload Screening (HEIRS) Study using health questionnaire responses, transferrin saturation (TfSat), serum ferritin (SF), and HFE genotyping. In eight homozygotes, we used denaturing high-performance liquid chromatography and sequencing to search for HFE2 (= HJV), TFR2, HAMP, SLC40A1 (= FPN1), and FTL mutations. Sixteen of 4,008 White or Hispanic participants aged 25-29 years had C282Y homozygosity (15 White, 1 Hispanic); 15 were previously undiagnosed. Eleven had elevated TfSat; nine had elevated SF. None reported iron overload-associated abnormalities. No deleterious non-HFE mutations were detected. The prevalence of C282Y homozygosity in White or Hispanic HEIRS Study participants aged 25-29 years did not differ significantly from the prevalence of C282Y homozygosity in older White or Hispanic HEIRS Study participants. The prevalences of reports of iron overload-associated abnormalities were not significantly different in these 16 C282Y homozygotes and in HFE wt/wt control participants aged 25-29 years who did not report having hemochromatosis or iron overload. We conclude that C282Y homozygotes aged 25-29 years diagnosed by screening infrequently report having iron overload-associated abnormalities, although some have elevated SF. Screening using an elevated TfSat criterion would fail to detect some C282Y homozygotes aged 25-29 years.
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PMID:HFE C282Y homozygotes aged 25-29 years at HEIRS Study initial screening. 1794 88

An African American male of West Indies descent was diagnosed to have elevated transferrin saturation, hyperferritinemia, severe iron deposition in hepatocytes, and hepatic cirrhosis at age 4. He was treated with serial phlebotomy to maintain a normal serum ferritin concentration thereafter. We evaluated him at age 23 and confirmed that he had normal serum ferritin levels, severe iron deposition in hepatocytes, hepatic cirrhosis, and portal hypertension. He did not have endocrinopathy, cardiomyopathy, or arthropathy. He was homozygous for the novel hemojuvelin (HJV) premature stop-codon mutation R54X (exon 3; c.160A-->T). He did not have either HFE C282Y, H63D, or S65C, or deleterious coding region mutations of SLC40A1, TFR2, or HAMP. His erythrocyte measures and hemoglobin electrophoresis were consistent with alpha-thalassemia trait. We conclude that homozygosity for HJV R54X accounts for his severe, early age-of-onset hemochromatosis; his phenotype was probably modified by serial phlebotomy therapy.
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PMID:Early age-of-onset iron overload and homozygosity for the novel hemojuvelin mutation HJV R54X (exon 3; c.160A-->T) in an African American male of West Indies descent. 1849 90


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