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James C. Barton - One of the best experts on this subject based on the ideXlab platform.
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hfe gene structure function mutations and associated iron abnormalities
Gene, 2015Co-Authors: James C. Barton, Corwin Q. Edwards, Ronald T. ActonAbstract:The Hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of Hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of Hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE Hemochromatosis and iron overload.
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probability of c282y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the Hemochromatosis and iron overload screening study
Hepatology, 2012Co-Authors: Paul C. Adams, James C. Barton, Mark Speechley, Christine E Mclaren, Gordon D Mclaren, John H EckfeldtAbstract:Background Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE C282Y homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload due to Hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of Hemochromatosis, but diagnosis rates are often low.
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genetic screening for iron overload no evidence of discrimination at 1 year
Journal of Family Practice, 2007Co-Authors: Mark A Hall, James C. Barton, Ronald T. Acton, Paul C. Adams, Christine E Mclaren, Jacob A Reiss, Oswaldo Castro, Andrea Ruggiero, Tara E Power, Thomas C BentAbstract:PURPOSE: This study measured the extent of insurance and employment problems associated with population screening for hereditary Hemochromatosis and iron overload. METHODS: 101,168 primary care patients from the US and Canada were screened for iron phenotypes and HFE genotypes associated with Hemochromatosis. Those identified to be at risk (2253) were offered a clinical examination, which 1677 (74%) accepted, and the 1154 of these who responded to an initial questionnaire about psychosocial issues were surveyed 1 year later about whether they had experienced problems with insurance or employment that they attributed to hereditary Hemochromatosis and iron overload. RESULTS: 832 (72.1%) of the 1154 participants surveyed after 1 year responded to the second survey. Three (0.4%) had verified problems with insurance or employment that they believed were related to hereditary Hemochromatosis and iron overload. Two had problems with life insurance, and one with long-term care insurance. All 3 had elevated iron levels but not a relevant HFE genotype. One of the life insurance problems was resolved; the second one was not serious. The participant who was denied long-term care insurance had other health conditions unrelated to hereditary Hemochromatosis and iron overload that could have contributed to the denial. No problems were verified for health insurance or employment, or from any of the comparison group participants (controls and those with inconclusive screening results). CONCLUSIONS: The risk of insurance or employment problems 1 year after phenotype and genotype screening for hereditary Hemochromatosis and iron overload is very low.
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comparison of the unsaturated iron binding capacity with transferrin saturation as a screening test to detect c282y homozygotes for Hemochromatosis in 101 168 participants in the Hemochromatosis and iron overload screening heirs study
Clinical Chemistry, 2005Co-Authors: Paul C. Adams, Ronald T. Acton, Christine E Mclaren, Gordon D Mclaren, David M Reboussin, Cathie Leiendeckerfoster, Godfrey C Moses, Fitzroy W Dawkins, Ishmael Kasvosve, James C. BartonAbstract:The diagnosis of Hemochromatosis was previously based on a combination of clinical and laboratory assessments that included history and physical examination, increased transferrin saturation (TS) and serum ferritin, liver biopsy, the amount of iron removed by phlebotomy, and pedigree studies identifying other family members with iron overload (1). Since the discovery of the Hemochromatosis gene (HFE) in 1996 (2), most studies from referral centers have shown that >90% of typical Hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene (3). Before the availability of DNA-based testing, it was assumed that most Hemochromatosis patients have increased TS. However, recent population screening studies incorporating HFE genotyping have now shown that many C282Y homozygotes will have a normal TS and may never develop clinical signs and symptoms related to iron overload (4)(5)(6)(7)(8). TS has been recommended in many studies as the most clinically useful screening test for Hemochromatosis because it is widely available and may be increased even in young adults with a genetic predisposition to Hemochromatosis. Another potential advantage over DNA-based testing as an initial screening test is that TS may detect many types of iron overload other than those associated with HFE mutations. In addition, screening for iron overload instead of performing DNA-based testing may reduce the risks of potential genetic discrimination that some authors suggest is associated with identification of a C282Y homozygote with normal serum iron tests (9)(10)(11). The TS is a 2-step assay in which serum iron is the numerator and the denominator is either total iron-binding capacity (TIBC), [serum iron + unsaturated iron-bonding capacity (UIBC)] or an adjusted serum transferrin. The UIBC is a 1-step automated colorimetric assay that has been reported to have similar or better operating characteristics than TS for …
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Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population
BMC Medical Genetics, 2004Co-Authors: James C. Barton, Charles A. Rivers, Sandrine Niyongere, Sean B Bohannon, Ronald T. ActonAbstract:Background Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV) in whites is a cause of early age-of-onset iron overload (juvenile Hemochromatosis), and of Hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical Hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile Hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples.
Paul C. Adams - One of the best experts on this subject based on the ideXlab platform.
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therapeutic recommendations in hfe Hemochromatosis for p cys282tyr c282y c282y homozygous genotype
Hepatology International, 2018Co-Authors: Paul C. Adams, Pierre Brissot, Sonia Distante, Albert Altes, Barbara Butzeck, Ioav Cabantchik, Rodolfo D Cancado, Patricia J Evans, Robert W EvansAbstract:Although guidelines are available for hereditary Hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE Hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.
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clinical evaluation of a Hemochromatosis next generation sequencing gene panel
European Journal of Haematology, 2017Co-Authors: Matthew B Lanktree, Bekim Sadikovic, John S Waye, Alexander Levstik, Bruce B Lanktree, Jovana Yudin, Mark Crowther, Guillaume Pare, Paul C. AdamsAbstract:Background Next-generation sequencing of an iron metabolism gene panel could identify pathogenic mutations, improving on standard Hemochromatosis genetic testing and providing a molecular diagnosis in patients with suspected iron overload. Methods A next-generation sequencing panel of 15 genes with known roles in iron metabolism was constructed. 190 patients were sequenced: 94 from a tertiary Hemochromatosis clinic, and 96 submitted for HFE testing with biochemical evidence of iron overload [elevated ferritin (>450 μg/L) or transferrin saturation (>55%)] obtained from a chart review. Results From the Hemochromatosis clinic cohort, 6 patients were diagnosed with non-HFE Hemochromatosis due to homozygous hemojuvelin (HFE2) mutations. Ten additional heterozygous pathogenic mutations were observed. From the chart review cohort, a C-terminus ferritin light chain (FTL) frameshift mutation was observed consistent with neuroferritinopathy. Heterozygous deletion of HFE2, and 4 additional rare pathogenic or likely pathogenic heterozygous mutations were identified in 7 patients. Conclusions An iron metabolism gene panel provided a molecular diagnosis in 6 patients with non-HFE iron overload, and is suitable for diagnostic purposes in exceptional cases in specialized clinics. Further research will be required to assess the modifier effect of rare heterozygous mutations in iron metabolism genes. This article is protected by copyright. All rights reserved.
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predicting c282y homozygote genotype for Hemochromatosis using serum ferritin and transferrin saturation values from 44 809 participants of the heirs study
Canadian Journal of Gastroenterology & Hepatology, 2014Co-Authors: Andrew S P Lim, Mark Speechley, Paul C. AdamsAbstract:INTRODUCTION: The simultaneous interpretation of serum ferritin level and transferrin saturation has been used as a clinical guide to diagnose genetic Hemochromatosis. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 North American participants for serum ferritin level and transferrin saturation, and C282Y genotyping for the HFE gene.
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probability of c282y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the Hemochromatosis and iron overload screening study
Hepatology, 2012Co-Authors: Paul C. Adams, James C. Barton, Mark Speechley, Christine E Mclaren, Gordon D Mclaren, John H EckfeldtAbstract:Background Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE C282Y homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload due to Hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of Hemochromatosis, but diagnosis rates are often low.
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genetic screening for iron overload no evidence of discrimination at 1 year
Journal of Family Practice, 2007Co-Authors: Mark A Hall, James C. Barton, Ronald T. Acton, Paul C. Adams, Christine E Mclaren, Jacob A Reiss, Oswaldo Castro, Andrea Ruggiero, Tara E Power, Thomas C BentAbstract:PURPOSE: This study measured the extent of insurance and employment problems associated with population screening for hereditary Hemochromatosis and iron overload. METHODS: 101,168 primary care patients from the US and Canada were screened for iron phenotypes and HFE genotypes associated with Hemochromatosis. Those identified to be at risk (2253) were offered a clinical examination, which 1677 (74%) accepted, and the 1154 of these who responded to an initial questionnaire about psychosocial issues were surveyed 1 year later about whether they had experienced problems with insurance or employment that they attributed to hereditary Hemochromatosis and iron overload. RESULTS: 832 (72.1%) of the 1154 participants surveyed after 1 year responded to the second survey. Three (0.4%) had verified problems with insurance or employment that they believed were related to hereditary Hemochromatosis and iron overload. Two had problems with life insurance, and one with long-term care insurance. All 3 had elevated iron levels but not a relevant HFE genotype. One of the life insurance problems was resolved; the second one was not serious. The participant who was denied long-term care insurance had other health conditions unrelated to hereditary Hemochromatosis and iron overload that could have contributed to the denial. No problems were verified for health insurance or employment, or from any of the comparison group participants (controls and those with inconclusive screening results). CONCLUSIONS: The risk of insurance or employment problems 1 year after phenotype and genotype screening for hereditary Hemochromatosis and iron overload is very low.
Antonello Pietrangelo - One of the best experts on this subject based on the ideXlab platform.
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hereditary Hemochromatosis pathogenesis diagnosis and treatment
Gastroenterology, 2010Co-Authors: Antonello PietrangeloAbstract:In the late 1800s, Hemochromatosis was considered an odd autoptic finding. More than a century later, it was finally recognized as a hereditary, multi-organ disorder associated with a polymorphism that is common among white people: a 845G→A change in HFE that results in C282Y in the gene product. Hemochromatosis is now a well-defined syndrome characterized by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (Hjv) (which all sense the accumulation of iron that hepcidin corrects) or ferroportin (Fpn) (the cellular iron exporter down-regulated by hepcidin), cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown Hemochromatosis. Unlike these rare instances, in white people, homozygotes for C282Y polymorphism in HFE are numerous, but they are only predisposed to Hemochromatosis; complete organ disease develops in a minority, when these individuals abuse alcohol or from other unidentified modifying factors. HFE gene testing can be used to diagnose Hemochromatosis, but analyses of liver histology and clinical features are still required to identify patients with rare, non-HFE forms of the disease. The role of hepcidin in the pathogenesis of Hemochromatosis reveals its similarities to endocrine diseases such as diabetes and indicates new approaches to diagnosis and management of this common disorder in iron metabolism.
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Hemochromatosis an endocrine liver disease
Hepatology, 2007Co-Authors: Antonello PietrangeloAbstract:This review acknowledges the recent and dramatic advancement in the field of Hemochromatosis and highlights the surprising analogies with a prototypic endocrine disease, diabetes. The term Hemochromatosis should refer to a unique clinicopathologic subset of iron-overload syndromes that currently includes the disorder related to the C282Y homozygote mutation of the Hemochromatosis protein HFE (by far the most common form of Hemochromatosis) and the rare disorders more recently attributed to the loss of transferrin receptor 2, HAMP (hepcidin antimicrobial peptide), or hemojuvelin or to certain ferroportin mutations. The defining characteristic of this subset is failure to prevent unneeded iron from entering the circulatory pool as a result of genetic changes compromising the synthesis or activity of hepcidin, the iron hormone. Like diabetes, Hemochromatosis results from the complex, nonlinear interaction between genetic and acquired factors. Depending on the underlying mutation, the coinheritance of modifier genes, the presence of nongenetic hepcidin inhibitors, and other host-related factors, the clinical manifestation may vary from simple biochemical abnormalities to severe multiorgan disease. The recognition of the endocrine nature of Hemochromatosis suggests intriguing possibilities for new and more effective approaches to diagnosis and treatment.
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hereditary Hemochromatosis a new look at an old disease
The New England Journal of Medicine, 2004Co-Authors: Antonello PietrangeloAbstract:For many years, hereditary Hemochromatosis was regarded as a clinically and genetically unique entity marked by a classic presentation consisting of diabetes, bronze skin pigmentation, and cirrhosis. In 1996, identification of “the Hemochromatosis gene,” HFE, was reported; since then, several other iron-metabolism genes have also been identified. This article reviews the current understanding and management of hereditary iron-overload disorders.
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heterogeneity of Hemochromatosis in italy
Gastroenterology, 1998Co-Authors: Alberto Piperno, Domenico Girelli, Anna Vergani, Cristina Arosio, M Sampietro, Antonello Pietrangelo, L Lupica, Giuliana Montosi, Mirella Fraquelli, Paolo PasqueroAbstract:Abstract Background & Aims: Patients with Hemochromatosis show variable phenotype expression. We evaluated the frequency of Hemochromatosis gene (HFE) mutations and the contribution of HFE genotype, ancestral haplotype, ethnic background, and additional factors (alcohol intake, hepatitis viruses, and β-thalassemia trait) to the severity of iron overload in a large series of Italian patients with a Hemochromatosis phenotype. Methods: HFE genotype was studied in 188 patients. Phenotype evaluation was available in 153 men and 20 women and was based mainly on iron removed. HFE genotype was determined by a polymerase chain reaction restriction assay and ancestral haplotype through D6S265 and D6S105 microsatellite analysis. Results: The frequency of C282Y homozygotes was 64%, with a decreasing gradient from north to south. C282Y homozygotes showed more severe iron overload than the other HFE genotypes. In the same group, ancestral haplotype was associated with a more severe phenotype. Additional factors may favor the development of a relatively mild Hemochromatosis phenotype in patients nonhomozygous for the C282Y mutation. Conclusions: Hemochromatosis in Italy is a nonhomogenous disorder in which genetic and acquired factors are involved. In patients with a single or no HFE mutation, further studies will enable a differentiation between true genetic disorders and interactions between genetic and acquired factors. GASTROENTEROLOGY 1998;114:996-1002
Ronald T. Acton - One of the best experts on this subject based on the ideXlab platform.
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hfe gene structure function mutations and associated iron abnormalities
Gene, 2015Co-Authors: James C. Barton, Corwin Q. Edwards, Ronald T. ActonAbstract:The Hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of Hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of Hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE Hemochromatosis and iron overload.
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genetic screening for iron overload no evidence of discrimination at 1 year
Journal of Family Practice, 2007Co-Authors: Mark A Hall, James C. Barton, Ronald T. Acton, Paul C. Adams, Christine E Mclaren, Jacob A Reiss, Oswaldo Castro, Andrea Ruggiero, Tara E Power, Thomas C BentAbstract:PURPOSE: This study measured the extent of insurance and employment problems associated with population screening for hereditary Hemochromatosis and iron overload. METHODS: 101,168 primary care patients from the US and Canada were screened for iron phenotypes and HFE genotypes associated with Hemochromatosis. Those identified to be at risk (2253) were offered a clinical examination, which 1677 (74%) accepted, and the 1154 of these who responded to an initial questionnaire about psychosocial issues were surveyed 1 year later about whether they had experienced problems with insurance or employment that they attributed to hereditary Hemochromatosis and iron overload. RESULTS: 832 (72.1%) of the 1154 participants surveyed after 1 year responded to the second survey. Three (0.4%) had verified problems with insurance or employment that they believed were related to hereditary Hemochromatosis and iron overload. Two had problems with life insurance, and one with long-term care insurance. All 3 had elevated iron levels but not a relevant HFE genotype. One of the life insurance problems was resolved; the second one was not serious. The participant who was denied long-term care insurance had other health conditions unrelated to hereditary Hemochromatosis and iron overload that could have contributed to the denial. No problems were verified for health insurance or employment, or from any of the comparison group participants (controls and those with inconclusive screening results). CONCLUSIONS: The risk of insurance or employment problems 1 year after phenotype and genotype screening for hereditary Hemochromatosis and iron overload is very low.
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comparison of the unsaturated iron binding capacity with transferrin saturation as a screening test to detect c282y homozygotes for Hemochromatosis in 101 168 participants in the Hemochromatosis and iron overload screening heirs study
Clinical Chemistry, 2005Co-Authors: Paul C. Adams, Ronald T. Acton, Christine E Mclaren, Gordon D Mclaren, David M Reboussin, Cathie Leiendeckerfoster, Godfrey C Moses, Fitzroy W Dawkins, Ishmael Kasvosve, James C. BartonAbstract:The diagnosis of Hemochromatosis was previously based on a combination of clinical and laboratory assessments that included history and physical examination, increased transferrin saturation (TS) and serum ferritin, liver biopsy, the amount of iron removed by phlebotomy, and pedigree studies identifying other family members with iron overload (1). Since the discovery of the Hemochromatosis gene (HFE) in 1996 (2), most studies from referral centers have shown that >90% of typical Hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene (3). Before the availability of DNA-based testing, it was assumed that most Hemochromatosis patients have increased TS. However, recent population screening studies incorporating HFE genotyping have now shown that many C282Y homozygotes will have a normal TS and may never develop clinical signs and symptoms related to iron overload (4)(5)(6)(7)(8). TS has been recommended in many studies as the most clinically useful screening test for Hemochromatosis because it is widely available and may be increased even in young adults with a genetic predisposition to Hemochromatosis. Another potential advantage over DNA-based testing as an initial screening test is that TS may detect many types of iron overload other than those associated with HFE mutations. In addition, screening for iron overload instead of performing DNA-based testing may reduce the risks of potential genetic discrimination that some authors suggest is associated with identification of a C282Y homozygote with normal serum iron tests (9)(10)(11). The TS is a 2-step assay in which serum iron is the numerator and the denominator is either total iron-binding capacity (TIBC), [serum iron + unsaturated iron-bonding capacity (UIBC)] or an adjusted serum transferrin. The UIBC is a 1-step automated colorimetric assay that has been reported to have similar or better operating characteristics than TS for …
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Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population
BMC Medical Genetics, 2004Co-Authors: James C. Barton, Charles A. Rivers, Sandrine Niyongere, Sean B Bohannon, Ronald T. ActonAbstract:Background Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV) in whites is a cause of early age-of-onset iron overload (juvenile Hemochromatosis), and of Hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical Hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile Hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples.
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genetic and clinical description of Hemochromatosis probands and heterozygotes evidence that multiple genes linked to the major histocompatibility complex are responsible for Hemochromatosis
Blood Cells Molecules and Diseases, 1997Co-Authors: James C. Barton, Charles A. Rivers, Ronald T. Acton, Wendy W H Shih, Ritsuko Sawadahirai, Leigh Harmon, Barry E RothenbergAbstract:Abstract ABSTRACT: We evaluated Alabama Hemochromatosis probands ( n = 74) and normal control subjects ( n = 142) for expression of the Hemochromatosis-associated mutations nt 845G→A (845A; Cys282Tyr) and nt 187C→G (His63Asp) in a gene linked to the major histocompatibility complex (MHC). We also tabulated parameters of iron metabolism and iron overload in probands and in obligate heterozygote family members of homozygous Cys282Tyr probands. Among probands, 59.4% were Cys282Tyr homozygotes and 20.3% were heterozygotes; 20.3% did not express this mutation. In normal control subjects, 14.7% were heterozygous for the Cys282Tyr mutation; one normal control subject was homozygous for the Cys282Tyr mutation. None (0 of 44) of our Cys282Tyr-homozygous Hemochromatosis probands had the His63Asp mutation. Of the Cys282Tyr-heterozygous and -negative probands, the His63Asp mutation occurred in 26.7% (4/15) and 53.3% (8/15), respectively. In normal control subjects, 23.2% were heterozygous for the His63Asp mutation; 2.8% were homozygous. Induction phlebotomy requirements and other manifestations of iron overload were significantly greater in Cys282Tyr homozygotes than among other probands. Cys282Tyr-heterozygous probands had significantly higher values of serum iron parameters than did obligate Cys282Tyr heterozygotes whose values were, on the average, normal. Co-expression of HLA-A3, HLA-B7, and D6S105(8) was significantly more frequent in all subgroups of probands stratified by Cys282Tyr expression than in normal control subjects. These results demonstrate that the severity of iron overload in Hemochromatosis is affected significantly by genetic factors. Further, our findings support the hypothesis that one or more MHC-linked genes other than that corresponding to the Cys282Tyr and His63Asp mutations contributes to increased iron absorption and iron overload in Hemochromatosis probands.
Clara Camaschella - One of the best experts on this subject based on the ideXlab platform.
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blunted hepcidin response to oral iron challenge in hfe related Hemochromatosis
Blood, 2007Co-Authors: Alberto Piperno, Domenico Girelli, Tomas Ganz, Elizabeta Nemeth, P Trombini, Claudia Bozzini, Erika Poggiali, Yen Phung, Clara CamaschellaAbstract:Inadequate hepcidin synthesis leads to iron overload in HFE-related Hemochromatosis. We explored the regulation of hepcidin by iron in 88 Hemochromatosis patients (61 C282Y/C282Y, 27 C282Y/H63D) and 23 healthy controls by analyzing urinary hepcidin before and 24 hours after a 65-mg oral iron dose. Thirty-four patients were studied at diagnosis and had iron overload, and 54 patients were iron depleted. At diagnosis, hepcidin values in C282Y homozygotes were similar to controls, whereas values in C282Y/H63D heterozygotes were higher (P = .02). However, the hepcidin/ferritin ratio was decreased in both homozygotes (P or = 10 ng/mg creatinine) was observed in 74% of controls, 15% of homozygotes, and 32% of heterozygotes. The hepcidin response to oral iron is blunted in HFE-related Hemochromatosis and not improved after iron depletion. The findings support the involvement of HFE in iron sensing and subsequent regulation of hepcidin.
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hepcidin is decreased in tfr2 Hemochromatosis
Blood, 2005Co-Authors: Elizabeta Nemeth, Clara Camaschella, Antonella Roetto, Tomas Ganz, Giovanni GarozzoAbstract:The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary Hemochromatosis are caused by hepcidin deficiency. Juvenile Hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE Hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the Hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. Urinary hepcidin was low or undetectable in 8 of 10 cases irrespective of the previous phlebotomy treatments. The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron.
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Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele
Blood Cells Molecules and Diseases, 2004Co-Authors: Giorgio Biasiotto, Antonella Roetto, Filomena Daraio, Anna Polotti, Gian Mario Gerardi, Domenico Girelli, Laura Cremonesi, Paolo Arosio, Clara CamaschellaAbstract:Abstract HFE-Hemochromatosis is the most common form of hereditary Hemochromatosis. The disorder is associated with the homozygous C282Y mutation and has variable phenotype, being modulated by environmental and genetic factors. Candidate modifier genes are hemojuvelin and hepcidin, which are responsible for juvenile Hemochromatosis. We used DHPLC to scan mutations in these genes in a cohort of unrelated patients with C282Y mutation. They consisted of 136 C282Y homozygous, 43 heterozygous, and 42 C282Y/H63D compound heterozygous, plus 62 controls subjects. Mutations and polymorphisms were found in 16 patients and 4 controls. Abnormally high indices of iron status were found in subjects C282Y/H63D heterozygous for the N196K hemojuvelin mutation and the −72C>T hepcidin substitution. The already described G71D mutation of hepcidin did not induce evident modification of the C282Y/H63D phenotype. The data show that heterozygous mutations of the hemojuvelin gene contribute like those of hepcidin to the phenotypic heterogeneity of Hemochromatosis. However, they are rare and explain only a minor portion of the variable penetrance of the disorder.
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a valine deletion of ferroportin 1 a common mutation in Hemochromatosis type 4
Blood, 2002Co-Authors: Antonella Roetto, Filomena Daraio, Alison T Merryweatherclarke, Karen Livesey, Jennifer J Pointon, Giuliana Barbabietola, Antonio Piga, Peter H Mackie, Kathryn J H Robson, Clara CamaschellaAbstract:Hemochromatosis type 4 is an atypical Hemochromatosis characterized by dominant inheritance, increased serum ferritin, normal transferrin saturation, and prevalent iron deposition in the reticuloendothelial (RE) cells rather than in hepatocytes. Heterozygous missense mutations of the iron export
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linkage to chromosome 1q in greek families with juvenile Hemochromatosis
Blood Cells Molecules and Diseases, 2001Co-Authors: George Papanikolaou, Clara Camaschella, Antonella Roetto, Marianna Politou, Sandra Bosio, Nikos Sakelaropoulos, Dimitris LoukopoulosAbstract: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.
