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Alterações moleculares associadas à hemocromatose hereditária; Molecular changes associated with hereditary hemochromatosis

SANTOS, Paulo C. J. L.; CANÇADO, Rodolfo D.; TERADA, Cristiane T.; GUERRA-SHINOHARA, Elvira M.
Fonte: Associação Brasileira de Hematologia e Hemoterapia e daSociedade Brasileira de Transplante de Medula Óssea Publicador: Associação Brasileira de Hematologia e Hemoterapia e daSociedade Brasileira de Transplante de Medula Óssea
Tipo: Artigo de Revista Científica
POR
Relevância na Pesquisa
66.81%
A hemocromatose hereditária (HH) é a mais comum doença autossômica em caucasianos e caracteriza-se pelo aumento da absorção intestinal de ferro, o qual resulta em acúmulo progressivo de ferro no organismo. A classificação da HH é realizada de acordo com a alteração genética encontrada, sendo os casos divididos em tipos 1, 2A, 2B, 3 e 4, quando a sobrecarga de ferro for associada aos genes HFE, HJV, HAMP, TFR2 e SLC40A1, respectivamente. Não existem estudos brasileiros que avaliaram a presença de mutações em genes relacionados à fisiopatologia da HH (genes HJV, HAMP, TFR2 e SLC40A1), além da pesquisa das três mutações no gene HFE (C282Y, H63D e S65C). Porém, está descrito, nos estudos realizados no Brasil, que alguns pacientes com sobrecarga de ferro primária não são portadores da HH tipo 1 (associada ao gene HFE). Portanto, é de suma importância a identificação das características genéticas dessa população, uma vez que outras mutações nos genes HJV, HAMP, TFR2 e SLC40A1 podem estar associadas à fisiopatologia da doença, podendo haver interações entre os genes alterados, de forma que possa auxiliar no entendimento da fisiopatologia da HH em pacientes brasileiros.; Hereditary Hemochromatosis (HH) is the most common autosomal disease in Caucasians. It is characterized by an increase in intestinal absorption of iron...

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis

BITTENCOURT, Paulo Lisboa; MARIN, Maria Lúcia Carnevale; COUTO, Cláudia Alves; CANÇADO, Eduardo Luiz Rachid; CARRILHO, Flair José; GOLDBERG, Anna Carla
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
56.71%
BACKGROUND: Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). AIMS: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS: Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A®. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. RESULTS: In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. CONCLUSIONS: One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.; (FAPESP) São Paulo Research Foundation

Hereditary hemochromatosis: Mutations in genes involved in iron homeostasis in Brazilian patients

SANTOS, Paulo C. J. L.; CANCADO, Rodolfo D.; PEREIRA, Alexandre C.; SCHETTERT, Isolmar T.; SOARES, Renata A. G.; PAGLIUSI, Regina A.; HIRATA, Rosario D. C.; HIRATA, Mario H.; TEIXEIRA, Ana C.; FIGUEIREDO, Maria Stella; CHIATTONE, Carlos S.; KRIEGER, Jose
Fonte: ACADEMIC PRESS INC ELSEVIER SCIENCE Publicador: ACADEMIC PRESS INC ELSEVIER SCIENCE
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
56.85%
Background: p.C282Y mutation and rare variants in the HFE gene have been associated with hereditary hemochromatosis (HH). HH is also caused by mutations in other genes, such as the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1). The low rate homozygous p.C282Y mutation in Brazil is suggestive that mutations in non-HFE genes may be linked to HH phenotype. Aim: To screen exon-by-exon DNA sequences of HFE, HJV, HAMP, TFR2 and SLC40A1 genes to characterize the molecular basis of HH in a sample of the Brazilian population. Materials and methods: Fifty-one patients with primary iron overload (transferrin saturation >= 50% in females and >= 60% in males) were selected. Subsequent bidirectional DNA sequencing of HFE, HJV, HAMP, TFR2 and SLC40A1 exons was performed. Results: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 21.6%). In addition, heterozygous HFE p.S65C mutation was found in combination with p.H63D in two patients and homozygous HFE p.H63D was found in two patients as well. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Molecular and clinical diagnosis of juvenile hemochromatosis (homozygous form for the HJV p.G320V) was described for the first time in Brazil. Three TFR2 polymorphisms (p.A75V...

Hemocromatose hereditária: associação entre as mutações no gene HFE e o estado de ferro em doadores de sangue e pesquisa de mutações nos genes HFE, HJV, HAMP, TFR2 e SLC40A1 em pacientes com sobrecarga de ferro primária; Hereditary hemochromatosis: relationship between HFE gene mutations and iron status in blood donors and HFE, HJV, HAMP, TFR2 and SLC40A1 gene sequencing in primary iron overload patients

Santos, Paulo Caleb Júnior de Lima
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/01/2011 PT
Relevância na Pesquisa
66.89%
A hemocromatose hereditária é caracterizada pelo aumento da absorção intestinal de ferro, acarretando progressivo acúmulo no organismo. Os objetivos foram: 1- determinar as frequências das mutações p.C282Y, p.H63D e p.S65C no gene HFE e avaliar os efeitos nas concentrações dos parâmetros do ferro em doadores de sangue; 2- pesquisar mutações nos genes: 2.1- HFE, 2.2- HJV e HAMP, 2.3- TFR2 e SLC40A1, em pacientes portadores de sobrecarga de ferro primária. Participaram 542 doadores de sangue provenientes do Hemocentro da Santa Casa de São Paulo. Foram incluídos 51 pacientes que apresentavam saturação de transferrina ≥ 50% (para mulheres) e ≥ 60% (para homens) e ausência de causas secundárias. Os genótipos para as mutações nos genes HFE foram avaliados pela PCR-RFLP. Foi realizado sequenciamento direto bidirecional para cada éxon dos genes, utilizando o sequenciador Genetic Analizer 3500XL®. Nos doadores de sangue, as frequências dos alelos HFE 282Y, HFE 63D e HFE 65C foram 2,1, 13,6 e 0,6%, respectivamente. Os homens que doaram pela primeira vez, portadores do genótipo HFE 282CY, apresentaram maiores valores de saturação de transferrina; e também os portadores dos genótipos HFE 63DD e 63HD apresentaram maiores concentrações de ferritina sérica...

Porfiria cutânea tardia com mutações do gene da hemocromatose C282Y e H63D e análise retrospectiva do perfil de ferro em relação ao tratamento: estudo de 60 casos; Porphyria cutanea tarda with hemochromatosis gene mutations C282Y and H63D and retrospective analysis of the iron profile in relation to treatment: study of 60 cases

Vieira, Fatima Mendonça Jorge
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 24/10/2012 PT
Relevância na Pesquisa
57.04%
Fundamentos: A porfiria cutânea tardia é a forma mais comum das porfirias e caracteriza-se pela diminuição da atividade da enzima uroporfirinogênio descarboxilase. Há vários relatos da associação das mutações do gene HFE da hemocromatose hereditária com porfiria cutânea tardia no mundo, mas até hoje apenas um estudo foi realizado no Brasil. Objetivo: Estudar a associação da porfiria cutânea tardia com as mutações C282Y e H63D do gene HFE da hemocromatose hereditária. Identificar a associação com etilismo, hepatite C, hepatite B e infecção pelo HIV e relacioná-los com a presença ou não das mutações do gene HFE e estudar retrospectivamente a resposta terapêutica à cloroquina. Métodos: Estudo ambispectivo para detectar as mutações C282Y e H63D em 60 pacientes com porfiria cutânea tardia no período de 2003 até 2012. O histórico familiar, etilismo, hepatite C, hepatite B e anti-HIV foram investigados. O estudo das mutações HFE foi realizado com PCR em tempo real. A resposta terapêutica foi avaliada utilizando a dosagem das porfirinas urinárias (urina de 24 horas), o perfil de ferro (ferro sérico, ferritina e saturação de transferrina) e as enzimas hepáticas antes e após a remissão bioquímica. Resultados: A frequência dos alelos das mutações foi significativamente mais elevada nos pacientes com PCT para C282Y (8...

Hereditary hemochromatosis: cellular response to oxidative stress; Hemocromatose hereditária: resposta celular ao stress oxidativo

Andrade, Lara Filipe Rocha
Fonte: Universidade de Aveiro Publicador: Universidade de Aveiro
Tipo: Dissertação de Mestrado
ENG
Relevância na Pesquisa
66.89%
Iron is a key element for basic cellular functions. If iron homeostasis is not maintained it may lead to iron overload. Patients with Hereditary Hemochromatosis (HH) and with the C282Y HFE mutation have a progressive severe iron overload that, if it is not treated, may lead to tissue damage, that mostly culminate in hepatic cirrhosis and carcinoma. Having in mind that tissue damage in HH may be related with oxidative stress (OS) caused by iron toxicity, it is important to understand in what way the OS defense is acting in cells from HH patients with severe forms of iron overload. Few studies have been performed concerning the eventual prooxidant state in blood cells, which bear a major source of OS. Nevertheless, in a recent study it was shown that cultured lymphocytes (LY) from HH, when compared with cultured LY from controls and patients with secondary forms of hemochromatosis, have an increased protection against chromosome instability (CI) induced by 1,2:3,4 diepoxybutane (DEB) – an OS-related alkylating agent. This suggests an adaptive response of HH cells to the high level of OS. However, it is not known yet if the same response can be observed with other sources of iron toxicity, namely in the presence of bleomycin (BLM), that acts forming a complex with non-transferrin bound iron (NTBI). In order to better understand the oxidant status of HH blood cells and the putative adaptive response of HH cells to iron toxicity...

The soluble transferrin receptor as a marker of iron homeostasis in normal subjects and in HFE-related hemochromatosis

Brandâo, M.; Oliveira, J.; Bravo, F.; Reis, J.; Garrido, I.; Porto, G.
Fonte: Ferrata Storti Foundation Publicador: Ferrata Storti Foundation
Tipo: Artigo de Revista Científica
Publicado em //2005 ENG
Relevância na Pesquisa
56.71%
Background and Objectives. The soluble transferrin receptor (sTfR) is a clinical marker of erythropoietic activity, also used in the diagnosis of iron deficiency. In the present paper we explore the meaning of this parameter in normal physiological conditions of iron homeostasis and in the setting of iron overload due to hereditary hemochromatosis (HH). Design and Methods. Reference values for sTfR were established in a population of 42 apparently healthy subjects, analyzed in relation to other hematologic parameters, namely, hemoglobin (Hb), mean corpuscular volume (MCV), transferrin saturation (TfSat) and serum ferritin. The same analysis was done in a group of 45 patients with HH who were homozygous for the C282Y mutation of HFE and had a wide range of TfSat values. In addition, individual serial profiles were analyzed in three patients. Results. In normal subjects circulating sTfR correlated significantly with the TfSat level, reflecting the systemic effect of iron availability on the erythropoietic activity in a normal physiological steady state. A TfSat of 25% appeared as a threshold value, below which there was a progressive increase in sTfR; this increase in sTfR occurred concomitantly with a decrease in Hb, MCV and serum ferritin. In HH patients the up-regulation of sTfR started at TfSat values as high as 50%. Interpretation and Conclusions. The fact that sTfR up-regulation started at higher TfSat values in HH patients suggests that the recognition of systemic iron available for erythropoiesis is altered in this condition. Based on these results...

Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis

Camacho, A; Funck-Brentano, T; Simão, M; Cancela, L; Ottaviani, S; Cohen-Solal, M; Richette, P
Fonte: Plos One Publicador: Plos One
Tipo: Artigo de Revista Científica
Publicado em //2015 ENG
Relevância na Pesquisa
56.79%
OBJECTIVE: Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. METHODS: A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. RESULTS: In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%)...

Effect of C282Y Genotype on Self-Reported Musculoskeletal Complications in Hereditary Hemochromatosis

Camacho, A; Funck-Brentano, T; Simão, M; Cancela, L; Ottaviani, S; Cohen-Solal, M; Richette, P
Fonte: Plos One Publicador: Plos One
Tipo: Artigo de Revista Científica
Publicado em //2015 ENG
Relevância na Pesquisa
56.79%
OBJECTIVE: Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. METHODS: A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. RESULTS: In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) µg/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%)...

Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis

Ferreira,Alessandro C. S.; Oliveira,Vanessa C.; Caxito,Fabíola A.; Gomes,Karina B.; Castro,Amanda M.; Pardini,Victor C.
Fonte: Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular Publicador: Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2008 EN
Relevância na Pesquisa
57%
Classical hereditary hemochromatosis is a recessive autosomal disease related to a systemic iron overload that is frequently related to C282Y and H63D mutations in the HFE gene. In Brazil, reports on HFE gene mutation frequencies are rare, mainly in regards to a representative sample population. This study intended to determine the prevalence of C282Y and H63D mutations among individuals with clinical suspicion of hereditary hemochromatosis. A total of 1955 patients were studied with C282Y and H63D mutations being detected by the polymerase chain reaction technique followed by enzymatic restriction. The sample consisted of 76.6% men and 23.4% women. The highest percentage of analyzed individuals (56.9%) was concentrated in the 41 to 60-year-old age group. Although there were no genic or genotypic differences between genders, a higher number of over 60-year-old women was observed. The C282Y mutation was found as homozygous in 2.9% of the cases and as heterozygous in 10.1%, while the H63D was homozygous in 4.3% and heterozygous in 30.6%. The C282Y and H63D mutant allele frequencies were 0.079 and 0.196, respectively. The highest frequency was observed for H63D which was in genetic equilibrium. This work is important to determine the genetic profile of the population with hereditary hemochromatosis in Brazi.

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis

Bittencourt,Paulo Lisboa; Marin,Maria Lúcia Carnevale; Couto,Cláudia Alves; Cançado,Eduardo Luiz Rachid; Carrilho,Flair José; Goldberg,Anna Carla
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2009 EN
Relevância na Pesquisa
56.71%
BACKGROUND: Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). AIMS: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS: Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A®. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. RESULTS: In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. CONCLUSIONS: One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A.

Edwards, C Q; Griffen, L M; Dadone, M M; Skolnick, M H; Kushner, J P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1986 EN
Relevância na Pesquisa
47.07%
We studied a family with HLA-linked hereditary hemochromatosis in which an informative recombination occurred within the HLA region. The father, an obligate heterozygote for hereditary hemochromatosis, had HLA haplotypes A2,B13 and A11,B27. The mother, also an obligate heterozygote, had HLA haplotypes A29,B44 and A2,B7. Three haplotypes were found among three homozygous affected offspring. Two affected siblings were HLA-identical with haplotypes A2,B13 and A29,B44. The proband had HLA haplotypes A2,B13 and A2,B44, the latter a recombinant haplotype inherited from her mother. Since the maternal hemochromatosis allele was linked to the A29,B44 haplotype, and since the proband has hemochromatosis, the maternal hemochromatosis allele was transmitted to the proband with the B44 antigen. This is the first known example of recombination in an individual with HLA-linked hemochromatosis in whom the hemochromatosis allele appeared to segregate with the HLA-B antigen instead of the -A antigen. The possibility of either a double reciprocal recombination event or a gene conversion event cannot be excluded. Combined with earlier observations of segregation of the hemochromatosis allele with the A locus in HLA recombinants, the findings in this pedigree map the hemochromatosis locus between the HLA-B and HLA-A loci rather than outside the HLA region.

HFE gene mutation, C282Y causing hereditary hemochromatosis in Caucasian is extremely rare in Korean population.

Lee, J. Y.; Yoo, K. H.; Hahn, S. H.
Fonte: Korean Academy of Medical Sciences Publicador: Korean Academy of Medical Sciences
Tipo: Artigo de Revista Científica
Publicado em /04/2000 EN
Relevância na Pesquisa
47%
Hereditary hemochromatosis (HFE), which affects 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals in Western population, results in multiple organ damage caused by iron deposition, and is treatable if detected early. C282Y mutation in HFE gene has been known to be responsible for the most hereditary hemochromatosis cases and 5-10% of white subjects are heterozygous for this mutation. However, the prevalence of hemochromatosis in the Asian population was reported to be very low and ethnic heterogeneity has been suspected. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutations in 502 unrelated Koreans. Results revealed that none of them had the mutant gene, suggesting a significant ethnic difference when compared with Caucasians. Our study excluded underlying possibility of hereditary hemochromatosis in Korean which could mimic the findings of alcoholic liver disease with iron overload or liver cirrhosis with chronic hepatitis C.

The C282Y polymorphism of the hereditary hemochromatosis gene is associated with increased sex hormone-binding globulin and normal testosterone levels in men

Yeap, B.; Beilin, J.; Shi, Z.; Knuiman, M.; Olynyk, J.; Chubb, S.; Bruce, D.; Milward, E.
Fonte: Editrice Kurtis S R L Publicador: Editrice Kurtis S R L
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
56.71%
BACKGROUND: Hereditary hemochromatosis resulting either from homozygosity for the C282Y polymorphism of the HFE gene, or compound heterozygosity for C282Y and H63D, manifests with liver disease and hypogonadism. However, it is unclear whether men who are heterozygotes for C282Y or H63D exhibit subtle abnormalities of sex hormone status. AIMS: To evaluate whether heterozygosity for either of the HFE gene polymorphisms C282Y or H63D is associated with circulating testosterone and SHBG in men. SUBJECTS AND METHODS: We performed a cross-sectional analysis of 388 community-dwelling men. Men were genotyped for C282Y and H63D. Sera were analysed for testosterone and SHBG, and insulin resistance was estimated using a homeostatic model (HOMA2-IR). RESULTS: Mean age of men in the cohort was 56.9 yr. Men who were heterozygous for the C282Y polymorphism in the HFE gene had higher SHBG levels than men who did not carry this polymorphism (mean ± SE, 38.2 ± 1.64 vs 32.8 ± 0.71 nmol/l, p=0.006). Total and free testosterone levels did not differ in the two groups. In multivariate analysis adjusting for potential confounders including age, waist circumference, testosterone, and HOMA2-IR, C282Y heterozygosity remained associated with SHBG levels (p<0.001). CONCLUSION: The C282Y polymorphism is associated with SHBG levels in men who do not manifest iron overload. Further studies are needed to clarify potential mechanisms and determine the clinical relevance of this finding.; http://www.ncbi.nlm.nih.gov/pubmed/20160468; B.B. Yeap...

Prevalence of alpha-1 antitrypsin deficiency and hereditary hemochromatosis gene mutations in Algarve, Portugal

Barreto da Silva, Marta; Gaio, Vânia; Fernandes, Aida; Mendonça, Francisco; Horta Correia, Filomena; Beleza, Álvaro; Gil, Ana Paula; Bourbon, Mafalda; Vicente, Astrid; Matias Dias, Carlos
Fonte: Instituto Nacional de Saúde Doutor Ricardo Jorge, IP Publicador: Instituto Nacional de Saúde Doutor Ricardo Jorge, IP
Tipo: Conferência ou Objeto de Conferência
Publicado em /10/2012 ENG
Relevância na Pesquisa
66.81%
Alpha-1 antitrypsin (AAT) deficiency and hereditary hemochromatosis (HH) are two of the most fatal genetic disorders in adult life, affecting million individuals worldwide. They are often under-diagnosed conditions and diagnosis is only made when the patient is already in the advanced stages of damage. AAT deficiency results from mutations in one highly pleiomorphic gene located on chromosome 14, SERPINA 1, being Z and S mutations the most relevant clinically. These mutations will lead to an AAT deficit that compromises the lungs protection, originating emphysema, chronic bronchitis, asthma or even chronic obstructive pulmonary disease (COPD) and it is also strongly associated with various liver diseases. On the other hand, C282Y and H63D mutations in the HFE gene, located on chromosome 6, are reported to be mostly responsible for the iron accumulation in HH disorder, leading to severe damage in different organs. Disease manifestations include cirrhosis, hepatic fibrosis, diabetes mellitus, arthropathy and hepatocarcinoma. Given the insufficient population-based information about the prevalence of these gene variants in the Portuguese population, the aim of this study was to assess their frequency in a representative sample from São Brás de Alportel...

Análise das mutações C282Y e H63D no gene da proteína HFE em pacientes com hiperferritinemia

Leão, Gioconda Dias Rodrigues
Fonte: Universidade Federal do Rio Grande do Norte; BR; UFRN; Programa de Pós-Graduação em Ciências Farmacêuticas; Bioanálises e Medicamentos Publicador: Universidade Federal do Rio Grande do Norte; BR; UFRN; Programa de Pós-Graduação em Ciências Farmacêuticas; Bioanálises e Medicamentos
Tipo: Dissertação Formato: application/pdf
POR
Relevância na Pesquisa
47.1%
Hereditary Hemochromatosis (HH) is a genetic disease caused by high iron absorption and deposition in several organs. This accumulation results in clinical disturbances such as cirrhosis, arthritis, cardiopathies, diabetes, sexual disorders and skin darkening. The H63D and C282Y mutations are well defined in the hemochromatosis etiology. The aim of this paper was that of identifying the H63D and C282Y genetical mutations in the hemochromatosis gene and the frequency assessment of these mutations in the HFE protein gene in patients with hyperferritin which are sent to the DNA Center laboratory in Natal, state of Rio Grande do Norte. This paper also evaluates the HH H63D and C282Y gene mutations genotype correlation with the serum ferritin concentration, glucose, alanine aminotransferasis, aspartato aminotransferasis, gama glutamil transferasis and with the clinical complications and also the interrelation with life habits including alcoholism and iron overload. The biochemical dosages and molecule analyses are done respectively by the enzymatic method and PCR with enzymatic restriction. Out of the 183 patients investigated, 51,4% showed no mutation and 48,6% showed some type of mutation: 5,0% were C282Y heterozygous mutation; 1...

Hereditary hemochromatosis: An opportunity for gene therapy

Asenjo de Leuze, Juan Alfonso; Núñez, Marco T.; Israel, Yedy; Rojas, Alejandro; Ezquer, Fernando
Fonte: SOCIEDAD BIOLGIA CHILE Publicador: SOCIEDAD BIOLGIA CHILE
Tipo: Artículo de revista
EN
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57.11%
Levels of body iron should be tightly controlled to prevent the formation of oxygen radicals. lipoperoxidation. genotoxicity, and the production of cytotoxic cytokines, which result in damage to a number of organs. Enterocytes ill the intestinal villae are involved in the apical uptake of iron from the intestinal lumen: iron is further exported from the cells into the circulation. The apical divalent metal transporter-1 (DMT1) transports ferrous iron from the lumen into the cells, while the basolateral transporter ferroportin extrudes iron front the enterocytes into the circulation. Patients with hereditary hemochromatosis display all accelerated transepithelial uptake of iron, which leads to body iron accumulation that results in cirrhosis. Hepatocellular carcinoma, pancreatitis, and cardiomyopathy. Hereditary hemochromatosis. a recessive genetic condition, is the most prevalent genetic disease in Caucasians, with a prevalence of one in 300 subjects. The majority of patients with hereditary hemochromatosis display mutations in the gene coding for HFE. a protein that normally acts as all inhibitor of transepithelial iron transport. We discuss the different control points ill the homeostasis of iron and the different mutations that exist in patients with hereditary hemochromatosis. These control sites may be influenced by gene therapeutic approaches: one general therapy for hemochromatosis of different etiologies is the inhibition of DMT1 synthesis by antisense-generating genes...

Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis

Bittencourt, Paulo Lisboa; Marin, Maria Lúcia Carnevale; Couto, Cláudia Alves; Cançado, Eduardo Luiz Rachid; Carrilho, Flair José; Goldberg, Anna Carla
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; ; ; ; ; Formato: application/pdf
Publicado em 01/01/2009 ENG
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BACKGROUND: Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). AIMS: To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS: Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A®. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. RESULTS: In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. CONCLUSIONS: One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.

Hereditary hemochromatosis

Geller, Stephen A.; Campos, Fernando Peixoto Ferraz de
Fonte: Universidade de São Paulo. Hospital Universitário Publicador: Universidade de São Paulo. Hospital Universitário
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; Peer-reviewed Article Formato: application/pdf
Publicado em 31/03/2015 ENG
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Hereditary hemochromatosis (HH) is the most commonly identified autosomal recessive genetic disorder in the white population, characterized by increased intestinal iron absorption and secondary abnormal accumulation in parenchymal organs, not infrequently accompanied by functional impairment. This entity is associated with mutations of the HFE gene (located on the short arm of chromosome 6 at location 6p22.2; closely linked to the HLA-A3 locus), which encodes the HFE protein, a membrane protein thought to regulate iron absorption by affecting the interaction between transferrin receptor and transferrin.

Iron Overload in a Murine Model of Hereditary Hemochromatosis Is Associated with Accelerated Progression of Osteoarthritis Under Mechanical Stress

Camacho, A; Simão, M; Ea, H-K; Cohen-Solal, M; Richette, P; Branco, J; Cancela, M L
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
Publicado em 25/09/2015 ENG
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OBJECTIVE: Hereditary hemochromatosis (HH) is a disease caused by mutations in the Hfe gene characterised by systemic iron overload and associated with an increased prevalence of osteoarthritis (OA) but the role of iron overload in the development of OA is still undefined. To further understand the molecular mechanisms involved we have used a murine model of HH and studied the progression of experimental OA under mechanical stress. DESIGN: OA was surgically induced in the knee joints of 10-week-old C57BL6 (wild-type) mice and Hfe-KO mice. OA progression was assessed using histology, micro CT, gene expression and immunohistochemistry at 8 weeks after surgery. RESULTS: Hfe-KO mice showed a systemic iron overload and an increased iron accumulation in the knee synovial membrane following surgery. The histological OA score was significantly higher in the Hfe-KO mice at 8 weeks after surgery. Micro CT study of the proximal tibia revealed increased subchondral bone volume and increased trabecular thickness. Gene expression and immunohistochemical analysis showed a significant increase in the expression of matrix metallopeptidase 3 (MMP-3) in the joints of Hfe-KO mice compared with control mice at 8 weeks after surgery. CONCLUSIONS: HH was associated with an accelerated development of OA in mice. Our findings suggest that synovial iron overload has a definite role in the progression of HH-related OA