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1.
Gastroenterology ; 150(3): 672-683.e4, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26582087

RESUMO

BACKGROUND & AIMS: Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. METHODS: We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. RESULTS: We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. CONCLUSIONS: We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload.


Assuntos
Proteína Morfogenética Óssea 6/genética , Hemocromatose/genética , Hemocromatose/metabolismo , Hepcidinas/biossíntese , Heterozigoto , Ferro/metabolismo , Fígado/metabolismo , Mutação de Sentido Incorreto , Idoso , Animais , Biópsia , Proteína Morfogenética Óssea 6/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Cromatografia Líquida , Análise Mutacional de DNA , Feminino , Ferritinas/sangue , Estudos de Associação Genética , Predisposição Genética para Doença , Hemocromatose/sangue , Hepcidinas/sangue , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Gambás , Fenótipo , Proteínas Smad Reguladas por Receptor/metabolismo , Espectrometria de Massas em Tandem , Transfecção
2.
Am J Hematol ; 91(12): 1202-1205, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27518069

RESUMO

p.Cys282Tyr (C282Y) homozygosity explains most cases of HFE-related hemochromatosis, but a significant number of patients presenting with typical type I hemochromatosis phenotype remain unexplained. We sought to describe the clinical relevance of rare HFE variants in non-C282Y homozygotes. Patients referred for hemochromatosis to the National Reference Centre for Rare Iron Overload Diseases from 2004 to 2010 were studied. Sequencing was performed for coding region and intronic flanking sequences of HFE, HAMP, HFE2, TFR2, and SLC40A1. Nine private HFE variants were identified in 13 of 206 unrelated patients. Among those, five have not been previously described: p.Leu270Argfs*4, p.Ala271Valfs*25, p.Tyr52*, p.Lys166Asn, and p.Asp141Tyr. Our results show that rare HFE variants are identified more frequently than variants in the other genes associated with iron overload. Rare HFE variants are therefore the most frequent cause of hemochromatosis in non-C282Y homozygote HFE patients. Am. J. Hematol. 91:1202-1205, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Variação Genética , Proteína da Hemocromatose/genética , Hemocromatose/genética , Adulto , Idoso , Feminino , Homozigoto , Humanos , Sobrecarga de Ferro/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA
3.
J Hepatol ; 62(3): 682-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25450707

RESUMO

BACKGROUND & AIMS: Mortality studies in patients with hemochromatosis give conflicting results especially with respect to extrahepatic causes of death. Our objective was to assess mortality and causes of death in a cohort of patients homozygous for the C282Y mutation in the HFE gene, diagnosed since the availability of HFE testing. METHODS: We studied 1085 C282Y homozygotes, consecutively diagnosed from 1996 to 2009, and treated according to current recommendations. Mortality and causes of death were obtained from death certificates and compared to those of the general population. Standardized mortality ratios (SMRs) were used to assess specific causes of death and the Cox model was used to identify prognostic factors for death. RESULTS: Patients were followed for 8.3±3.9 years. Overall the SMR was the same as in the general population (0.94 CI: 0.71-1.22). Patients with serum ferritin⩾2000 µg/L had increased liver-related deaths (SMR: 23.9 CI: 13.9-38.2), especially due to hepatic cancer (SMR: 49.1 CI: 24.5-87.9). Patients with serum ferritin between normal and 1000 µg/L had a lower mortality than the general population (SMR: 0.27 CI: 0.1-0.5), due to a decreased mortality, related to reduced cardiovascular events and extrahepatic cancers in the absence of increased liver-related mortality. Age, diabetes, alcohol consumption, and hepatic fibrosis were independent prognostic factors of death. CONCLUSIONS: In treated HFE hemochromatosis, only patients with serum ferritin higher than 2000 µg/L have an increased mortality, mainly related to liver diseases. Those with mild iron burden have a decreased overall mortality in relation to reduced cardiovascular and extrahepatic cancer-related events. These results support a beneficial effect of early and sustained management of patients with iron excess, even when mild.


Assuntos
Hemocromatose/genética , Hemocromatose/mortalidade , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Adulto , Substituição de Aminoácidos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/mortalidade , Causas de Morte , Estudos de Coortes , Feminino , Ferritinas/sangue , França/epidemiologia , Hemocromatose/terapia , Proteína da Hemocromatose , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Transferrina/metabolismo
4.
J Hepatol ; 62(3): 664-72, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25457201

RESUMO

BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is the most common form of genetic iron loading disease. It is mainly related to the homozygous C282Y/C282Y mutation in the HFE gene that is, however, a necessary but not a sufficient condition to develop clinical and even biochemical HH. This suggests that modifier genes are likely involved in the expressivity of the disease. Our aim was to identify such modifier genes. METHODS: We performed a genome-wide association study (GWAS) using DNA collected from 474 unrelated C282Y homozygotes. Associations were examined for both quantitative iron burden indices and clinical outcomes with 534,213 single nucleotide polymorphisms (SNP) genotypes, with replication analyses in an independent sample of 748 C282Y homozygotes from four different European centres. RESULTS: One SNP met genome-wide statistical significance for association with transferrin concentration (rs3811647, GWAS p value of 7×10(-9) and replication p value of 5×10(-13)). This SNP, located within intron 11 of the TF gene, had a pleiotropic effect on serum iron (GWAS p value of 4.9×10(-6) and replication p value of 3.2×10(-6)). Both serum transferrin and iron levels were associated with serum ferritin levels, amount of iron removed and global clinical stage (p<0.01). Serum iron levels were also associated with fibrosis stage (p<0.0001). CONCLUSIONS: This GWAS, the largest one performed so far in unselected HFE-associated HH (HFE-HH) patients, identified the rs3811647 polymorphism in the TF gene as the only SNP significantly associated with iron metabolism through serum transferrin and iron levels. Because these two outcomes were clearly associated with the biochemical and clinical expression of the disease, an indirect link between the rs3811647 polymorphism and the phenotypic presentation of HFE-HH is likely.


Assuntos
Genes Modificadores , Hemocromatose/genética , Hemocromatose/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Transferrina/genética , Adulto , Substituição de Aminoácidos , Feminino , França , Estudo de Associação Genômica Ampla , Proteína da Hemocromatose , Homozigoto , Humanos , Ferro/sangue , Itália , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Transferrina/metabolismo
5.
Blood Cells Mol Dis ; 54(2): 151-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25486930

RESUMO

As our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome.


Assuntos
Hepcidinas/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Erros Inatos do Metabolismo dos Metais/genética , Mutação , Transferrina/deficiência , Transferrina/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Expressão Gênica , Genótipo , Proteína da Hemocromatose , Hepcidinas/metabolismo , Heterozigoto , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/patologia , Masculino , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo dos Metais/sangue , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/patologia , Pessoa de Meia-Idade , Linhagem , Transferrina/metabolismo
6.
Hum Mutat ; 34(11): 1529-36, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23943237

RESUMO

Ferroportin (FPN) mediates iron export from cells and this function is modulated by serum hepcidin. Mutations in the FPN gene (SLC40A1) lead to autosomal dominant iron overload diseases related either to loss or to gain of function, and usually characterized by normal or low transferrin saturation versus elevated transferrin saturation, respectively. However, for the same mutation, the phenotypic expression may vary from one patient to another. Using in vitro overexpression of wild-type or mutant FPN proteins, we characterized the functional impact of five recently identified FPN gene mutations regarding FPN localization, cell iron status, and hepcidin sensitivity. Our aim was to integrate functional results and biological findings in probands and relatives. We show that while the p.Arg371Gln (R371Q) mutation had no impact on studied parameters, the p.Trp158Leu (W158L), p.Arg88Gly (R88G), and p.Asn185Asp (N185D) mutations caused an iron export defect and were classified as loss-of-function mutations. The p.Gly204Ser (G204S) mutation induced a gain of FPN function. Functional studies are useful to determine whether or not a FPN gene mutation found in an iron overloaded patient is deleterious and to characterize its biological impact, especially when family studies are not fully informative and/or additional confounding factors may affect bio-clinical expression.


Assuntos
Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Estudos de Associação Genética , Sobrecarga de Ferro/congênito , Proteínas de Transporte de Cátions/química , Ferritinas/metabolismo , Expressão Gênica , Células HEK293 , Humanos , Espaço Intracelular/metabolismo , Ferro/metabolismo , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Mutação , Transferrina/metabolismo
7.
Gastroenterology ; 140(4): 1199-1207.e1-2, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21199650

RESUMO

BACKGROUND & AIMS: Ferroportin disease is characterized by iron overload. It has an autosomal-dominant pattern of inheritance and has been associated with mutations in the SLC40A1 gene, which encodes the cellular iron exporter ferroportin. Since the first description in 2001, about 30 mutations have been reported; the heterogeneity of ferroportin disease phenotypes has led to the hypothesis that the nature of the mutation affects the function of the protein in different ways. We studied genotypes and phenotypes of a large cohort of patients with ferroportin disease. METHODS: We studied clinical, biochemical, imaging, histologic, and genetic data from 70 affected subjects from 33 families with 19 mutations. RESULTS: We found that ferroportin disease, at the time of diagnosis, has limited consequences in the absence of cofactors. Data indicated that transferrin saturation, which correlated with fibrosis and levels of alanine aminotransferase, might be a marker of disease severity. Although the study was performed in a large number of families, we observed incomplete penetrance and no correlation between genotypes and phenotypes. CONCLUSIONS: Members of families with ferroportin disease should be screened for biochemical parameters of iron metabolism as well as genotype to detect silent mutations that might cause disease with acquired or genetic cofactors. Patients should be followed up long term to identify potential complications of the disease.


Assuntos
Proteínas de Transporte de Cátions/genética , Hemocromatose/genética , Caracteres Sexuais , Adolescente , Adulto , Idoso , Feminino , Proteínas Ligadas por GPI/genética , Testes Genéticos , Genótipo , Hemocromatose/diagnóstico , Proteína da Hemocromatose , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Receptores da Transferrina/genética , Índice de Gravidade de Doença , Transferrina/metabolismo , Adulto Jovem
8.
Ann Biol Clin (Paris) ; 70(3): 305-13, 2012.
Artigo em Francês | MEDLINE | ID: mdl-22565179

RESUMO

HFE-related hemochromatosis (HFE hemochromatosis) or type 1 hemochromatosis is an autosomal recessive disease characterized by progressive iron overload usually expressed in adulthood. The HFE gene, located on the short arm of chromosome 6 (6p21.3), encodes a protein that plays a crucial role in iron metabolism by modulating hepcidin synthesis in the liver. Homozygosity for the p.Cys282Tyr mutation accounts for nearly 80% of cases of hemochromatosis in France. Genetic testing is the key investigation to confirm the diagnosis of HFE hemochromatosis. A survey on routine practices was carried out among the eight reference laboratories of the French national network on genetic iron disorders. The main findings from this survey are as follows: 1) the p.Cys282Tyr mutation must be searched for as an initial step to establish the diagnosis of HFE hemochromatosis. This is in agreement with the recommendations of the French Health Authority (HAS) published in 2005. In these recommendations, homozygosity for the p.Cys282Tyr mutation with at least elevated transferrin saturation, is considered the only genotype that confirms of the diagnosis of HFE hemochromatosis; 2) in combination with the p.Cys282Tyr mutation (compound heterozygous genotypes), the p.Ser65Cys and the p.His63Asp variants may contribute to the occurrence of mild iron overload; 3) family screening is mandatory following the detection of homozygous individuals for the p.Cys282Tyr mutation.


Assuntos
Hemocromatose/diagnóstico , Antígenos de Histocompatibilidade Classe I/genética , Laboratórios Hospitalares , Proteínas de Membrana/genética , Técnicas de Diagnóstico Molecular , Mutação , Termos de Consentimento , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Coleta de Dados , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/normas , Testes Diagnósticos de Rotina/estatística & dados numéricos , França , Hemocromatose/genética , Proteína da Hemocromatose , Humanos , Laboratórios Hospitalares/normas , Laboratórios Hospitalares/estatística & dados numéricos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Mutação/fisiologia , Padrões de Referência
9.
Blood Cells Mol Dis ; 47(4): 243-8, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21871825

RESUMO

BACKGROUND: DMT1 is a transmembrane iron transporter involved in iron duodenal absorption and cellular iron uptake. Mutations in the human SLC11A2 gene coding DMT1 lead to microcytic anemia and hepatic iron overload, with unexpectedly low levels of plasma ferritin in the presence of iron stores. DESIGN AND METHODS: We report a patient with a similar phenotype due to two mutations in the SLC11A2 gene, the known p.Gly212Val (G212V) mutation and a novel one, p.Asn491Ser (N491S). To assess the expression of DMT1 in human liver, we studied the expression of the four DMT1 mRNA isoforms by real-time quantitative PCR in control human liver samples. We also studied the effect of G212V and N491S DMT1 mutations on RNA splicing in blood leukocytes and cellular trafficking of dsRed2-tagged-DMT1 protein in the human hepatic cell line HuH7. RESULTS: Our results showed that i) only the isoforms 1B-IRE and 1B-nonIRE were significantly expressed in human liver; ii) the G212V mutation did not seem to affect mRNA splicing and the N491S mutation induced a splicing alteration leading to a truncated protein, which seemed quantitatively of low relevance; and iii) the N491S mutation, in contrast to the G212V mutation, led to abnormal protein trafficking. CONCLUSIONS: Our data confirm the major role of DMT1 in the maintenance of iron homeostasis in humans and demonstrate that the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload.


Assuntos
Anemia Hipocrômica/genética , Proteínas de Transporte de Cátions/genética , Sobrecarga de Ferro/genética , Fígado/metabolismo , Mutação , Adulto , Processamento Alternativo , Substituição de Aminoácidos , Anemia Hipocrômica/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular , Feminino , Humanos , Sobrecarga de Ferro/metabolismo , Fígado/patologia , Transporte Proteico , Isoformas de RNA/metabolismo , Análise de Sequência de DNA
11.
Haematologica ; 94(5): 720-4, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19286879

RESUMO

Low levels of hepcidin are responsible for the development of iron overload in p.Cys282Tyr HFE related hemochromatosis. Every genetic factor lowering the hepcidin gene expression could contribute to a more severe phenotype in HFE hemochromatosis. Based on this hypothesis, we identified a heterozygous nc.-153 C>T mutation in the hepcidin gene promoter sequence in a patient homozygous for the p.Cys282Tyr HFE mutation who presented massive iron overload, resisting to well conducted iron depletive treatment. Our results demonstrate that the nc.-153 C>T mutation, located within a BMP-RE (Bone Morphogenetic Protein-Responsive Element): i) decreases the transcriptional activity of the hepcidin promoter, ii) alters its IL-6 (Interleukin-6) total responsiveness, and iii) prevents the binding of the SMAD protein complex (1/5/8 and 4) to the BPM-RE. In conclusion, our results suggest that a mutation in the BMP-RE of hepcidin promoter may impact on human iron metabolism.


Assuntos
Peptídeos Catiônicos Antimicrobianos/genética , Hemocromatose/genética , Mutação Puntual , Regiões Promotoras Genéticas/genética , Substituição de Aminoácidos , Proteínas Morfogenéticas Ósseas/farmacologia , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Hemocromatose/diagnóstico , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Luciferases/genética , Luciferases/metabolismo , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Elementos de Resposta/genética , Transfecção
12.
Haematologica ; 94(3): 335-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19176363

RESUMO

BACKGROUND: Elevated serum ferritin levels are frequently encountered in clinical situations and once iron overload or inflammation has been ruled out, many cases remain unexplained. Genetic causes of hyperferritinemia associated to early cataract include mutations in the iron responsive element in the 5' untranslated region of the L ferritin mRNA, responsible for the hereditary hyperferritinemia cataract syndrome. DESIGN AND METHODS: We studied 91 probands with hyperferritinemia comprising 25 family cases belonging to families with at least two cases of unexplained hyperferritinemia, and 66 isolated cases. In the families, we also analyzed 30 relatives. Hyperferritinemia was considered as unexplained when transferrin saturation was below 45% and/or serum iron below 25 mumol/L and/or no tissue iron excess was detected, when inflammation had been ruled out and when iron responsive element mutation was absent. We carried out sequencing analysis of the FTL gene coding the L ferritin. RESULTS: A novel heterozygous p.Thr30Ile mutation in the NH2 terminus of L ferritin subunit was identified in 17 probands out of the cohort. The mutation was shown to cosegregate with hyperferritinemia in all the 10 families studied. No obvious clinical symptom was found associated with the presence of the mutation. This unique mutation is associated with an unusually high percentage of ferritin glycosylation. CONCLUSIONS: This missense mutation of FTL represents a new cause of genetic hyperferritinemia without iron overload. We hypothesized that the mutation increases the efficacy of L ferritin secretion by increasing the hydrophobicity of the N terminal "A" alpha helix.


Assuntos
Ferritinas/sangue , Sobrecarga de Ferro/sangue , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Apoferritinas , Criança , Saúde da Família , Feminino , Ferritinas/química , Ferritinas/genética , Ferritinas/metabolismo , Glicosilação , Heterozigoto , Humanos , Sobrecarga de Ferro/genética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Estrutura Secundária de Proteína , Adulto Jovem
13.
Blood Rev ; 22(4): 195-210, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18430498

RESUMO

Iron overload diseases of genetic origin are an ever changing world, due to major advances in genetics and molecular biology. Five major categories are now established: HFE-related or type1 hemochromatosis, frequently found in Caucasians, and four rarer diseases which are type 2 (A and B) hemochromatosis (juvenile hemochromatosis), type 3 hemochromatosis (transferrin receptor 2 hemochromatosis), type 4 (A and B) hemochromatosis (ferroportin disease), and a(hypo)ceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to an impairment of hepcidin synthesis, account for the development of cellular excess in types 1, 2, 3, and 4B hemochromatosis whereas decreased cellular iron egress is involved in the main form of type 4A) hemochromatosis and in aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. The combination of magnetic resonance imaging (for diagnosing visceral iron overload) and of genetic testing has drastically reduced the need for liver biopsy. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases paves the road for innovative therapeutic approaches.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hemocromatose , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas de Membrana/metabolismo , Peptídeos Catiônicos Antimicrobianos/deficiência , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Benzoatos/uso terapêutico , Proteínas de Transporte de Cátions/imunologia , Deferasirox , Hemocromatose/etiologia , Hemocromatose/imunologia , Hemocromatose/patologia , Hemocromatose/terapia , Proteína da Hemocromatose , Hepcidinas , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/imunologia , Sobrecarga de Ferro/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Flebotomia , Triazóis/uso terapêutico
15.
Presse Med ; 36(9 Pt 2): 1292-4, 2007 Sep.
Artigo em Francês | MEDLINE | ID: mdl-17544612

RESUMO

Screening for hereditary HFE hemochromatosis in the general population, by either phenotype or genotype, is not currently recommended by the French High Health Authority. Targeted screening for hereditary HFE hemochromatosis in groups with specific diseases (people with asthenia, arthropathic disorders, liver or heart disease, etc.) has not been shown to be effective. Family screening in first-degree relatives of any proband homozygous for C282Y is strongly advised. This should involve both phenotypic screening, that is, testing for serum iron markers and, if possible, a genotype study of siblings and adult children, conducted according to the rules for genetic counseling and testing. This type of screening is cost-effective. One obstacle today is that the national health insurance fund does not reimburse the HFE test.


Assuntos
Hemocromatose/epidemiologia , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Programas de Rastreamento/métodos , Proteínas de Membrana/genética , Artropatia Neurogênica/epidemiologia , Astenia/epidemiologia , Biomarcadores , Análise Custo-Benefício , Feminino , Aconselhamento Genético , Genótipo , Hemocromatose/economia , Proteína da Hemocromatose , Humanos , Reembolso de Seguro de Saúde , Masculino , Programas de Rastreamento/economia , Pessoa de Meia-Idade , Fenótipo
16.
Presse Med ; 36(9 Pt 2): 1271-7, 2007 Sep.
Artigo em Francês | MEDLINE | ID: mdl-17521857

RESUMO

Hereditary type 1 HFE hemochromatosis is associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene (C282Y mutation). The p.Cys282Tyr mutation of the HFE gene leads to an abnormal reduction in hepatic expression of hepcidin, a protein that appears to control the release of iron from enterocytes and macrophages towards plasma. Abnormally low hepcidin levels promote an increase in the bioavailability of plasma iron, characterized by elevated transferrin saturation and the appearance of non transferrin bound iron. This nontransferrin-bound iron is avidly taken up by the liver, heart, and pancreas, the principal target organs for systemic iron overload. The variable penetrance of this disease is related to environmental and genetic factors. Among the genetic factors, mutations of some newly identified genes may aggravate the phenotype of iron overload associated with homozygosity for the p.Cys282Tyr mutation of the HFE gene; these new genes include those of hemojuvelin (HJV), transferrin receptor 2 (TfR2), and hepcidin (HAMP).


Assuntos
Hemocromatose/genética , Hemocromatose/fisiopatologia , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas Ligadas por GPI , Hemocromatose/metabolismo , Proteína da Hemocromatose , Hepcidinas , Humanos , Ferro/sangue , Peroxidação de Lipídeos , Estresse Oxidativo/fisiologia , Mutação Puntual/genética , Receptores da Transferrina/genética
18.
Rev Prat ; 56(19): 2118-22, 2006 Dec 15.
Artigo em Francês | MEDLINE | ID: mdl-17416048

RESUMO

Hepatic iron overload conditions can be classified as genetic, mainly related to HFE haemochromatosis, and secondary, mainly associated with haematological and hepatic disorders and with metabolic syndrome. The strict affirmation of iron excess relies upon liver biopsy, MRI or calculation of the amount of iron removed through phlebotomies. Determination of its cause relies upon the assessment of transferrin saturation which, when increased, suggests the diagnosis of either haemochromatosis--implying HFE testing--or overload secondary to dysmyelopoiesis or to end-stage cirrhosis, and, when normal, suggests the diagnosis of dysmetabolic iron overload syndrome.


Assuntos
Sobrecarga de Ferro/diagnóstico , Adulto , Anemia Macrocítica/complicações , Anemia Macrocítica/diagnóstico , Biópsia , Hemocromatose/diagnóstico , Hemocromatose/genética , Homozigoto , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/patologia , Fígado/patologia , Cirrose Hepática/complicações , Hepatopatias/complicações , Hepatopatias/diagnóstico , Imageamento por Ressonância Magnética , Síndrome Metabólica/complicações , Síndrome Metabólica/diagnóstico , Mutação , Siderose/diagnóstico , Transferrina/análise
19.
Nephrol Ther ; 2 Suppl 5: S298-303, 2006 Nov.
Artigo em Francês | MEDLINE | ID: mdl-17373274

RESUMO

Iron overload diseases are a quickly and deeply changing world, due to major advances in genetics and molecular biology. Five main entities are concerned: a frequent one, namely HFE-related or type1 haemochromatosis, and four rare or exceptional diseases which are types 2, 3 and 4 haemochromatosis and aceruloplasminemia. Increased duodenal iron absorption and enhanced macrophagic iron recycling, both due to hypo-hepcidinemia, account for the development of cellular excess in types 1, 2, 3 haemochromatosis whereas decreased cellular iron egress is the main explanation for type 4 haemochromatosis and aceruloplasminemia. Non-transferrin bound iron plays an important role in cellular iron excess and damage. Phlebotomies remain an essential therapeutic tool but the improved understanding of the intimate mechanisms underlying these diseases open the road for innovative therapeutic approaches.


Assuntos
Sobrecarga de Ferro/genética , Ferro/metabolismo , Peptídeos Catiônicos Antimicrobianos/deficiência , Peptídeos Catiônicos Antimicrobianos/genética , Ceruloplasmina/deficiência , Ferritinas/sangue , Regulação da Expressão Gênica , Hemocromatose/genética , Hepcidinas , Humanos
20.
Bull Acad Natl Med ; 189(8): 1635-47; discussion 1647, 2005 Nov.
Artigo em Francês | MEDLINE | ID: mdl-16737091

RESUMO

Iron, associated with proteins and enzymes, mainly as heminic groups and Fe/S clusters, is essential for oxygen transport and many other biological functions. Systemic iron homeostasis is essentially a closed system. There is no regulated mechanism of iron excretion, for example through the liver or kidneys: iron losses occur only through bleeding and by shedding of mucosal and skin cells. These losses are compensated for by intestinal absorption. In contrast, iron absorption is tightly regulated. Three recently identified proteins, named HFE, hepcidin and hemojuvelin, play an important role in this regulation. About 20 other proteins have been shown to play a part in iron metabolism, often through studies of genetic diseases in humans or other animals. Mitochondria play a major role in iron metabolism.


Assuntos
Ferro/metabolismo , Homeostase , Humanos , Absorção Intestinal , Proteínas de Membrana/metabolismo
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