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Andriopoulos, Bill. "Systemic iron distribution during hemochromatosis and inflammation." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18749.
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Juvenile hemochromatosis (JH), anemia of chronic disease (ACD) and various inflammatory conditions such as Hepatitis C and alcoholic steatohepatitis exhibit improper handling of systemic iron. Patients with JH have mutations in either the hemojuvelin (Hjv) or hepcidin genes. Hjv appears to control the levels of hepatic hepcidin, the master hormonal regulator of iron stores. Interestingly, Hjv exists in both a cellular and soluble form that is expressed primarily in the muscle and to a lesser extent in the liver. Cellular Hjv (cHjv), localized in the liver, is a GPI-anchored protein that enhances bone morphogenic protein (BMP) mediated induction of hepcidin. On the other hand, soluble Hjv (sHjv) is a negative regulator of hepatic hepcidin expression. We hypothesize that sHjv plays an important systemic role in regulating iron homeostasis. Thus, our goal was to 1) investigate the signals regulating shedding of muscle sHjv and 2) study the hormonal function of sHjv in the target liver. Surprisingly, using in vitro and in vivo models, we observed elevated release of Hjv during hemolytic conditions. Furthermore, in contrast to previously published reports, both cell culture and animal model studies reveal sHjv as a positive regulator of hepatic hepcidin. Upon induction of hepcidin expression in the liver, the hormonal peptide exerts its actions by binding and internalizing the iron exporter ferroportin in the reticuloendothelial system (RES) and duodenum. Using a co-culture system, we investigated the effects of secreted hepatic hepcidin on the iron metabolism of target monocytes. As a result, hepatic hepcidin was shown to inhibit iron export and promote iron retention within monocytes. Inappropriate levels of hepcidin, whether low or high, results in improper handling of iron stores which may potentially cause disease, on both sides of the iron spectrum. On one side of the scale, such as in hemochromatosis, inappropriately low hepcidin expression permits elevated mobL'hemochromatose juvénile (HJ), anémie de maladie chronique (ACD) et des conditions inflammatoires variées, telles que l'Hépatite C et la steatopathie de l'alcoolique démontrent la mauvaise manipulation du fer systémique. Les patients atteints de l'HJ ont des mutations dans soit, les gènes hemojuvelin (Hjv) ou hepcidine. Jusqu'à maintenant, Hjv semble contrôler les niveaux d'hepcidine hépatique, le régulateur maître pour les réserves de fer. D'autre part, l'Hjv soluble (sHjv) est un régulateur négatif d'expression d'hepcidine hépatique. Nous avons élaboré l'hypothèse que le sHjv joue un rôle systémique important dans la régulation d'homeostasie du fer. Alors, notre objectif était de 1) rechercher les signaux régulant la perte de muscle sHjv et 2) d'étudier la fonction hormonale du sHjv dans le foie cible. Étonnement, en utilisant des modèles in vitro et in vivo, nous avons observé la perte élevée de Hjv pendant des conditions hémolytiques. De plus, en contraste à des rapports précédemment publiés, les cultures cellulaires ainsi que les modèles basés sur les animaux révèlent que la sHjv et un régulateur positif d'hepcidine hépatique. Dès l'induction d'expression d'hepcidine dans le foie, la peptide hormonale exerce son action en fusionnant et en internalisant l'exportateur de fer, ferroportine dans le système réticuloendothélial (RES). En utilisant un système de co-culture, nous avons cherché les effets d'hepcidine hepatique secrété sur le métabolisme du fer de monocytes cibles. Des niveaux inappropriés de hepcidine, soit bas ou élevés, résultent dans la manipulation inappropriée des réserves de fer qui peuvent potentiellement mener à des maladies, des deux côtes du spectre de fer. D'un côté de la balance, tel que dans l'hémochromatose, des niveaux bas d'expression d'hepcidine permettent des niveaux de mobilisation élevés dans les réserves de fer du RES. La mobilisation accrue sature éventuellement s
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Andrade, Lara Filipe Rocha. "Hereditary hemochromatosis: cellular response to oxidative stress." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12495.
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Mestrado em Bioquímica - Bioquímica ClínicaIron 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, a study was performed to characterize two selected OS parameters: evaluation of reduced glutathione (GSH) depletion and of lipid peroxidation (LPO). The study was performed in red blood cells (RBC) and lymphocytes (LY), either basal and after 36h in culture, with and without induction of OS. Induction of OS was performed with DEB and with BLM. A second objective of the present work was to test if the previously observed adaptive response of HH cells to DEB-induced OS can also be observed after induction with BLM. Characterization of the OS parameters was performed in RBC and LY from 5 HH patients with severe iron overload and 6 healthy donors (HD), at day 0 and after 36h of culture, non-treated and treated with DEB or BLM. Studies of CI were performed in BLM-induced LY from the same 5 HH patients and 6 HD. The results show that RBC from HH patients, compared with those from HD, have a larger GSH depletion and more LPO, either at day 0 and after 36h in culture medium. This suggests an increased level of OS in HH RBC. On the contrary, LY from HH patients present less GSH depletion after 36h of culture than LY from HD, being this effect more pronounced in DEB and BLM-treated cultures. Additionally, LPO levels were decreased in LY from HH patients after 36h of culture when compared with LY from HD. This result suggests that HH cultured LY, either non-treated or treated with DEB and BLM, have a still not completely understood mechanism of defense against OS. BLM-induced CI in cultured LY from HH patients was not different from the observed in cultured LY from HD. Therefore, we can postulate that toxicity induced by BLM did not increased CI in cells from HH patients with severe iron overload.
O ferro é um dos elementos chave para as funções celulares básicas. Se a sua homeostasia não for corretamente mantida, poderá ocorrer uma sobrecarga de ferro no organismo. Os doentes com Hemocromatose Hereditária (HH), com a mutação C282Y no gene HFE, possuem uma progressiva e severa sobrecarga de ferro que, se não for tratada, pode levar a dano nos tecidos, podendo mesmo culminar em cirrose hepática e carcinoma. Tendo em conta que o dano tecidular pode estar associado ao stress oxidativo (OS) causado pela sobrecarga de ferro, é importante perceber de que modo atua o sistema de defesa contra o OS nas células dos doentes HH com forma severa de sobrecarga de ferro. Poucos estudos foram realizados sobre o potencial estado oxidante nas células do sangue, onde se encontra uma das maiores fontes de reações oxidativas. Contudo, num estudo recente foi demonstrado que linfócitos de doentes com HH, quando comparados com linfócitos de controlos e pacientes com formas secundárias de hemocromatose, apresentam uma maior proteção relativamente à instabilidade cromossómica (CI) induzida por 1,2:3,4 diepoxibutano (DEB) – um agente alquilante que provoca OS. Este estudo sugere uma resposta adaptativa das células HH a níveis elevados de OS. No entanto, ainda não se sabe se esta mesma resposta pode ser observada com outras fontes de toxicidade do ferro, nomeadamente na presença de bleomicina (BLM) cuja atividade depende da formação de complexos com o ferro não ligado à transferrina (NTBI). Para compreender melhor o estado oxidante das células do sangue dos doentes HH e a suposta resposta adaptativa das células dos doentes de HH à toxicidade do ferro, foi feita a análise de dois parâmetros de OS selecionados: avaliação da depleção da glutationa reduzida (GSH) e da peroxidação lipídica (LPO). Esta análise foi efetuada em eritrócitos (RBC) e linfócitos (LY), tanto no tempo 0 como passadas 36h em cultura, com ou sem indução de OS. O segundo objetivo deste trabalho foi testar se a BLM promove uma resposta adaptativa à CI comparável à que foi observada com o DEB. Tanto a caracterização dos parâmetros de OS como os estudos de CI foram efetuados em células de 5 doentes com HH, com elevada sobrecarga de ferro, e em células de 6 dadores saudáveis (HD). Os resultados mostraram que os RBC dos doentes com HH, comparativamente com os dos HD, apresentam uma maior depleção de GSH e maior LPO, quer ao dia 0 quer após 36h em meio de cultura. Estes resultados sugerem um aumento de OS nos RBC dos doentes. Contrariamente, os LY dos doentes de HH apresentaram menor depleção de GSH após 36h de cultura, sendo esta mais notória nas culturas induzidas com DEB e BLM. Adicionalmente, os níveis de LPO são menores em LY dos doentes de HH, após 36h de cultura, comparativamente com os dos HD. Isto sugere que culturas de LY, quer não-tratadas quer tratadas com DEB ou BLM, têm um algum tipo de mecanismo de defesa contra o OS, ainda não compreendido. A frequência de CI induzida por BLM em LY de doentes com HH não é significativamente diferente da observada em LY de HD, não se observando assim uma diferença na capacidade de resposta à BLM, entre células de doentes e controlos. Pode-se então concluir que a toxicidade induzida por BLM não aumenta a CI em células de doentes com HH com forma severa de sobrecarga de ferro.
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Pratiwi, Rarastoeti. "Genetic analysis of haemochromatosis and characterisation of the role of HFE in iron metabolism /." [St. Lucia, Qld.], 2000. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16204.pdf.
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Hagen, Karin. "Studies on genetic hemochromatosis and the hepatotoxicity of iron /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-201-9/.
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Gomes, Cidália Maria Teixeira. "HLA and hemochromatosis disease association in São Miguel Island." Master's thesis, Universidade de Aveiro, 2008. http://hdl.handle.net/10773/792.
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Mestrado em Biologia Molecular e CelularA hemocromatose hereditária uma doença autossómica recessiva do metabolismo do ferro, geralmente associada à mutação C282Y no gene HFE. Presume-se que a origem desta mutação tenha ocorrido por acaso no haplótipo HLA-A*03-B*07 de um indivíduo do noroeste da Europa. O presente trabalho visou caracterizar a associação entre os alelos e haplótipos dos loci HLA-A e -B com a mutação C282Y na população da ilha de São Miguel (Açores). Este estudo englobou 130 indivíduos, negativos para as mutações HFE H63D e S65C, que foram classificados em dois grupos: grupo C282Y (48 homozigóticos ou portadores da C282Y) e grupo controlo (82 dadores de sangue sem as três mutações no gene HFE). Para todos os indivíduos, foi efectuado a genotipagem HLA-A e -B por PCR-SSP e a detecção das mutações HFE por PCR-RFLP. A análise estatística revelou que quatro alelos – A*03 (p=0.003, OR=3.33), A*26 (p=0.003, OR=8.38), A*29 (p<0.001, OR=19.18) e B*45 (p=0.003, OR=8.37) – encontram-se significativamente aumentados no grupo C282Y. Os resultados demonstram, igualmente, uma associação significativa com a mutação C282Y para o haplótipo ancestral HLA-A*03-B*07 (p=0.006, OR=8.96) e dois haplótipos não ancestrais: A*02-B*58 (p<0.001, OR=19.78) e A*29-B*45 (p<0.001, OR=27.57). Além disso, outro haplótipo A*24-B*15 foi detectado por inferência directa num doente homozigótico para o HLA-A-B e para a mutação C282Y. Provavelmente, o mecanismo genético de recombinação gerou esta diversidade de haplótipos; no entanto, não se pode excluir a hipótese de uma mutação C282Y de novo no gene HFE associada ao haplótipo HLA-A*24-B*15. Em conclusão, além do haplótipo ancestral A*03-B*07, três novos haplótipos – A*02-B*58, A*24-B*15 e A*29-B*45 – sugerem estar associados à mutação C282Y na população da ilha de São Miguel. A elevada diversidade genética observada na população açoriana pode explicar a associação entre a mutação C282Y e os haplótipos HLA.
Hereditary hemochromatosis is an autosomal recessive disease of the iron metabolism, where HFE C282Y is commonly implicated. This mutation seems to have originated by chance on the HLA-A*03-B*07 haplotype in a northwestern European individual, and spread by migration. Given that recombination generates new haplotypes, the present investigation aimed to characterize the chromosomal background of C282Y in the São Miguel Island population (Azores). This study comprises 130 individuals, all negative for H63D and S65C, which were classified into two groups: 48 homozygous or carriers for C282Y, and 82 healthy individuals without these mutations. The subjects were HLA-A and -B genotyped by PCR-SSP, and HFE mutation detection was performed by PCR-RFLP. Statistical analysis revealed that four alleles – A*03 (p=0.003, OR=3.33), A*26 (p=0.003, OR=8.38), A*29 (p<0.001, OR=19.18) and B*45 (p=0.003 OR=8.37) – and the A*03-B*07 haplotype (p=0.006, OR=8.96) were significantly increased in the C282Y group. Two non-ancestral haplotypes were also significantly associated with C282Y: A*02-B*58 (p<0.001, OR=19.78) and A*29-B*45 (p<0.001, OR=27.57). This last haplotype showed the strongest association to the mutation in study, suggesting that it may be the principal hemochromatosis-haplotype in São Miguel Island population. Another haplotype – A*24-B*15 – was detected by direct inference in a C282Y and HLA-A-B homozygous patient. Recombination most probably generated these haplotypes, before or after the island settlement. However, we can not exclude the hypothesis of a recent de novo HFE C282Y mutation on the A*24-B*15 haplotype in an individual living in the São Miguel Island. Overall, in this population, besides the ancestral A*03-B*07, three new non-ancestral haplotypes – A*02-B*58, A*24-B*15 and A*29-B*45 – appear to be associated with C282Y. The association between this recessive mutation and these haplotypes undoubtedly reflects the high genetic diversity observed in the Azoreans.
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Berlin, Daniel. "The role of HFE (hemochromatosis) gene mutations in sporadic Alzheimer disease /." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78245.
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Although a central etiology for Alzheimer disease (AD) has not yet been determined, support has amassed for the notion that oxidative stress may be involved in the pathogenesis of AD. The disruption of iron homeostasis and iron's excessive deposition in AD brain tissues has received increased attention due to the metal's capacity to promote the production of harmful free radicals. Several studies have recently examined whether DNA mutations involved in the iron overload disorder, hemochromatosis, pose an increased risk of acquiring AD. However, the small sample size and low generalizability of previous studies have warranted further investigation. We genotyped 213 AD patients, 106 Mild Cognitively Impaired (MCI) individuals, and 63 Normal Elderly Control (NEC) subjects for the H63D and C282Y HFE mutations to examine whether a relationship exists between HFE gene status and AD presentation in our patient population. DNA analysis was conducted by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). We did not find any statistically significant associations between HFE gene status and the clinical, demographic, or neuropsychological aspects of AD in our patient population. Interesting trends that fell short of statistical significance included: (a) a deleterious effect of HFE mutations on motor performance, (b) an influence of H63D homozygosity on an earlier onset of cognitive decline, and (c) an influence of H63D homozygosity on an accelerated progression from MCI to AD.
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Dixon, Jeannette. "Screening for hereditary haemochromatosis : a pilot study /." [St. Lucia, Qld. : s.n.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17400.pdf.
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Shearman, Jeremy David. "The molecular genetics of haemochromatosis." Thesis, University of Oxford, 1996. http://ora.ox.ac.uk/objects/uuid:ecb03d17-3cbf-4147-91aa-f252a2e5137e.
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Haemochromatosis is the most common single gene disorder to afflict North- West European populations. It is probably the most common genetic disorder of iron metabolism worldwide. As many as 1 in 250 people in the UK are affected and although the phenotype causes only a mild increase in gastrointestinal iron absorption a proportion of affected individuals will accumulate sufficient iron over their life-time to cause cirrhosis and hepatocellular carcinoma. Venesection treatment instituted before cirrhosis has established ensures a normal life expectancy, but clinical presentation is often late in life after irreversible organ injury has occurred. Identification of people at risk in the early, asymptomatic stage by measurements of iron status is unreliable. The genetic defect responsible for haemochromatosis has been sought in the hope that its identification might facilitate early diagnosis and that studies on the gene product would lead to a greater understanding of the mechanisms of mammalian iron absorption. Genetic linkage to HLA-A3 placed the gene responsible for haemchromatosis in, or close to, the major histocompatibilty complex (MHC) on the short arm of chromosome 6 and a positional cloning strategy has been adopted. This thesis describes work directed to the identification of the haemochromatosis gene by positional cloning. The region telomeric to the MHC was mapped using yeast artificial chromosomes, from which new microsatellites were isolated. These markers were used in linkage disequilibrium analyses and the mapping of a recombination breakpoint that defined a haemochromatosis gene region. This region was physically mapped in fine detail and positional candidates sought by EST database analysis. Before a systematic search for genes in the region began a strong positional candidate was reported (Feder et al 1996). Analysis of this mutation in patients from the UK confirmed this to be the ancestral haemochromatosis mutation.
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Chamoun, Stephanie, and Sarajlic Medina. "Genotypning av HFE c.845G>A, HFE c.187C>G och HFE c.193A>T för hemokromatos med hjälp av Realtids-Polymerase Chain Reaction : En kvalitetsutvecklande studie i Jönköpings län." Thesis, Hälsohögskolan, Högskolan i Jönköping, HHJ, Avd. för naturvetenskap och biomedicin, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-30788.
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Hereditär hemokromatos (HH) är en vanlig multigenetisk defekt som leder till ett onormalt förhöjt järnupptag i tarmen och ses framförallt hos kaukasisk befolkning. Sjukdomen har på senare år visats orsakats av mutationen c.845G>A men även mer ovanliga varianter som c.187C>G och c.193A>T, vilka alla finns belägna i genen HFE. HFE som finns lokaliserad intill Human Leukocyte Antigen (HLA)-genen på kromosom sex korta arm kodar för ett HFE-protein som har till uppgift att reglera kroppens järnmetabolism i interaktion med hormonet hepcidin. Vid HH avtar proteinets järnregulatoriska funktion och järnackumulation uppstår. Idag diagnostiseras HH främst via genotypning där ovanstående genvarianter påvisas. Beroende på genvariant löper individer olika hög risk för sjukdomsutveckling. I studien var syftet att verifiera det kommersiella kitet LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y diagnostics kit för kvalitativ diagnostik av HFE-genotyper via Realtids-Polymerase Chain Reaction (PCR) via smältkurveanalys för eventuell införsel i rutindiagnostik. I studien kunde samtliga patientprover (n=49) ifrån Halmstad med misstänkt hemokromatos genotypas för genvarianterna i HFE-genen. Utifrån godkända resultat i prov-till-prov variation tillsammans med icke-frekventa skillnader i imprecisionstest samt 100 % samstämmighet gentemot referensmetoder på externa laboratorier, kunde slutsatsen dras att metoden är relevant för rutinverksamheten på Länssjukhuset Ryhov, Region Jönköpings Län.Hereditary hemochromatosis (HH) is a common multi-genetic defect that results in abnormally elevated iron uptake mainly in Caucasian populations. The disease has recently been found to be caused by mutation c.845G>A, in addition to the unusual variants c.187C>G and c.193A>T, all of which are detected in the gene HFE. HFE is located adjacent to the Human Leukocyte Antigen (HLA)-gene on chromosome six’s short arm and encodes for a HFE-protein, responsible for the body's iron metabolism regulation in interaction with the hormone hepcidin. As HH decreases the protein's iron-regulatory function, the iron accumulation increases. Today HH is diagnosed primarily through genotyping where variants in the HFE-gene are detected. Depending on the variant, individuals are put at varying high risk of disease development. The aim of this study was to verify the commercial LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y for qualitative diagnosis of HFE-genotypes through Real-time Polymerase Chain Reaction (PCR) and melting-curve analysis for possible introduction in routine diagnostics. In the study, all samples (n=49) from patients with suspicious hemochromatosis were genotyped for the gene variants in HFE-gene. Based on all accepted results with non-frequent differences in imprecision test and 100 % consistency against the reference methods at external laboratories conclusions could be drawn that the method is applicable for routine diagnostics at the County Hospital Ryhov in Region Jönköping.
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Hallendorff, Michelle-Angelique. "Ironing out haemochromatosis : a study of an Indian family." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21458.
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Thesis (MSc)--University of Stellenbosch, 2008.ENGLISH ABSTRACT: Iron metabolism disorders comprise the most common disorders in humans. Hereditary haemochromatosis (HH) is a common condition resulting from inappropriate iron absorption. The most common form of the disease (Type 1) is associated with mutations in the HFE gene. The C282Y homozygous genotype accounts for approximately 80% of all reported cases of HH within the Caucasian population. A second HFE mutation, H63D, is associated with less severe disease expression. The C282Y mutation is extremely rare in Asian and African populations. The H63D mutation is more prevalent and has been observed in almost all populations. Iron overload resulting from haemochromatosis is predicted to be rare in Asian Indian populations and is not associated with common HFE mutations that are responsible for HH in the Caucasian population. The aberrant genes associated with HH in India have not yet been identified. The present study attempted to identify variants in six iron regulatory genes that were resulting in the Type 1 HH phenotype observed in two Asian Indian probands from a highly consanguineous family. The promoter and coding regions of the HMOX1, HFE, HAMP, SLC40A1, CYBRD1 and HJV genes were subjected to mutation analysis. Gene fragments were amplified employing the polymerase chain reaction (PCR) and subsequently subjected to heteroduplex single-strand conformational polymorphism (HEX-SSCP) analysis. Samples displaying aberrations were then analysed using bi-directional semi-automated DNA sequencing analysis to identify any known or novel variants within the six genes. Variants disrupting restriction enzyme recognition sites were genotyped employing restriction fragment length polymorphism (RFLP) analysis. Mutation analysis of the six genes revealed 24 previously identified variants, five novel variants (HFE: 5’UTR-840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR- 1272T→C; HJV: 5’UTR-534G→T, 5’UTR-530G→T), one previously described microsatellite and two novel repeats. Variants identified within the SLC40A1, CYBRD1 and HJV genes do not seem to be associated with the iron overload phenotype. A previously described HAMP variant (5’UTR-335G→T) was observed in the homozygous state in both probands. This variant seems to be the genetic aberration responsible for iron overload in this Indian family. The severe juvenile haemochromatosis phenotype usually associated with HAMP mutations, was not exhibited by the two Indian probands. Their symptoms resembled those observed in classic Type 1 HH. It is suggested that variants identified in the HMOX1 and HFE genes are modifying the effect of the HAMP variant and resulting in the less severe disease phenotype. Although this variant has only been identified in one Indian family, it could shed some light in the hunt for the iron-loading gene in India.
AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is ‘n algemene siektetoestand wat ontstaan as gevolg van oneffektiewe opname van yster in die liggaam. Die mees algemene vorm van die siekte (Tipe 1) word geassosieer met mutasies in die HFE-geen. Die C282Y homosigotiese genotipe is verantwoordelik vir ongeveer 80% van alle gerapporteerde gevalle van OH binne die Kaukasiese bevolking. ‘n Tweede HFE mutasie, H63D, word geassosieer met minder ernstige siekte simptome. Die C282Y mutasie is besonder skaars in Asiese en Afrika bevolkings. Daar word bespiegel dat oorerflike ysteroorlading as gevolg van hemochromatose skaars is in Asiese Indiër bevolkings en word nie geassosieer met algemene HFE mutasies wat verantwoordelik is vir OH in Kaukasiese bevolkings nie. Die abnormale gene wat wél geassosieer word met OH in Indië is tot dusver nog nie identifiseer nie. Die doel van hierdie studie was om die variante in ses yster-regulerende gene te identifiseer wat die Tipe 1 OH fenotipe in hierdie familie veroorsaak. Hierdie fenotipe is waargeneem in twee Asies Indiese familielede afkomstig van ‘n bloedverwante familie. Die promotor en koderingsareas van die HMOX1, HFE, HAMP, SLC40A1, CYBRD1 en HJV gene is gesif vir mutasies. Geen fragmente is geamplifiseer met behulp van die polimerase kettingsreaksie (PKR) en daarna aan heterodupleks enkelstring konformasie polimorfisme (HEX-SSCP) analise blootgestel. PKR produkte wat variasies getoon het, is daarna geanaliseer deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise om enige bekende of nuwe variante binne die ses gene te identifiseer. Variante waar restriksie ensiem herkenningsetels teenwoordig is, is verder analiseer met behulp van die restriksie fragment lengte polimorfisme (RFLP) analise sisteem. Mutasie analise van die ses gene het 24 bekende variante, vyf nuwe variante (HFE: 5’UTR- 840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR-1272T→C, HJV: 5’UTR-534G→T, 5’UTR-530G→T), een bekende herhaling en twee nuwe herhalings gewys. Variante wat binne die SLC4041, CYBRD1 en HJV gene geïdentifiseer is, blyk nie om by te dra tot die ysteroorladings-fenotipe nie. Die bekende HAMP variant (5’UTR-335G→T) is waargeneem in die homosigotiese toestand in beide van die aangetaste individue. Hierdie variant blyk om die genetiese fout te wees wat verantwoordelik is vir die ysteroorlading in die betrokke Indiese familie. Die erge juvenielehemochromatose fenotipe wat meestal geassosieer word met HAMP-mutasies, is nie waargeneem in hierdie familie nie. Hul simptome kom ooreen met die simptome van die klassieke Tipe 1 OH. Dit blyk moontlik te wees dat die variante identifiseer in die HMOX1 en HFE gene die impak van die HAMP variant modifiseer en die matiger siekte-fenotipe tot gevolg het. Alhoewel hierdie variant slegs in een Indiese familie geïdentifiseer is, kan dit lig werp op die soektog na die veroorsakende ysterladingsgeen in Indië.
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Kamihara-Ting, Junne. "Studies at the hemochromatosis (HFE) locus : gene conversions, haplotypes, and association analysis." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34193.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2006.Includes bibliographical references.
Haplotype-based association studies offer an exciting potential methodology for the identification of genes that contribute to complex traits. There is thus great interest in understanding the biological forces that shape haplotypes. We have studied a well-characterized genetic locus surrounding the gene responsible for hereditary hemochromatosis (HFE) to investigate the impact of meiotic recombination events upon haplotype structure in this region. First we identified crossover hotspots in order to define the boundaries of haplotype blocks in this locus. We then found that gene conversion events play a significant role in shaping haplotype structure within these haplotype blocks. These gene conversion events were not limited to recombination hotspots and occurred with a frequency as high as 1 in 104 per site per generation. Gene conversions lead to the creation of new haplotypes and we suggest that they are important for the spread of disease alleles in a population. In addition, we discuss how these events can be used as important tools in haplotype-based association studies. We also present an association study in a large Venezuelan cohort to search for genes that contribute to residual age of onset in Huntington's disease. We demonstrate significant association between multiple alleles in a region on chromosome 6p21.3.
(cont.) We identify two candidate genes in this region, HFE and histone Hlt and demonstrate significant association of this region with age of onset in a male-specific model.
by Junne Kamihara-Ting.
Ph.D.
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Göhring, Claudia [Verfasser]. "Hepcidin knockout mice constitute a suitable mouse model for hereditary hemochromatosis / Claudia Göhring." Ulm : Universität Ulm. Medizinische Fakultät, 2015. http://d-nb.info/1076828523/34.
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Keller, Marianne Dorothea. "New applications of MRI in toxicological research to determine in vivo changes in liver and brain /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17517.pdf.
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Shiono, Yuhta, Hisao Hayashi, Shinnya Wakusawa, Fujiko Sanae, Toshikuni Takikawa, Motoyoshi Yano, Kenntaro Yoshioka, and Hiros Saito. "Body iron stores and Iron restoration rate in Japanese patients with chronic Hepatitis C as measured during therapeutic Iron removal revealed neither Increased body iron stores nor effects of C282y and H63d mutations on iron indices." Nagoya University School of Medicine, 2001. http://hdl.handle.net/2237/5367.
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Gay, Choon Lin Melvin. "Development of a mass spectrometry diagnostic assay to monitor hepcidin levels in hemochromatosis patients." Thesis, Gay, Choon Lin Melvin (2010) Development of a mass spectrometry diagnostic assay to monitor hepcidin levels in hemochromatosis patients. PhD thesis, Murdoch University, 2010. https://researchrepository.murdoch.edu.au/id/eprint/4875/.
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Hepcidin has been identified as the principle regulatory peptide essential for iron homeostasis. Expression of this cysteine-rich peptide is up-regulated by inflammation and iron overload, whereas hypoxia, iron deficiency and erythropoiesis suppress hepcidin expression. The quantitative analysis of hepcidin in bodily fluids will provide an insight into the pathogenesis of disorders of iron metabolism such as hereditary hemochromatosis.
A mass spectrometry-based approach was taken to detect and quantify urinary hepcidin as urine is readily available and collection of this sample type is non-invasive. Samples were first purified using micro solid phase extraction (μSPE), followed by matrix assisted laser desorption/ionization-orthogonal-time-of-flight mass spectrometry (MALDI-TOF-MS) with inclusion of an internal standard for the quantitative analysis of unlabelled urinary hepcidin.
Monoisotopic resolution of hepcidin-25 was observed with the MALDI-TOF-MS and extraction recovery of more than 70% was achieved. Spot-to-spot variations of less than 3.5% RSD and intra- and inter-day precision of less than 9.5% RSD was observed.
In our study, average hepcidin-25 levels of 1.7 nmol/mmol creatinine were observed in healthy subjects, compared to an average of 1.1 nmol hepcidin-25/mmol creatinine in hemochromatosis patients. In one of the patients, the hepcidin level was below the detection limit (1.25 nM). From the stability experiments of hepcidin-25, it is recommended that urine samples be stored at -80oC and undergo minimal freeze-thaw cycles. It is also advised that extraction be carried out within 3 hours of thawing.
Preliminary analysis using LC-ESI-IT-MS showed multiple charge states of hepcidin-25. However, a variation of less than 5% in hepcidin-25 concentration was observed when the same sample was analyzed with both LC-MS and MALDI-TOF-MS, and thus they can be used to counter-validate each other.
In summary, a validated method has been developed for the quantification of unlabelled urinary hepcidin-25 which can be used to investigate the levels of hepcidin-25 in iron-related disorders.
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Mortimore, Marianne. "The regulation of monocyte and macrophage iron metabolism in heriditary haemochromatosis / Marianne Mortimore." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17518.pdf.
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Young, Megan. "General practitioners' familiarity with and practices related to haemochromatosis /." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17037.pdf.
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Ibrahim, MohD, Omer sheikh, Pratyksha Sankhyan, Qaryoute Ayah Al, Abdulrahman Ibrahim, Akilesh Mahajan, Nilesh Mahajan, Mohsen Pourmoteza, and Jason Mckinney. "Terbinafine induced fulminant hepatic failure and patient death." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/108.
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A 72 year-old-patient without known past medical history presented to the hospital with worsening cough, dyspnea on exertion, decreased appetite, weight loss for two months. Prior to admission, he was treated with a 10- day course of levofloxacin and prednisone as a case of bronchitis with minimal improvement. Then he started to develop red urine with marked changes in mental status. On physical examination, the patient had notifiable scleral icterus, confusion and abdominal tenderness in the right upper quadrant. On admission his labs were significant for alkaline phosphatase 541, aspartate transaminase 557, alanine transaminase 94, total bilirubin 8.6, lactate 11.7. CT scan of abdomen showed hepatosplenomegaly, mild ascites and trace bilateral pleural effusion. Work up with Viral hepatitis serology, cryptococcal antigen, histoplasma antigen, respiratory virus panel, Epstein Barr virus tests were negative. Anti-nuclear antibodies (ANA) and anti-mitochondrial antibody were also negative. Blood level of amylase, lipase, acetaminophen and alcohol were negative at admission too. The patient was started initially on broad spectrum antibiotics, N-acetyl cysteine empirically and aggressive intravenous fluid hydration. Patient condition rapidly worsened and he developed profound shock requiring mechanical ventilation and started on stress dose steroid and pressor support. Upon further investigation, patient was noted to take terbinafine for toe onychomycosis (day 112). Ferritin level was elevated to 1596 with 93% iron saturation. Ceruloplasmin level was normal. Patient was not a transplant candidate due to multiple organ failure. As per family request, patient was palliatively extubated and died.
Terbinafine is a fungicidal drug with activity against dermatophytes including Epidermophyton flccosum and trichophyton rubrum. It works by inhibition of squalene epoxidase with a resultant accumulation of squalene in the fungal cell and killing it as a result. Commonly used orally to treat onychomycosis and other fingernails and toenails infections. Shortly after its introduction to the market, DILI had been reported with elevation with serum aminotransferases elevation that was usually self-limited. Usually presents within first 6 weeks of therapy with either hepatocellular or cholestatic initially with sings of hypersensitivity. Mechanism of injury entails hypersensitivity reaction, though the full pathogenesis was not elucidated yet, but genetic polymorphism is implicated in the variable presentation especially among HLA-A 33:01 allele carriers. Terbinafine DILI resolves usually within 6 months of stopping the medication but can lead to death or need liver transplantation in some cases.
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Spradling, Victoria Baird. "Phenolics in red wine pomace and their potential application in animal and human health." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/5644.
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Thesis (M.S.)--University of Missouri-Columbia, 2008.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 14, 2009) Includes bibliographical references.
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Kuek, Conchita Maria. "Hereditary haemochromatosis and the C282Y genotype : implications in diagnosis and disease." University of Western Australia. School of Surgery and Pathology, 2003. http://theses.library.uwa.edu.au/adt-WU2004.0024.
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[Truncated abstract. Please see the pdf format for the complete text.] The discovery of the C282Y mutation and its role in the development of hereditary haemochromatosis has allowed a greater understanding into the effects of iron overload and its involvement in other conditions such as diabetes and heart disease. It has also allowed the better classification of heterozygotes, who were previously only diagnosed through the use of family studies. There are however, areas of conflict between phenotyping and genotyping methods. My research involved examining the relationship between Haemochromatosis and certain diseases such as diabetes and heart disease; genotyping versus phenotyping discrepancies and the possible interaction of secondary mutations. In Chapter 3 a population study was undertaken with the aim of comparing genotyping versus phenotyping methods as well as increasing general practitioner awareness regarding hereditary haemochromatosis and its diagnosis. It was determined that a minimum of 5000 subjects would be required to give the study sufficient power. Individuals were to be between the ages of 20—40 years, and thus presumably presymptomatic. Participation was entirely voluntary and a consent form was to be signed. Recruitment of subjects proved to be difficult and there was a selective bias towards individuals already displaying symptoms of haemochromatosis. In total less than a 100 subjects were recruited for the study. There were several issues encountered in the implementation of this study. Firstly the number of GPs participating was probably insufficient to recruit the subjects required. A more extensive campaign was probably required to enroll more GPs. Secondly it is very difficult for a busy GP to find the time necessary to explain the study to each of his patients and to get them to sign the consent form. Finally a bias developed in some of the requests. The subjects participating in this study were supposed to be random but in many cases the GPs had enrolled them in the study because they had symptoms of iron overload. In effect the biggest obstacle this study faced was the recruitment of subjects. Due to the small number of subjects little statistical data could be obtained from this study. It was noted, however, that genotyping methods detected two individuals who were homozygous for the C282Y mutation. Both also had increased transferrin saturation levels. Phenotyping detected 5 individuals with increased transferrin saturation. The three others detected via phenotyping were C282Y heterozygotes. Haemochromatosis has long been though to be related to the development of diabetes due to the effect of iron overload on the pancreas. If this is so it would be logical to assume that the prevalence of haemochromatosis would be higher in a diabetic population. Chapter 4 examined the possibility that diabetics have a higher frequency of the C282Y mutation. A population group consisting of 1355 diabetics was genotyped for the C282Y mutation and iron studies were performed on all heterozygotes and C282Y homozygotes. Initial findings indicated that there was a significant difference between the diabetic and control population. However, this finding was the opposite of what was expected, there seemed to be a decreased frequency of the Y allele in the diabetic population rather than an increased one. The control and diabetic populations were not matched in terms of ethnicity. The removal of the ethnic bias in the diabetic population altered the statistics so there was no longer a significant difference between the two groups. This study highlighted the importance of using appropriate control populations as comparison groups. The final results of the study indicated that there was no significant difference between the diabetic population and the control population. This would seem to indicate that there is not an increased occurrence of the C282Y mutation in the diabetic population when compared to the control group. Chapter 5 considered the possible association between C282Y heterozygosity and cardiovascular disease as well as the potential for early mortality. Several recent studies have indicated that C282Y heterozygosity may be a risk factor for the development of atherosclerosis, possibly on the basis of increased iron loading. Using a control population and a population of individuals with known coronary events the incidence of the C282Y mutation was compared against other risk factors. C282Y heterozygosity did not appear to be a risk factor for atherosclerosis. There was however, a statistically significant link between increased ferritin in women and carotid plaques. A population of elderly women was genotyped in order to examine the effects of C282Y heterozygosity on longevity. The first hypothesis addressed in chapter 5 was that C282Y heterozygosity was a risk factor for the development of coronary heart disease.
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Bouwens, C. S. H. "Analysis of hereditary haemochromatosis and clinical correlations in the elderly." Thesis, Stellenbosch : Stellenbosch University, 2000. http://hdl.handle.net/10019.1/51584.
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Thesis (MSc)--Stellenbosch University, 2000.ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are not taken. HH is often not considered as a cause of these conditions, particularly not in the elderly where the background frequencies of type II diabetes, osteoarthritis and heart failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in approximately 80% of affected individuals worldwide, has been linked to a raised incidence of malignancies of the colon and rectum, stomach and the haematological system. One of the highest carrier-frequencies (116) in the world for this mutation has been reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in approximately 1 in every 115 people in this group. A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype association studies. Their clinical presentation was denoted, biochemical iron-status determined and HFE genotyping performed. Either an increase or decrease in survival, or both, were proposed, depending on possible gender effects. HH has been positively associated with various cancer types, but may also protect against iron-deficiency anaemia which is by far the most frequent cause of anaemia in the older person. This study has led to the following findings: 1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population (similar in males and females), which is slightly lower than the 1/6 reported in younger adults from the same population. Only one C282Y homozygote and two C282YIH63D compound heterozygotes were detected, all of them female. 2. The prevalence of diabetes, heart disease, arthropathy or a combination of these conditions did not differ significantly in C282Y heterozygotes and the mutationnegative group. 3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was detected compared with two cases with rectal- and seven with colonic malignancies in 153 mutation-negative individuals. The single female C282Y homozygote identified suffered from both rectal and colon carcinoma and died approximately 6 months ago as a consequence of her colon malignancy. 4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in the elderly where a variety of factors that may influence the levels are often present in elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities. 5. Serum ferritin levels were lower than expected in elderly subjects with mutation C282Y and compound heterozygotes with both C282Y and H63D, which may be related to a variable penetrance of the HFE gene mutations. It is possible that variation in other genes exist that confer protection against iron-loading by gene-gene interaction. The probability that environmental factors (e.g. a low iron diet) are more important in this respect cannot be excluded, although this is considered less likely in the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant iron loading have died before reaching their seventies, particularly since none of the males included in this study were homozygous or compound heterozygous for the mutations analysed. In conclusion, possession of a mutant HFE gene does not appear to confer a survival advantage in old age, neither does it seem that mutation carriers with significant ironloading are overlooked by the medical fraternity. Further investigations are warranted to shed more light on the contributions of gene-gene and gene-environment interaction in the clinical manifestation of Hll, and how these processes can be manipulated to prevent the symptoms of this largely underdiagnosed disease.
AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is 'n outosomaal resessiewe yster-oorladingssiekte waar akkumulasie van yster in parenkimale organe kan lei tot suikersiekte, hartversaking, lewer sirrose, artropatie, moegheid en 'n verskeidenheid van ander probleme indien voorkomende maatreëls nie getref word nie. OH word gewoonlik nie oorweeg as moontlike oorsaak vir hierdie toestande nie, veral nie in ouer mense nie waar die agtergrond-frekwensie van tipe II diabetes, osteoartritis en hartversaking in elk geval hoog is. Heterosigositeit vir die HFE mutasie C282Y, wat OH veroorsaak in ongeveer 80% van geaffekteerde gevalle wêreldwyd, is geassosieer met 'n verhoogde voorkoms van kanker van die kolon, rektum, maag en ook die hematologiese sisteem. Van die hoogste draer frekwensies ter wêreld vir hierdie mutasie (1/6) is gevind in die Afrikaner populasie van Suid-Afrika, wat daarop dui dat 1 uit elke 115 mense in die groep homosigoties vir die C282Y mutasie kan wees. Eenhonderd sewe-en-negentig bejaarde Afrikaner vrywilligers het aan die studie deelgeneem wat daarop gemik was om genotipe/fenotipe korrelasies uit te voer. Die kliniese beeld van elke individu is gedokumenteer, die yster status biochemies bepaal en HFE genotipering uitgevoer. Die a priori veronderstelling was dat oorlewing sou toeneem of afneem, of beide, afhangende van die geslag van die individu. Daar is voorheen 'n verband gevind tussen OH en die ontwikkeling van bogenoemde maligniteite, maar aan die ander kant kan dit moontlik ook beskerm teen anemie as gevolg van yster gebrek, wat juis die mees algemene oorsaak van anemie in die ouer persoon is. Hierdie studie het tot die volgende bevindings gelei: 1. Die draer frekwensie van mutasie C282Y was 1/8 in die bejaardes (dieselfde in mans en vrouens), wat effens laer is as die 1/6 wat gerappoteer is in jonger volwassenes. Slegs een C282Y homosigoot en twee C282YIH63D saamgestelde heterosigote is opgespoor, en al drie was vroulik. 2. Die voorkoms van suikersiekte, hartsiekte, gewrigspyne of 'n kombinasie van hierdie aandoenings het nie betekenisvol verskil tussen die C282Y heterosigote en die mutasienegatiewe groep nie. 3. Daar was slegs een persoon met rektum karsinoom in die groep van 24 bejaarde C282Y heterosigote, terwyl daar twee gevalle met rektum kanker en sewe gevalle met kolon kanker gevind is onder die 153 mutasie-negatiewe individue. Die enkele vroulike C282Y homosigoot wat opgespoor is het beide rektum- en kolonkanker gehad en is ongeveer 6 maande vóór voltooing van die tesis oorlede aan haar kolon karsinoom. 4. Dit wil voorkom asof serum ferritien veral in bejaardes 'n hoogs onbetroubare maatstaf is vir yster status, aangesien dit deur 'n verskeidenheid faktore beïnvloed word wat dikwels in bejaardes aanwesig is as gevolg van veroudering of veelvuldige komorbiditeite. 5. Die serum ferritien vlakke was laer as verwag in sowel die bejaarde C282Y-homosigoot as in die twee saamgestelde heterosigote met mutasies C282Y en H63D, wat moonlik die gevolg is van die wisselende graad van penetrasie van HFE mutasies. Dit is moontlik dat variasie in ander gene beskerming bied teen yster-oorlading deur middel van geen-geen interaksie. Die moontlikheid dat omgewingsfaktore (soos 'n lae-yster dieet) 'n belangrike rol speel in hierdie verband kan nie uitgesluit word nie, hoewel dit minder waarskynlik lyk te wees in die lig van die feit dat dieselfde neiging waargeneem is in alle mutasie-positiewe bejaardes. Die kans is dus redelik groot dat individue met die C282Y mutasie en betekenisvolle yster oorlading oorlede is voordat hulle die sewentiger jare kon bereik, veral omdat geeneen van die mans wat ingesluit is in die studie homosigoot of 'n saamgestelde heterosigoot was vir die mutasies wat geanaliseer is nie. Opsommend wil dit voorkom asof die teenwoordigheid van 'n mutante HFE geen nie 'n beter oorlewingskans bied op ouer leeftyd nie, en dit blyk ook dat mutasie draers met betekenisvolle ysteroorlading nie deur dokters misgekyk word nie. Verdere navorsing is nodig om meer lig te werp op die bydrae van geen-geen- en geen-omgewing interaksie in die kliniese manifestasie van OH, en ook hoe hierdie prosesse gemanipuleer kan word om die simptome van hierdie onder -gediagnoseerde siekte te voorkom.
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Varga, Daniel. "Screening of candidate genes for mutations causing hereditary hemochromatosis in patients lacking the common mutations C282Y and H63D /." [S.l.] : [s.n.], 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000277048.
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Kučinskas, Laimutis. "Metabolinės kepenų ligos: Vilsono ligos ir hfe-hemochromatozės genetinė charakteristika." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130621_093349-72294.
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Vilsono liga (VL) ir HFE-hemochromatozė – monogeninės, pagal Mendelio dėsnius paveldimos retos ligos. Šių ligų priežastis yra ATP7B arba HFE genų mutacijos, sukeliančios gyvybei pavojingas lėtines ligas. Šio darbo metu buvo tirti ligonių, sergančių metabolinėmis kepenų ligomis – VL ir HFE–hemochromatoze genų mutacijos, jų dažnis, ligų fenotipinės charakteristikos bei HFE geno dažniausių mutavusių alelių dažnis Lietuvos savanorių kraujo donorų populiacijoje. Buvo nustatyta, kad Rytų ir Centrinės Europos šalių populiacijoms būdinga c.3207C>A (p.His1069Gln) mutacija ATP7B gene taip pat dažniausia ir Lietuvoje. Patvirtinta, kad VL jautriausias metodas - molekulinis genetinis diagnostikos metodas. Kitiems klinikiniams laboratoriniams tyrimo metodams buvo būdingas mažesnis jautrumas. Ištyrus Lietuvos savanorius kraujo donorus nustatyta, kad HFE–hemochromatozės geno c.845G>A (p.Cys282Tyr) ir c.187C>G (p.His63Asp) mutacijų dažnis yra artimiausias Lenkijai ir kitoms Rytų ir Centrinės Europos šalims. HFE-hemochromatozės išsivystymo rizika yra 1,3 proc. Lietuvos savanoriams kraujo donorams, kurių genotipas c.[845G>A]; [845G>A] (0,1 proc. tiriamųjų) arba genotipas c.[845G>A];[187C>G], (1,2 proc. tiriamųjų). Tiriant HFE geno mutacijų paplitimą tarp skirtinguose Lietuvos etnokultūriniuose regionuose gyvenančių savanorių kraujo donorų nustatyta, kad c.845G>A mutacijos dažnis statistiškai patikimai buvo dažnesnis Žemaitijoje.Wilson’s disease (WD) and HFE-hemochromatosis are monogenic rare diseases inherited following Mendel’s laws. These diseases are caused by ATP7B or HFE gene mutations, which cause life-threatening chronic diseases. This study analyzed gene mutations in patients with metabolic liver diseases – WD and HFE–hemochromatosis, the frequency of such mutations, the phenotypic characteristics of these diseases, and the frequency of the most common mutations in the alleles of the HFE gene in the population of Lithuanian volunteer blood donors. The study showed that the ATP7B gene mutation c.3207C>A (p.His1069Gln), which is characteristic of the populations of Central and Eastern Europe, was also most common in Lithuania. The study confirmed that molecular genetic diagnostics was the most sensitive technique in detecting WD. Other clinical laboratory diagnostic techniques demonstrated lower sensitivity. The examination of Lithuanian volunteer blood donors showed that the frequency of HFE–hemochromatosis mutations c.845G>A (p.Cys282Tyr) and c.187C>G (p.His63Asp) was closest to that in Poland and other Eastern and Central European countries. The risk of developing HFE-hemochromatosis among Lithuanian volunteer blood donors with genotype c.[845G>A]; [845G>A] (0.1% of the subjects) or c.[845G>A];[187C>G] (1.2% of the subjects) was 1.3%. The analysis of the prevalence of HFE gene mutations among Lithuanian volunteer blood donors from different ethno-cultural regions of Lithuania showed that... [to full text]
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Carvalho, Lya Bueno. "Avaliação da expressão da talassemia Beta no Brasil pela coherança com defeitos de hemocromatose /." São José do Rio Preto : [s.n.], 2003. http://hdl.handle.net/11449/92518.
Full textAbstract:
Orientador: Claudia Regina Bonini DomingosBanca: Ricardo Luiz Dantas Machado
Banca: Paula Rahal Liberatore
Resumo: A talassemia beta constitui um grupo heterogêneo de distúrbios genéticos da síntese de hemoglobina sendo uma das doenças monogênicas mais comums, identificada e estudada por várias décadas. É originária da região do Mediterrâneo porém, atualmente apresenta-se amplamente distribuída pelo mundo devido ao fluxo gênico pela migração das populações. No Brasil, os tipos de talassemia mais prevalentes são as talassemias alfa e beta e apresentam número variável de indivíduos portadores devido ao alto grau de miscigenação da população. As formas graves de talassemia beta são facilmente diagnosticadas entretanto, as formas mais suaves muitas vezes são interpretadas e tratadas como anemia ferropriva. O presente estudo teve como objetivo caracterizar as formas talassêmicas do tipo beta e verificar os interferentes na expressão do fenótipo como a possível co-herança com hemocromatose hereditária. Através da associação de análise hematimétrica, metodologias clássicas e análise por HPLC analisamos 332 amostras de sangue com suspeita de talassemia beta. Um total de 70 amostras foram identificadas como portadores de hemoglobinas normais (AA), 145 portadores de talassemia beta heterozigota (BTH) e 117 portadores de talassemia alfa/beta (ABT). A análise estatística por regressão linear entre as metodologias clássicas e HPLC para quantificação de hemoglobina A2 e Fetal para os três grupos foram estatisticamente significativas. A análise molecular por PCR-ASO para identificação dos mutantes para hemocromatose hereditária mostraram 11,76% de mutação C282Y e 70,58% para H63D no grupo de talassemia beta e 25% de mutação C282Y e 75% H63D para o grupo de talassemia alfa/beta. Esses resultados evidenciam a necessidade da associação de metodologias para o correto diagnóstico da talassemia beta, bem como caracterização molecular para hemocromatose...(Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The beta-thalassemia constitutes a heterogeneous group of genetic disorders of hemoglobin synthesis. It has been one of the most common monogenic diseases identified and studied for many decades. Its origins are from Mediterranean region, although nowadays it is spread for the whole world due to gene flow of migration populations. In Brazil, the most prevalent types of thalassemia are the alpha-thalassemia and beta-thalassemia. They present a variable number of individual carriers due to high degree of miscigenation. The serious forms of beta-thalassemia are easily identified, but the milder forms are many times diagnosed and treated as iron deficiency anemia. The objective of the present study was to characterize the thalassemic forms and verify the interferents in the expression of the phenotype as the possible co-inheritance with hereditary hemochromatosis. It was analysed, utilizing hematimetric analysis, classic methodologies and HPLC analysis, 332 blood samples suspect of beta-thalessemia. The total of 70 samples were identified as carriers of normal hemoglobins (AA), 145 carriers of beta-thalassemia heterozigote (BTH) and 117 carriers of alpha/beta-thalassemia (ABT). The statistic analysis by linear regression between classic methodologies and HPLC for quantification of hemoglobin A2 and Fetal hemoglobin were statistically differents and significants. The molecular analysis by PCR-ASO to identify the mutants with hereditary hemochromatosis showed 11,76% of mutation C282Y and 70,58% to H63D in the beta-thalassemia group and 25% of mutation C282Y and 75% of H63D in the alpha/beta- thalassemia group. These results prove the necessity of association of methodologies in order to achieve the correct diagnosis of beta-thalassemia, as well as the molecular characterization of hemochromatosis, due to the fact of its possible co-inheritance with beta-thalassemia in the vast genotypic diversity found in Brazil.
Mestre
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HOLMGREN, LISA MICHELLE. "THE IMPACT OF TEST OUTCOME CERTAINTY ON INTEREST IN GENETIC TESTING AMONG COLLEGE WOMEN." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin994694629.
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Giannetti, Anthony Michael Rees Douglas C. "Biochemical, biophysical, and cellular investigations of the interactions of transferrin receptor with transferrin and the hereditary hemochromatosis protein, HFE /." Diss., Pasadena, Calif. : California Institute of Technology, 2004. http://resolver.caltech.edu/CaltechETD:etd-05262004-173612.
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Liljeholm, Maria. "Congenital Dyserythropoietic Anemia type III (CDA III) : diagnostics, genetics and morbidity." Doctoral thesis, Umeå universitet, Institutionen för strålningsvetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-117454.
Full textAbstract:
The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies. In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis. Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls. In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.
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Cheat, Eng Lim. "Establishment of a PCR and restriction enzyme assay for the detection of the hemochromatosis gene in normal subjects and diabetic patients." FIU Digital Commons, 1998. http://digitalcommons.fiu.edu/etd/2121.
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The purpose of this study was to establish a polymerase chain reaction (PCR)-restriction enzyme assay for detecting the hereditary hemochromatosis (HHC) mutation, C282Y, in gestational and gestational diabetic subjects in South Florida. DNA samples from 43 gestational subjects were amplified by PCR, digested with RsaI, and analyzed by electrophoresis. An allelic frequency of 2.33%, or 4.65% heterozygosity, was observed. The assay is successful and applicable to future studies on HHC and gestational diabetes.
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Chlosta, Sabine [Verfasser]. "Ferroportin 1 expression regulates intracellular growth of Salmonella enterica serovar Typhimurium, a link between innate immunity and hereditary hemochromatosis / Sabine Chlosta." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1022764241/34.
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Fonseca, Paula Fernanda da Silva. "Avaliação da qualidade de vida e da percepção de saúde em pacientes com hemocromatose hereditária." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/5/5166/tde-09082017-102533/.
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Introdução: A hemocromatose hereditária (HH) é uma doença autossômica recessiva caracterizada principalmente pelo aumento da absorção intestinal de ferro e seu acúmulo em órgãos. O diagnóstico da HH baseia-se nas avaliações de exames laboratoriais de ferro, imagem por ressonância magnética (RMN) e/ou testes genéticos. Diferentes genótipos são identificados como resultados de testes genéticos em pacientes com suspeita de sobrecarga de ferro primário. Além disso, questionários como o SF-36 (short form health survey), têm sido cada vez mais utilizados para avaliar o impacto das doenças na qualidade de vida (QV) do paciente. No presente estudo, nossos objetivos foram: avaliar se os domínios de QV avaliados pelo questionário SF-36 são diferentes de acordo com os grupos genotípicos em pacientes com suspeita de HH e desenvolver materiais informativos e educativos sobre HH para pacientes, familiares e profissionais de saúde. Métodos: Foram utilizados os questionários SF-36, PHQ-9 (patient health questionnaire-9) e dados gerais e específicos para avaliar domínios de qualidade de vida e depressão e características gerais da doença. Pacientes com sobrecarga de ferro primária foram incluídos (n=79) e dois grupos genotípicos foram formados: grupo 1: genótipo homozigoto para a mutação HFE p.Cys282Tyr e grupo 2: outros genótipos. Resultados: O grupo 1 apresentou maiores médias de saturação de transferrina (86±19%) e ferritina sérica (1669±1209 ng/mL) comparado ao grupo 2 (71±12%, 1252±750 ng/mL, respectivamente; P=0,001). Quatro domínios foram significativamente diferentes entre os grupos 1 e 2: capacidade funcional (P=0,03), dor (P=0,03), vitalidade (P=0,02) e aspectos sociais (P=0,01). O grupo 1 apresentou valores mais baixos para estes domínios. O grupo brasileiro de hemocromatose hereditária (GBHH) foi criado, o site foi desenvolvido e foram recebidos vários cadastros. O material informativo/educativo foi desenvolvido e distribuído aos pacientes, familiares e profissionais de saúde envolvidos neste estudo. Conclusões: O principal achado deste estudo foi que os pacientes com genótipo homozigoto para p.Cys282Tyr apresentaram um pior cenário de QV avaliado pelo SF-36, em comparação aos pacientes com sobrecarga de ferro sem o mesmo genótipo. O conhecimento desta relação entre genótipos e QV pode ser útil no manejo geral de pacientes com suspeita de HH. Este estudo foi capaz de contribuir para mais informações sobre a HH, aumentando a educação em saúde e a divulgação deste cenárioBackground: Hereditary hemochromatosis (HH) is an autosomal recessive disease mainly characterized by increased intestinal absorption of iron and its accumulation in organs. The diagnosis of HH is based on laboratory tests of iron, magnetic resonance imaging (MRI) evaluations and / or genetic testing. Different genotypes are identified as results of genetic tests in patients with suspected of primary iron overload. In addition, questionnaires such as the SF-36 (short form health survey), have been increasingly used to assess the impact of diseases on the patient\'s quality of life (QL). In the present study, our aims were: evaluate if the domains of QL by SF-36 questionnaire are different according to genotypic groups in patients with suspected of HH and develop informative and educational materials about HH for patients, family members and health professionals. Methods: The SF-36, PHQ-9 (Patient health questionnaire-9) questionnaires, general and disease-specific data were used to evaluate the domains of quality of life and depression and general characteristics of the disease. Patients with primary iron overload were included (n=79) and two genotypic groups were formed group 1: homozygous genotype for the HFE p.Cys282Tyr mutation and group 2: other genotypes. Results: Group 1 presented higher mean values of transferrin saturation (86±19%) and serum ferritin (1669±1209 ng/mL) compared to group 2 (71±12%, 1252±750 ng/mL, respectively, P= 0.001). Four domains were significantly different between groups 1 and 2: physical functioning (P= 0.03), bodily pain (P= 0.03), vitality (P= 0.02) and social functioning (P= 0.01). Group 1 presented lower values for these domains. The \"Brazilian group of hereditary hemochromatosis\" (GBHH) was created, the website was developed and several registrations were received. The informative/educational material was developed and distributed to patients, family members and health professionals involved in this study. Conclusion: The main finding of this study was that patients with genotype homozygous for p.Cys282Tyr presented worse scenario of QL evaluated by SF-36, compared to patients with iron overload without the same genotype. The knowledge of this relationship between genotypes and QL may be useful in the general management of patients with suspected of HH. This study was able to contribute with more information about HH, increasing health education and the divulgation of this scenario
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Silva, Roberto Souto da. "Prevalência da mutação do gene HFE em pacientes com porfiria cutânea tardia do Hospital Universitário Pedro Ernesto- UERJ." Universidade do Estado do Rio de Janeiro, 2013. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=7090.
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A Porfiria Cutânea Tardia (PCT) é uma desordem dermatológica, caracterizada por fotossensibilidade induzida pela circulação de porfirinas que se depositam na pele. Tanto a forma familial como a esporádica são desordens dependentes do acúmulo de ferro. A presença da mutação do gene da Hemocromatose (HFE) é um importante fator de risco para o acúmulo de ferro e pouco se sabe sobre sua prevalência na população brasileira. Da mesma forma, existem poucos relatos a respeito da associação entre mutação do gene HFE e Porfiria Cutânea Tardia. No presente trabalho descrevemos as frequências dos principais alelos e genótipos do gene da Hemocromatose HFE1 em uma coorte de 25 pacientes brasileiros atendidos no HUPE, com Porfiria Cutânea Tardia, durante o período de janeiro 1990 à dezembro 2012, realizando uma correlação da presença desta mutação com a sobrecarga de ferro neste grupo de pacientes. Neste estudo foi utilizado um grupo controle da população fluminense pareado por idade, sexo e grupo étnico informado, para comparar com os dados avaliados dos pacientes com PCT. A pesquisa das mutações genéticas C282Y e H63D do gene da hemocromatose ocorreu através de técnicas de PCR tempo real e e os resultados ratificados por sequenciamento de Sanger. Dos resultados encontrados, não ocorreram diferenças estatísticas significativas nas frequências alélicas e genotípicas das mutações C282Y e H63D entre a coorte com PCT e a população controle. Entretanto, há um forte indício da participação da mutação H63D em um paciente homozigoto, para desenvolvimento da doença, conforme observado na literatura. Dos ensaios bioquímicos, os níveis de ferritina encontrados entre os pacientes portadores de PCT com a mutação H63D foram maiores que os indivíduos sem a mutação.Porphyria cutanea tarda (PCT) is a dermatological disorder characterized by photosensitivity induced by circulating porphyrins being deposited on the skin. Both the familial form, as sporadic disorders are dependent on the accumulation of iron. Although the cause of this excess hepatic iron is still unknown, the presence of the mutation of the hemochromatosis gene (HFE) is an important risk factor for iron accumulation. Likewise, little is known about the association between HFE gene mutation and porphyria cutanea tarda. In this paper we describe the main frequencies of genotypes and alleles of the gene for hemochromatosis HFE1 in a cohort of 25 patients treated at a dermatology outpatient clinic with Porphyria Cutaneous Late during the period of 1990-2012, performing a correlation with the presence of this mutation and iron overload in these patients. This study used a control group matched for age, sex and ethnic group reported, to compare with the data evaluated in patients with PCT. The research of genetic mutations C282Y and H63D mutations of the hemochromatosis gene occurred through real-time PCR results and ratified by Sanger sequencing. Results found no statistically significant differences in allele and genotype frequencies of the C282Y and H63D between the PCT cohort and population control. However, there is a strong indication of the participation of the H63D mutation in a patient homozygous for disease development, as noted in the literature. Of biochemical analysis, ferritin levels found among patients with PCT with the H63D mutation were higher than those without the mutation.
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Carvalho, Lya Bueno [UNESP]. "Avaliação da expressão da talassemia Beta no Brasil pela coherança com defeitos de hemocromatose." Universidade Estadual Paulista (UNESP), 2003. http://hdl.handle.net/11449/92518.
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carvalho_lb_me_sjrp.pdf: 1246135 bytes, checksum: f9e7b5e083804e53df6d7ddd95e67ddc (MD5)A talassemia beta constitui um grupo heterogêneo de distúrbios genéticos da síntese de hemoglobina sendo uma das doenças monogênicas mais comums, identificada e estudada por várias décadas. É originária da região do Mediterrâneo porém, atualmente apresenta-se amplamente distribuída pelo mundo devido ao fluxo gênico pela migração das populações. No Brasil, os tipos de talassemia mais prevalentes são as talassemias alfa e beta e apresentam número variável de indivíduos portadores devido ao alto grau de miscigenação da população. As formas graves de talassemia beta são facilmente diagnosticadas entretanto, as formas mais suaves muitas vezes são interpretadas e tratadas como anemia ferropriva. O presente estudo teve como objetivo caracterizar as formas talassêmicas do tipo beta e verificar os interferentes na expressão do fenótipo como a possível co-herança com hemocromatose hereditária. Através da associação de análise hematimétrica, metodologias clássicas e análise por HPLC analisamos 332 amostras de sangue com suspeita de talassemia beta. Um total de 70 amostras foram identificadas como portadores de hemoglobinas normais (AA), 145 portadores de talassemia beta heterozigota (BTH) e 117 portadores de talassemia alfa/beta (ABT). A análise estatística por regressão linear entre as metodologias clássicas e HPLC para quantificação de hemoglobina A2 e Fetal para os três grupos foram estatisticamente significativas. A análise molecular por PCR-ASO para identificação dos mutantes para hemocromatose hereditária mostraram 11,76% de mutação C282Y e 70,58% para H63D no grupo de talassemia beta e 25% de mutação C282Y e 75% H63D para o grupo de talassemia alfa/beta. Esses resultados evidenciam a necessidade da associação de metodologias para o correto diagnóstico da talassemia beta, bem como caracterização molecular para hemocromatose...
The beta-thalassemia constitutes a heterogeneous group of genetic disorders of hemoglobin synthesis. It has been one of the most common monogenic diseases identified and studied for many decades. Its origins are from Mediterranean region, although nowadays it is spread for the whole world due to gene flow of migration populations. In Brazil, the most prevalent types of thalassemia are the alpha-thalassemia and beta-thalassemia. They present a variable number of individual carriers due to high degree of miscigenation. The serious forms of beta-thalassemia are easily identified, but the milder forms are many times diagnosed and treated as iron deficiency anemia. The objective of the present study was to characterize the thalassemic forms and verify the interferents in the expression of the phenotype as the possible co-inheritance with hereditary hemochromatosis. It was analysed, utilizing hematimetric analysis, classic methodologies and HPLC analysis, 332 blood samples suspect of beta-thalessemia. The total of 70 samples were identified as carriers of normal hemoglobins (AA), 145 carriers of beta-thalassemia heterozigote (BTH) and 117 carriers of alpha/beta-thalassemia (ABT). The statistic analysis by linear regression between classic methodologies and HPLC for quantification of hemoglobin A2 and Fetal hemoglobin were statistically differents and significants. The molecular analysis by PCR-ASO to identify the mutants with hereditary hemochromatosis showed 11,76% of mutation C282Y and 70,58% to H63D in the beta-thalassemia group and 25% of mutation C282Y and 75% of H63D in the alpha/beta- thalassemia group. These results prove the necessity of association of methodologies in order to achieve the correct diagnosis of beta-thalassemia, as well as the molecular characterization of hemochromatosis, due to the fact of its possible co-inheritance with beta-thalassemia in the vast genotypic diversity found in Brazil.
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Ferreira, Jerenice Esdras. "Avaliação de polimorfismos do gene SLC40A1 em pacientes com hemocromatose hereditária e adquirida." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/99/99131/tde-17022016-104522/.
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A hemocromatose é uma desordem caracterizada por armazenamento alterado de ferro em órgãos vitais. A hemocromatose hereditária pode ser causada por mutações nos genes HFE, SLC40A1, HAMP, HJV e TfR2. A forma adquirida da doença pode ser ocasionada por sobrecarga de ferro, alcoolismo, infecção pelo vírus da hepatite C, anemias hemolíticas e doença hepática crônica. O objetivo deste estudo foi descrever as variantes do gene SLC401 em uma série de casos de pacientes em seguimento no ambulatório de Hematologia do Hospital das Clínicas da FMUSP com hemocromatose hereditária e adquirida e verificar se estas variantes poderiam estar associadas a um pior quadro de hemocromatose. No período de 2008 a 2011 foram coletadas 54 amostras de pacientes com diagnóstico prévio de hemocromatose, acompanhados no ambulatório de anemias do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram separados, de acordo com a suspeita clínica, em dois grupos: 38 pacientes com Hemocromatose Hereditária e 16 pacientes com Hemocromatose Adquirida. O DNA foi extraído de sangue periférico pelo kit Qiamp Blood, e as amplificações dos exomas descrito por Wakusawa (2005). As reações de sequenciamento foram realizadas no aparelho AB 3130 e as sequências do gene editadas, alinhadas no programa Sequencer e comparadas com GenBank. Os pacientes com hemocromatose hereditária e adquirida (secundária) apresentaram uma frequência acima de 45% entre a faixa etária de 40 a 60 anos, mostrando uma sobrecarga de ferro mais tardia. O gênero masculino apresentou maior frequência em ambos os grupos (superior a 60%), já em relação à etnia/cor da pele, mais de 80% eram brancos. No diagnóstico laboratorial de ferritina, ferro, CTLF e IST dos pacientes com hemocromatose hereditária e adquirida (secundária) mostra que não houve diferenças significativas. As mutações no gene HFE nos pacientes com hemocromatose hereditária foram C282Y homozigose (21%) e na adquirida (secundária) H63D heterozigose (25%). Entre as mutações do gene HFE, não houve diferença estatística significativa nos grupos. A mutação foi identificada no éxon 3 do gene SLC40A1, no códon 80, descrita p.I80L (c.586C>A). No éxon 4 do gene SLC40A1 foram identificados 3 polimorfismos com a substituição de um nucleotídeo nas posições: c. A630G (190437579), c.648A>G (190437597), c.738Y>C (190437688). Já no éxon 6 foram identificados dois polimorfismos c.1014C>T (190430229) e c.1014Y>T (190430229). As mutações encontradas no gene HFE e SLC40A1 estão associadas com a sobrecarga férrica caracterizando a hemocromatose hereditária. Os polimorfismos encontrados no gene SLC40A1 foram identificados nos pacientes com hemocromatose hereditária e adquirida (secundária) numa frequência de 50%, semelhante aos doadores de sangue, sugerindo que este polimorfismo provavelmente não contribui para o desenvolvimento da doença.Hemochromatosis is a disorder characterized by altered storage iron in vital organs. Hereditary hemochromatosis can be caused by mutations in the HFE gene, SLC40A1, HAMP, and HVJ TFR2. The acquired form of the disease can be caused by iron overload, alcoholism, infection by the hepatitis C virus, hemolytic anemias and chronic liver disease. The objective of this study was to describe variants of the SLC401 gene in a number of cases of patients being followed at hematology clinic Hospital das Clínicas FMUSP with hereditary hemochromatosis and acquired and verify that these variants could be associated with a worse hemochromatosis frame. In the period 2008 to 2011 were collected 54 samples from patients previously diagnosed with hemochromatosis, anemia accompanied the clinic of the Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo. The patients were divided, according to clinical suspicion, into two groups: 38 patients with Hereditary Hemochromatosis and 16 patients with Acquired Hemochromatosis. The DNA was extracted from peripheral blood by Qiamp Blood Kit, and amplifications of exomas described by Wakusawa (2005). The sequencing reactions were performed in AB 3130 apparatus and the sequences of the gene edited, aligned in Sequencer program and compared with GenBank. Patients with hereditary hemochromatosis and acquired (secondary) had a frequency above 45% between the age group 40-60 years showing a later iron overload. The males showed higher frequency in both groups (over 60%), as compared to ethnicity / skin color, over 80% were white. In the laboratory diagnosis of ferritin, iron, TIBC and STI patients with hereditary hemochromatosis and acquired (secondary) shows no significant differences. Mutations in the HFE gene in patients with hereditary hemochromatosis C282Y homozygosity were (21%) and acquired (secondary) H63D heterozygosity (25%). Between HFE mutations, there was no statistically significant difference in the groups. The mutation was identified in exon 3 of the SLC40A1 gene at codon 80, described p.I80L (c.586C> A). In exon 4 of the SLC40A1 gene were identified polymorphisms 3 with substitution of a nucleotide in position: c. A630G (190,437,579), c.648A> L (190,437,597), c.738Y> C (190 437 688). Already in exon 6 were identified two polymorphisms c.1014C> T (190 430 229) and c.1014Y> T (190 430 229). The mutations found in the HFE gene and SLC40A1 are associated with iron overload characterizing hereditary hemochromatosis. The polymorphisms found in the SLC40A1 gene have been identified in patients with hereditary hemochromatosis and acquired (secondary) at a frequency of 50%, similar to blood donors, suggesting that this polymorphism will probably not contribute to the development of the disease.
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Silva, Ana Lúcia Bernardes da. "O papel das mutações do gene HFE e da sobrecarga de ferro na evolução da hepatite crônica pelo VHC." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5147/tde-08122009-181724/.
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Introdução: A infecção pelo VHC é uma epidemia de proporções globais, que se torna crônica em cerca de 85% dos indivíduos. Sobrecarga de ferro secundária a mutações HFE vem sendo proposta como fator agravante na evolução da hepatite crônica C. Objetivos: Avaliar se sobrecarga de ferro, mutações no gene HFE estão associadas a progressão da fibrose hepática e a carcinoma hepatocelular (CHC) em portadores crônicos VHC. Casuística e Métodos: De um banco de 2300 pacientes matriculados nos Ambulatórios de Hepatologia e de Transplante Hepático do HCFMUSP, selecionaram-se 320 portadores de hepatite crônica C. Os homens (55,6%) apresentaram 50,8 anos de idade em média e as mulheres 54,3. Obtiveram-se dados clínicos e laboratoriais da época da biópsia hepática, admissionais ou com pelo menos um ano de wash-out do tratamento antiviral. Considerou-se sobrecarga bioquímica níveis de ferro, saturação da transferrina e ferritina acima dos valores de referência. Sobrecarga de ferro tecidual foi identificada pela coloração de Perls graus 3-4. As mutações HFE C282Y e H63D foram pesquisadas pela técnica de PCR em tempo real, em DNA extraído de sangue total, após assinatura de TCLE aprovado pelo comitê de ética local. A fibrose hepática foi considerada avançada para graus 3-4 da classificação SBH/SBP e Metavir (n=167, 52,2%). CHC foi definido por biópsia ou por imagem típica por 2 métodos e AFP 400 mg/dL (n=45, 14,1%). Investigaram-se antecedentes de etilismo, diabetes mellitus, IMC e esteatose em biópsia hepática. A partir dos resultados de genotipagem HFE, constituiu-se um subgrupo caso-controle (n=182) com os portadores de mutações e pares de idade, sexo, etnia e IMC similares. Procederam-se análises de correlação bivariada e multivariada (IC=95%) nos grupos geral e caso-controle. Resultados: Quando se compararam casos com fibrose leve vs avançada, observaram-se níveis elevados de ferro em 17,7% vs 25,2% (p=0,019); saturação da transferrina em 24,3% vs 36,7% (p=0,001); ferritina em 25,8% vs 32,4% (p=0,040) e sobrecarga de ferro tecidual em 3,6% vs 1,4% (p=0,126). Quanto à mutação C282Y, observaram-se frequências alélicas de 0,9% vs 2,0% (p=0,110) e à H63D 5,0% vs 8,0% (p=0,033). No subgrupo casocontrole, as associações de C282Y e H63D com fibrose avançada ocorreram com significâncias de p=0,072 e 0,008, respectivamente. A análise multivariada, tendo fibrose como variável dependente nesse mesmo subgrupo, confirmou as associações com C282Y (OR=31,45; p=0,006) e H63D (OR=33,70; p=0,001). Neste mesmo subgrupo, a presença de pelo menos um alelo mutante esteve associada à ocorrência de CHC (p=0,015). Não se identificaram outros parâmetros associados a transformação carcinomatosa. Na análise multivariada, foram variáveis associadas a evolução da fibrose idade avançada (OR=2,36; p=0,000), etilismo (OR=2,18; p=0,007), saturação da transferrina (OR=2,11; p=0,010) e mutação H63D (OR=1,97; p=0,03). Discussão e Conclusões: Houve correlação de graus mais avançados de fibrose com níveis elevados de ferro, saturação da transferrina e ferritina; contudo, esses marcadores também podem estar igualmente elevados nos indivíduos com pouca fibrose. Ao contrário, em muitos casos, a sobrecarga bioquímica de ferro pode ser conseqüência da progressão da doença hepática, e não sua causa. As mutações H63D e C282Y ocorreram em associação com maiores graus de alteração arquitetural; mas, como não houve associação entre siderose tecidual e fibrose, é possível que seu papel na agressão hepática não ocorra diretamente por meio da sobrecarga de ferro. Os portadores de mutações HFE apresentam CHC com maior frequência que seus casos-controle.Introduction: HCV infection is an epidemic of global proportions, which becomes chronic in about 85% of individuals. Iron overload due to HFE mutations has been proposed as aggravating factor in the evolution of chronic hepatitis C. Objectives: To assess whether iron overload, mutations in the HFE gene are associated with progression of liver fibrosis and hepatocellular carcinoma (HCC) in chronic HCV. Patients and Methods: From a database of 2300 patients enrolled in the outpatient clinics of Hepatology and Liver Transplantation, HCFMUSP, 320 patients with chronic hepatitis C were selected. Men (55.6%) were 50.8 years old on average and women 54.3. Admissional clinical and laboratory data at the time of liver biopsy were obtained; when patient had been previously treated with antiviral drugs, the wash-out period required was of at least one year. Biochemical iron overload was defined as iron, ferritin and transferrin saturation above the reference values. Tissue iron overload was identified by Perls staining of grades 3-4. The HFE C282Y and H63D mutations were searched by real-time PCR technique in DNA extracted from whole blood, after signing of FICT approved by the local ethics committee. The liver fibrosis was considered advanced for grades 3-4 in the classification SBH/SBP and METAVIR(n = 167, 52.2%). HCC was defined by biopsy or by typical image by 2 methods and AFP 400 mg / dL (n = 45, 14.1%). Personal history of alcoholism, diabetes mellitus, BMI and steatosis in liver biopsy were obtained. A casecontrol group was constituted based on the results of HFE genotyping (n = 182), subjects were paired by age, gender, ethnicity and BMI. Bivariate correlation and multivariate analysis (CI = 95%) groups in general and case-control were carried-out. Results: When comparing patients with mild vs advanced fibrosis, biochemical high levels of iron were detected in 17.7% vs 25.2% (p = 0.019), transferrin saturation in 24.3% vs 36.7% (p = 0.001), ferritin in 25.8% vs 32.4% (p = 0.040) and tissue iron overload in 3.6% vs 1.4% (p = 0.126). Regarding to HFE mutations, the allelic frequencies of C282Y were 0.9% vs 2.0% (p = 0.110); and of H63D, 5.0% vs 8.0% (p = 0.033). In casecontrol group, associations of C282Y and H63D with advanced fibrosis occurred with significance of p=0.072 and 0.008, respectively. Multivariate analysis with fibrosis as the dependent variable in that group, confirmed the associations with C282Y (OR = 31.45, p = 0.006) and H63D (OR = 33.70, p = 0.001). In this same subgroup, the presence of at least one mutant allele was associated with occurrence of HCC (p = 0.015). There were not any other parameters found in association with carcinomatous transformation. The multivariate analysis using fibrosis as dependent variable showed association with age (OR = 2.36, p = 0.000), alcoholism (OR = 2.18, p = 0.007), transferrin saturation (OR = 2.11, p = 0.010) and H63D mutation (OR = 1.97, p = 0.03). Discussion and Conclusions: Advanced degrees of fibrosis were correlated with high levels of iron, transferrin saturation and ferritin; however, these markers can also be elevated in individuals with slight fibrosis. In contrary, in many cases, the biochemistry of iron overload may be a consequence of progression of liver disease. C282Y and H63D mutations occurred in association with more advanced fibrosis. However, as there was not any correlation between tissue siderosis and fibrosis, it might be possible that liver injury occurs not by the iron overload pathway. Finally, carriers of HFE mutations were found with HCC more frequently than their casecontrol.
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Cullen, Lara Michelle. "Molecular analysis of hereditary haemochromatosis." Thesis, Queensland University of Technology, 1999.
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Peltier, Lucas. "Impact d’une exposition au fer sur l’axe S1P/S1PR dans la lignée ostéoblastique humaine MG-63." Thesis, Rennes 1, 2017. http://www.theses.fr/2017REN1B059/document.
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Les surcharges en fer, qu’elles soient d’origine génétique ou secondaire, favorisent la baisse de densité minérale osseuse et par conséquent l’apparition d’une ostéoporose. Des liens entre surcharge en fer et perte osseuse ont pu être établis in vivo et in vitro, néanmoins les mécanismes mis en jeu, notamment sur la cellule ostéoblastique, restent incomplètement caractérisés. Notre objectif a donc été de préciser les mécanismes cellulaires conduisant à l’altération du phénotype et de l’activité ostéoblastique observée en présence d’un excès de fer. La réalisation préalable d’une étude transcriptomique sur la lignée ostéoblastique humaine MG-63 nous a permis d’identifier plusieurs gènes susceptibles de voir leur niveau d’ARNm régulé par le fer. Il a été fait l’hypothèse que ces différents gènes pouvaient être impliqués dans la survenue des pertes osseuses observées au cours des surcharges en fer. Ainsi l’expression du gène SPNS2, dont la protéine permet l’export de la Sphingosine-1-Phosphate (S1P), a été identifiée comme potentiellement induite par un excès de fer. Les relations entre l’expression du gène SPNS2 et un excès de fer ont ainsi été investiguées et les résultats obtenus ont mis en évidence une augmentation fer-dépendante de l’ARNm du gène SPNS2 dans la lignée MG-63, non retrouvée dans d’autres types cellulaires. Cette caractérisation nous a ainsi conduits à déterminer, dans la lignée MG-63, l’impact fonctionnel d’une exposition au fer sur l’export cellulaire de la S1P. Nous avons donc pour cela mis au point une méthode d’étude basée sur une stratégie « fluxomique » nous permettant d’évaluer l’efflux de la S1P au moyen d’un outil de spectrométrie de masse. Nos résultats objectivent une diminution des capacités de synthèse et d’export de la S1P en présence de fer et ceci malgré la surexpression du gène SPNS2. La diminution concomitante de l’expression du récepteur S1PR1 et du gène COL1A1 codant pour la chaîne α du collagène de type I suggère un impact fonctionnel de la baisse de concentration en S1P extracellulaire sur la cellule MG-63. La mise en évidence, dans un modèle ostéoblastique, d’une altération fer-dépendante de l’axe de signalisation S1P/S1PR ouvre de nouvelles perspectives quant à la compréhension des mécanismes mis en jeu lors des pertes osseuses associées aux surcharges en ferOsteoporosis may complicate genetic or secondary iron overload as reported in clinical and animal studies. However, the mechanisms leading to disrupted bone homeostasis are still to be fully elucidated. In vitro, iron exposure of both osteoblast and osteoclast cell models induces phenotypic and functional impairment, but the molecular mechanisms of iron excess on bone cell physiology are not well characterized, particularly in osteoblast. Our objective was to study the impact of iron overload on osteoblast biology and characterize the molecular mechanisms involved. Transcriptomic analysis previously performed by our group on MG-63 osteoblast-like cell-line to identify iron-modulated genes revealed that expression of SPNS2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P), is potentially induced by iron. The purpose of this work was to characterize the SPNS2 iron-related regulation and analyze its potential impact on S1P efflux and the S1P/S1PR signaling pathway in MG-63 cells. Our findings showed that iron exposure induces a dose-dependent increase of SPNS2 mRNA levels in MG-63 osteoblast-like cells that was not observed in hepatocyte and enterocyte cell models. We then performed a fluxomic assay on MG-63 cells to investigate iron potential impact on S1P efflux. Unexpectedly, our data showed that extracellular S1P levels were decreased in presence of iron excess and its associated SPNS2 upregulation. Furthermore, based on the observed iron associated S1PR1 and COL1A1 decrease, the defect in S1P export system seems to have functional consequence on MG-63 cells. These results suggest that iron may affect osteoblast S1P/SPR signaling and potentially alter a wide range of bone processes, thus participating in bone impairment in situations of chronic iron overload. These data open a new door for the understanding of mechanisms involved in iron-induced osteoporosis
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Evangelista, Andréia Silva. "Caracterização fenotípica e genotipagem HFE em portadores de doença hepática crônica com sobrecarga de ferro." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-01082013-134115/.
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A doença hepática associada a sobrecarga de ferro pode ocorrer devido a causas genéticas ou secundárias. Esse estudo avaliou pacientes com hepatopatia crônica com sobrecarga de ferro submetidos à pesquisa das mutações HFE no período de 2007-2009 e classificou como portadores de hemocromatose hereditária HFE (HH-HFE) aqueles que apresentavam as mutações C282Y/C282Y ou C282Y/H63D e como sobrecarga de ferro não HFE aqueles que apresentavam outras mutações no gene HFE como C282Y/-, H63D/- e H63D/H63D ou pacientes sem qualquer uma dessas mutações mencionadas. Os objetivos do estudo foram 1) analisar e correlacionar os aspectos fenotípicos e genotípicos de grupo de indivíduos com doença hepática crônica e sobrecarga de ferro; 2) caracterizar o quadro clínico, laboratorial e anatomopatológico, em busca de achados compatíveis com o fenótipo de hemocromatose; 3) Correlacionar o quadro clínico com as mutações no gene HFE. Foram analisados 108 indivíduos portadores de hepatopatia crônica selecionados a partir de saturação de transferrina (ST) > 45% e ferritina sérica > 350 ng/mL. Foram estudados e comparados 16 pacientes no grupo HH-HFE com 92 no grupo sobrecarga de ferro não HFE. Da casuística geral, a idade média ao diagnóstico da doença foi de 46,69 anos (16-77), com 70,73% constituída por indivíduos de cor branca, 77,57% do sexo masculino e 64,8% tinham cirrose hepática. A frequência de cirrose hepática não diferiu entre os grupos, entretanto, artropatia, carcinoma hepatocelular, diabetes e osteoporose foram mais frequentes no grupo HH- HFE (53,8% x 15,9%, 31,2% x 7,06%, 56,2% x 30%, 72,7% x 32,1%, respectivamente, p < 0,05). Os pacientes com mutações HFE diagnósticas de HH apresentaram maior chance de ter carcinoma hepatocelular (OR= 5,0, p= 0,032) quando comparados com os portadores de outros genótipos HFE e aqueles sem mutação. Os níveis de ST, ferro e ferritina também foram maiores naquele grupo, bem como os graus de siderose 3 e 4 (p= 0,026). A ST foi a variável que se correlacionou independentemente com o diagnóstico das mutações C282Y/C282Y e C282Y/H63D. A frequência de fatores de risco para sobrecarga de ferro não diferiu entre os grupos. Observou-se, entretanto, que no grupo HH-HFE havia maior número de pacientes sem qualquer fator de risco detectado (p= 0,019). Níveis de ST > 82% apresentaram maior valor preditivo negativo para o diagnóstico de HH-HFE do que os de ferritina, ferro, capacidade total de ligação de ferro e de transferrina. Concluímos que os portadores de HH-HFE têm maiores graus de sobrecarga de ferro quando comparados ao grupo de sobrecarga de ferro não-HFE; em indivíduos com doença hepática crônica. ST > 82% tem maior acurácia para diagnóstico de HH-HFE; portadores de mutações C282Y em homozigose ou em heterozigose composta com H63D têm maior chance de apresentar carcinoma hepatocelular do que os portadores de outras mutações no gene HFE e pacientes sem mutaçãoChronic liver disease related to iron overload may occur due to genetic or secondary causes. This study analyzed patients with chronic liver diseases and iron overload who were tested for HFE mutations from 2007 to 2009. Patients with C282Y/C282Y or C282Y/H63D mutations were diagnosed with HFE hereditary hemochromatosis (HFE-HH) and those with other HFE genotypes (C282Y/-, H63D/- or H63D/H63D) or individuals without HFE mutations (wild type) were designed as non-HFE iron overload. The aims of this study were: 1) to analyze and to establish correlations between phenotypic and genotypic aspects of individuals with chronic liver disease and with iron overload; 2) to charachterize the clinical manifestations, laboratory and histological findings consistent with the phenotype of hemochromatosis; 3) to verify associations between clinical manifestations and HFE mutations. One hundred and eight patients with chronic liver diseases and with iron overload, defined as transferrin saturation (TS) > 45% and serum ferritin levels > 350 ng/mL were included. Sixteen patients had HH-HFE and were compared with 92 patients with non-HFE iron overload group. The average of age at diagnosis was 46.69 years (16-77), 70.73% were Caucasians, 77.57% were male and 64.8% had hepatic cirrhosis. The proportion of hepatic cirrhosis was similar in both groups, nevertheless arthropathy, hepatocellular carcinoma, diabetes and osteoporosis were more frequent in the HFE-HH group (53,8% x 15,9%, 31,2% x 7,06%, 56,2% x 30%, 72,7% x 32,1%, respectively, p < 0,05). The HFE C282Y/C282Y or C282Y/ H63D genotypes had a higher chance to develop hepatocellular carcinoma (OR= 5.0, p= 0.032) when compared with the other HFE genotypes and with those wild type. The levels of TS, serum iron and ferritin were greater in HFE-HH group, as well as hepatic siderosis grade 3 and 4 (p= 0.026). TS was the biochemical marker of iron overload with the higher independent correlation with the presence of C282Y/C282Y and C282Y/H63D mutations. The frequency of risk factors for iron overload was not different between the groups, however, in HFE-HH group a greater number of patients without any risk factor was detected (p= 0.019). TS > 82% had a higher predictive negative value for diagnosing HFE-HH when compared to the levels of ferritin, serum iron, total iron binding capacity and transferrin. We concluded that the HFE-HH patients had a greater iron overload than patients with chronic liver diseases with non-HFE iron overload. TS > 82% had more accuracy to diagnose HFE-HH. The carriers of C282Y/C282Y or C282Y/H63D mutations had a higher probability to develop hepatocellular carcinoma, when compared to the patients with HFE genotypes and patients wild type
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Baracioli, Lígia Márcia da Silveira Viana [UNESP]. "Processo oxidativo em doadores de sangue portadores de hemoglobina S e mutantes no gene HFE." Universidade Estadual Paulista (UNESP), 2008. http://hdl.handle.net/11449/102735.
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As hemoglobinopatias são as mais comuns das doenças genéticas e são classificadas em Talassemias e Variantes de Hemoglobinas. A Hb S é originada por uma mutação de ponto no códon que origina o aminoácido da posição seis da cadeia beta globina, resultando em uma modificação estrutural na molécula que altera sua solubilidade e cristalização. A Hb S apresenta efeito sobre as células sangüíneas, desencadeando processos oxidativos com geração de radicais livres. Efeito semelhante observa-se no acúmulo de ferro, em decorrência da hemocromatose hereditária. Os defeitos de metabolismo do ferro, em especial aqueles oriundos dos polimorfismos no gene HFE, levam ao acúmulo de ferro tecidual, com potencial capacidade oxidante e peroxidação lipídica. Fundamentados no possível efeito tóxico da mutação no gene da globina βS (Hb S) e do acúmulo de ferro tecidual, relatados na literatura, objetivou-se avaliar a influência dos polimorfismos do gene HFE na peroxidação lipídica dos portadores dessa alteração de hemoglobina e sua relação com o aumento da destruição eritrocitária e geração de estresse oxidativo. Foram analisadas 16.000 amostras de doadores de sangue e encontrou-se uma freqüência de Hb AS de 1,69% na região Noroeste do Estado de São Paulo. Destes, 43 apresentaram herança da Hb S e de pelo menos um dos dois polimorfismos no gene HFE testados. A freqüência dos polimorfismos C282Y e H63D, no gene HFE, no grupo de doadores com Hb AS, esta de acordo com os dados da literatura. No grupo de doadores de sangue com Hb AS observamos que, na herança concomitante dos dois polimorfismos, os níveis de MDA, indicativo de peroxidação lipídica, estavam elevados, indicando a influência de ambas afecções genéticas, no aumento dos níveis de peroxidação lipídica. Entretanto, os níveis médios da TEAC, indicativo da capacidade oxidante, apresentaram-se...
The hemoglobinopathies are the most common of the genetic disease and are classified in Thalassemia and Hemoglobin Variants. Hb S is originated by a point mutation in the codon that originates the sixth aminoacid of the β globin chain, resulting in a structural modification in the molecule that modifies the solubility and crystallization. Hb S presents an effect on the blood cells, unchaining the oxidative processes with the free radicals generation. Similar effect is observed in the iron accumulation, in result of the hereditary hemochromatosis. The iron metabolism defects, in special those one from the HFE gene polymorphism, lead to the tissue iron accumulation with potential oxidant capacity and lipid peroxidation. Based on the possible toxic effect of the mutation in the globin βS gene (Hb S) and tissue iron accumulation, mentioned in the literature, we was aimed evaluate the influence of HFE gene polymorphism in the lipid peroxidation in blood donors with hemoglobin S alteration and the relation with the eritrocitary destruction increase and oxidative stress generation. 16,000 samples of blood donor had been analyzed and it was found a Hb frequency of 1,69% from the Northwest São Paulo state region. Among them, 43 had presented concomitance in the Hb S inheritance and one of the two HFE gene polymorphism. The frequency of C282Y and H63D polymorphism, in the HFE gene, in the blood donor group with Hb S, is in according to the literature. We also verified in the blood donor group with Hb AS that, in the concomitant inheritance of the two polymorphism, the MDA levels, indicative of lipid peroxidation, were raised, showing the influence of both genetic affections, in the levels of lipid peroxidation. However, the TEAC average levels, indicative of the oxidant capacity, had been presented normal, indicating that in spite of a lipid peroxidation raise, this is not followed... (Complete abstract click electronic access below)
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Booley, Fadwah. "Analysis of genes implicated in iron regulation in individuals presenting with primary iron overload in the South African population." Thesis, Stellenbosch : University of Stellenbosch, 2007. http://hdl.handle.net/10019.1/2220.
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Thesis (MSc (Genetics))—University of Stellenbosch, 2007.Hereditary haemochromatosis (HH), a common autosomal recessive disease, is characterized by increased iron absorption leading to progressive iron accumulation in organs such as the liver, heart and pancreas. In the South African population the disease is prevalent in individuals of Caucasian origin, with a carrier frequency of one in six for the C282Y mutation in the HFE gene. We investigated the role of genes implicated in iron metabolism, including the high-iron gene (HFE), haem oxgenase-1 gene (HMOX1), solute carrier family 40 (iron-regulated transporter) member 1 gene (SLC40A1), cytochrome b reductase gene (CYBRD1), hepcidin antimicrobial peptide gene (HAMP) and the hemojuvelin gene (HJV) in a patient cohort with non-HFE iron overload. DNA analysis was performed on samples from 36 unrelated South African Caucasian patients presenting with primary iron overload, who tested either negative or heterozygous for C282Y. In this study, mutation screening was performed by PCR amplification and HEX-SSCP analysis. Sixteen previously described and two novel variants were identified by semi-automated DNA sequencing. Common variants identified in the HFE gene included C282Y, H63D, IVS2+4T→C, IVS4-44T→C, IVS4+48G→A and IVS5-47G→A. The Q127H mutation in exon 3 of the HFE gene was identified in one patient, who tested negative for both C282Y and H63D. Mutation S65C was identified only in the population-matched controls and was absent in the patient group. Other previously described polymorphisms identified included the IVS5+51delTGGCTGTCTGACT deletion in HMOX1, I109 and V221 in SLC40A1, IVS1-4C→G, IVS2+8T→C and S266N, in the CYBRD1 gene and, S264 and A310G in the HJV gene. The novel variants, -89C→T, in the promoter region of the CYBRD1 gene, was detected in only one patient, while S333 in exon 4 of the HJV gene was present in three patients. These variants were not identified in any of the population-matched controls screened and could explain the non-HFE iron overload presented by these patients. This study clearly demonstrates the importance of modifier genes in patients with iron overload that cannot be explained by the common C282Y mutation. Studies on iron-related genes and the identification of mutations in these genes in non-HFE patients could lead to improved diagnosis and counselling of South African patients presenting with primary iron overload.
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Le?o, Gioconda Dias Rodrigues. "An?lise das muta??es C282Y e H63D no gene da prote?na HFE em pacientes com hiperferritinemia." Universidade Federal do Rio Grande do Norte, 2007. http://repositorio.ufrn.br:8080/jspui/handle/123456789/13434.
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Previous issue date: 2007-08-29Hereditary 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; 1,1%, C282Y homozygous mutation; 31%, H63D heterozygous mutation; 8,7%, H63D homozygous mutation; and 3,3%, heterozygous for the mutation in both genes. As to gender, we observed a greater percentage of cases with molecular alteration in men in relation to women in the two evaluated mutations. The individuals with negative results showed clinical and lab signs which indicate hemochromatosis that other genes could be involved in the iron metabolism. Due to the high prevalence of hemochromatosis and taking into account that hemochromatosis is considered a public health matter, its gravity being preventable and the loss treatment toxicity, the early genetic diagnosis is indicated, especially in patients with high ferritin, and this way it avoids serious clinical manifestations and increases patients' life expectation. Our findings show the importance of doing such genetic studies in individuals suspected of hereditary hemochromatosis due to the high incidence of such a hereditary disease in our region
A hemocromatose heredit?ria (HH) ? uma doen?a gen?tica causada pela absor??o e deposi??o elevada de ferro em v?rios ?rg?os. Este ac?mulo resulta em complica??es cl?nicas como cirrose, artrite, cardiopatias, diabetes, desordens sexuais e escurecimento da pele. As muta??es H63D e C282Y est?o bem definidas na etiologia da hemocromatose. O objetivo deste trabalho foi a identifica??o das muta??es gen?ticas H63D e C282Y no gene da Hemocromatose e avalia??o da freq??ncia dessas muta??es no gene da prote?na HFE em pacientes com hiperferritinemia que s?o encaminhados ao laborat?rio DNA Center Natal / RN. Al?m disso, avaliar a correla??o dos gen?tipos das muta??es H63D e C282Y do gene da HH com a concentra??o s?rica da ferritina, glicose, alanina aminotransferase, aspartato minotransferase, gt e com as complica??es cl?nicas e ainda a interrela??o com os h?bitos de vida incluindo o etilismo e dieta com sobrecarga de ferro. As dosagens bioqu?micas e an?lises moleculares foram realizadas respectivamente atrav?s do m?todo enzim?tico e PCR com restri??o enzim?tica. Dos 183 pacientes investigados 51,4% apresentaram aus?ncia de muta??o e 48,6% com algum tipo de muta??o: 5,0% C282Y heterozigoto mutado; 1,1% C282Y homozigoto mutado; 31% H63D heterozigoto mutado; 8,7% H63D homozigoto mutado; e 3,3% heterozigoto para a muta??o em ambos os genes. Com rela??o ao sexo, observou-se o maior percentual de casos com altera??o molecular em homens em rela??o a mulheres nas duas muta??es avaliadas. Os indiv?duos com resultados negativos apresentaram sinais cl?nicos e laboratoriais indicativos de hemocromatose sugerindo que outros genes poder?o estar envolvidos no metabolismo do ferro. Devido ? alta preval?ncia da hemocromatose, e tendo em vista que a hemocromatose ? considerada um problema de sa?de p?blica, sua gravidade ser preven?vel e a baixa toxicidade do tratamento, o diagn?stico gen?tico precoce torna-se indicado, principalmente nos pacientes com ferritina elevada, e com isso evitar manifesta??es cl?nicas graves e aumentar a expectativa de vida dos pacientes com esta doen?a. Nossos achados mostram a import?ncia da realiza??o de estudos gen?ticos em indiv?duos com suspeita de hemocromatose heredit?ria em virtude de elevada incid?ncia dessa doen?a de cunho heredit?rio em nossa regi?o
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Baracioli, Lígia Márcia da Silveira Viana. "Processo oxidativo em doadores de sangue portadores de hemoglobina S e mutantes no gene HFE /." São José do Rio Preto : [s.n.], 2009. http://hdl.handle.net/11449/102735.
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Orientador: Claudia Regina Bonini DomingosBanca: Rodolfo Delfini Cançado
Banca: Ivan de Lucena Angulo
Banca: Maria Tercilia de Azeredo Oliveira
Banca: Eduardo Alves de Almeida
Resumo: As hemoglobinopatias são as mais comuns das doenças genéticas e são classificadas em Talassemias e Variantes de Hemoglobinas. A Hb S é originada por uma mutação de ponto no códon que origina o aminoácido da posição seis da cadeia beta globina, resultando em uma modificação estrutural na molécula que altera sua solubilidade e cristalização. A Hb S apresenta efeito sobre as células sangüíneas, desencadeando processos oxidativos com geração de radicais livres. Efeito semelhante observa-se no acúmulo de ferro, em decorrência da hemocromatose hereditária. Os defeitos de metabolismo do ferro, em especial aqueles oriundos dos polimorfismos no gene HFE, levam ao acúmulo de ferro tecidual, com potencial capacidade oxidante e peroxidação lipídica. Fundamentados no possível efeito tóxico da mutação no gene da globina βS (Hb S) e do acúmulo de ferro tecidual, relatados na literatura, objetivou-se avaliar a influência dos polimorfismos do gene HFE na peroxidação lipídica dos portadores dessa alteração de hemoglobina e sua relação com o aumento da destruição eritrocitária e geração de estresse oxidativo. Foram analisadas 16.000 amostras de doadores de sangue e encontrou-se uma freqüência de Hb AS de 1,69% na região Noroeste do Estado de São Paulo. Destes, 43 apresentaram herança da Hb S e de pelo menos um dos dois polimorfismos no gene HFE testados. A freqüência dos polimorfismos C282Y e H63D, no gene HFE, no grupo de doadores com Hb AS, esta de acordo com os dados da literatura. No grupo de doadores de sangue com Hb AS observamos que, na herança concomitante dos dois polimorfismos, os níveis de MDA, indicativo de peroxidação lipídica, estavam elevados, indicando a influência de ambas afecções genéticas, no aumento dos níveis de peroxidação lipídica. Entretanto, os níveis médios da TEAC, indicativo da capacidade oxidante, apresentaram-se... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The hemoglobinopathies are the most common of the genetic disease and are classified in Thalassemia and Hemoglobin Variants. Hb S is originated by a point mutation in the codon that originates the sixth aminoacid of the β globin chain, resulting in a structural modification in the molecule that modifies the solubility and crystallization. Hb S presents an effect on the blood cells, unchaining the oxidative processes with the free radicals generation. Similar effect is observed in the iron accumulation, in result of the hereditary hemochromatosis. The iron metabolism defects, in special those one from the HFE gene polymorphism, lead to the tissue iron accumulation with potential oxidant capacity and lipid peroxidation. Based on the possible toxic effect of the mutation in the globin βS gene (Hb S) and tissue iron accumulation, mentioned in the literature, we was aimed evaluate the influence of HFE gene polymorphism in the lipid peroxidation in blood donors with hemoglobin S alteration and the relation with the eritrocitary destruction increase and oxidative stress generation. 16,000 samples of blood donor had been analyzed and it was found a Hb frequency of 1,69% from the Northwest São Paulo state region. Among them, 43 had presented concomitance in the Hb S inheritance and one of the two HFE gene polymorphism. The frequency of C282Y and H63D polymorphism, in the HFE gene, in the blood donor group with Hb S, is in according to the literature. We also verified in the blood donor group with Hb AS that, in the concomitant inheritance of the two polymorphism, the MDA levels, indicative of lipid peroxidation, were raised, showing the influence of both genetic affections, in the levels of lipid peroxidation. However, the TEAC average levels, indicative of the oxidant capacity, had been presented normal, indicating that in spite of a lipid peroxidation raise, this is not followed... (Complete abstract click electronic access below)
Doutor
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Estevão, Isabeth da Fonseca [UNESP]. "Frequência dos mutantes C282Y e H63D do gene HFE e sua influência no metabolismo do ferro e na expressão da beta talassemia heterozigota." Universidade Estadual Paulista (UNESP), 2007. http://hdl.handle.net/11449/92482.
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estevao_if_me_sjrp.pdf: 1151592 bytes, checksum: 9e2d3a0a29b1ad6405857d13d891a9f1 (MD5)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A beta talassemia é um dos mais freqüentes distúrbios genéticos no mundo. Estima-se que 1,5% a 3% da população mundial seja portadora do traço talassêmico. Esses portadores geralmente são oligo ou assintomáticos e têm uma expectativa de vida semelhante à dos não portadores. Entretanto, níveis elevados de ferritina sérica têm sido observados em alguns estudos comparativos entre beta talassemia heterozigota e não portadores e, alguns indivíduos, que nunca foram transfundidos, apresentam sinais clínicos e laboratoriais de sobrecarga de ferro. A fisiopatologia dessa complicação continua em discussão. Vários pesquisadores têm sugerido um efeito modulador da mutação do gene da beta globina e mutações em genes codificadores de proteínas relacionadas ao metabolismo do ferro. Mutações no gene HFE são as mais freqüentemente associadas à hemocromatose hereditária. O objetivo do presente trabalho foi avaliar a freqüência das mutações C282Y e H63D no gene HFE em portadores de beta talassemia heterozigota e analisar sua influência no metabolismo do ferro. Foram estudados 162 portadores de beta talassemia heterozigota, residentes na cidade de São Carlos ou região, caucasóides e, acompanhados no serviço de Hematologia. O diagnóstico de traço talassêmico foi confirmado em todos por meio do eritrograma e da quantificação da Hb A2 e Hb fetal por HPLC. O metabolismo do ferro foi avaliado pelas dosagens de ferro sérico, capacidade total de ligação do ferro, ferritina e saturação da transferrina e, a análise molecular das mutações no gene HFE, pela técnica de PCR-RLFP. Foram realizadas análises de correlação linear de Pearson por idade e gênero entre hemoglobina...
Beta thalassemia is one of the most frequent genetic disorder in the world. It is estimated that 1.5% to 3% of the world population is a thalassemia carrier. These individuals are generally slightly symptomatic or asymptomatic and they have a life expectancy similar to those who are non-carriers. However, high levels of serum ferritin have been observed in some comparative studies between heterozygous for beta thalassemia and non-carriers, and some individuals that were never transfused, present clinic and laboratories signs of iron overload. The physiopathology of this disease continues in discussion. Several researchers have suggested a modulator effect from the mutation of the beta globin gene and mutations in genes related with the iron metabolism. Mutations of the gene HFE are the most frequently associated to the hereditary hemochromatosis. The aim of this study was evaluate the frequency of C282Y and H63D mutations in the HFE gene in beta thalassemia carriers, and analyze its influence in the iron metabolism. 162 beta thalassemia carriers, Caucasoid, residing in the city of Sao Carlos or region and accompanied in the Hematology service were studied. The diagnostic of thalassemia trait was confirmed in every one through a complete erythrogram and quantification of Hb A2 and Hb fetal by HPLC. The iron metabolism was evaluated by serum iron, total iron-binding capacity, serum ferritin and percent saturation of transferring. The molecular analysis of the mutations in the HFE gene was made by PCR-RLFP. There were made analysis of linear Pearson’ correlation, by age and gender, among hemoglobin, Hb A2, VCM and among reticulocytes count and the values of saturation of transferrin and serum ferritin.
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Menezes, Figueiredo Joelma. "Estudo de polimorfismos em genes de moléculas associadas ao estresse oxidativo na doença falciforme: associação com dados hematológicos, bioquímicos e fenotípicos." reponame:Repositório Institucional da FIOCRUZ, 2010. https://www.arca.fiocruz.br/handle/icict/4225.
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Joelma Figueiredo Menezes Estudo de polimorfismos....pdf: 11425878 bytes, checksum: 175372593b635c3bd50b3a10af52fc30 (MD5)Made available in DSpace on 2012-07-20T20:46:00Z (GMT). No. of bitstreams: 1 Joelma Figueiredo Menezes Estudo de polimorfismos....pdf: 11425878 bytes, checksum: 175372593b635c3bd50b3a10af52fc30 (MD5) Previous issue date: 2010
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil
Indivíduos com doença falciforme (DF) apresentam estresse oxidativo (EO) constante, que é decorrente da deficiência nos sistemas antioxidantes, caracterizados pela produção de espécies reativas do oxigênio (EROS) de origem multifatorial, principalmente geradas pelo processo hemolítico. Objetivo. Investigar polimorfismos relacionados ao estresse oxidativo nos genes HFE da hemocromatose hereditária (c.282C>Y, c.63H>D e c.65S>C); haptoglobina (HP), glutationa S-transferase (GST) (GSTT1 e GSTM1) e paraoxonase (PON1) (c.55L>M e c.192Q>R), associando-os aos dados hematológicos e bioquímicos, aos níveis séricos de vitamina C, paraoxonase 1 e receptor de transferrina e histórico clínico de pacientes com doença falciforme. Casuística e Métodos. A casuística foi composta por 153 indivíduos com DF (HbSS e HbSC) e 196 crianças saudáveis. O perfil de hemoglobinas foi determinado por HPLC. Os polimorfismos nos genes HFE, HP, GST, PON1, a presença da talassemia alfa 3,7Kb e 4,2Kb e dos haplótipos ligados ao grupo de genes da globina beta foram investigados por PCR e PCR-RFLP. A avaliação do perfil lipídico, hepático, função renal, inflamatório e metabolismo do ferro foram realizadas por técnicas espectrofotométricas. Os níveis séricos de vitamina C, receptor de transferrina solúvel e hemeoxigenase 1 total foram detectados por ELISA. Resultados. O estudo de polimorfismos no gene da GST demostrou que o genótipo Mu nulo foi o mais frequente em ambos os grupos estudados; a análise hematológica , nos indivíduos HbSS revelou diferença significante para os parâmetros de leucócitos (p=0,0452), de segmentados neutrófilos (p=0,0224) e o evento de STA (p=0,0423); nos indivíduos com DF foram encontradas diferenças para a uréia (p=0,0288) e ferritina (p=0,0316). No estudo do gene da Haptoglobina nos indivíduos com DF encontrou-se diferença significativa para contagem de reticulócitos (p=0,0167), ferritina sérica (p=0,0493); contagem de linfócitos típicos (p=0.0422) e LDH (p=0,0181); nos HbSS encontrou-se diferença para creatinina (p=0,0178) e ALT (p=0,0127). Para o gene HFE foi encontrada diferença significativa entre os alelos selvagem e mutante para o polimorfismo c.63H>D e contagem de plaquetas (p=0,0311) em indivíduos com DF; para o polimorfismo c.65S>C observou-se diferenças estatisticamente significativas para hemoglobina (p=0,0044) e hematócrito (p=0,0078). Nos HbSC para o polimorfismo c.63H>D observou-se entre os alelos selvagem e mutante diferenças significativas com o VCM (p=0,0032), HCM (p=0,0010) e linfócitos típicos (p=0,0242). Entre os indivíduos HbSS observou-se diferença significativa entre os alelos estudados e plaquetas (p=0,0078). Para a mutação c.65S>C observou-se diferenças significativas para os parâmetros de hemoglobina (p=0,0265) e hematócrito (p=0,0407) nos indivíduos HbSS e hemoglobina (p=0,0051) e hematócrito (p=0,0060) nos indivíduos HbSC. A análise do histórico clínico dos indivíduos com DF e o polimorfismo c.63H>D demonstrou diferença significativa para esplenomegalia, OR=3,38 (0,93 -12,22) e p=0,0402. Nos indivíduos HbSS foi encontrada diferença significativa entre os alelos c.63H>D e infecção, com OR=0,29 (0.07 -1,18) e p=0,0455. Para o gene PON1, a avaliação da atividade da PON1 nos indivíduos DF entre os alelos selvagem e mutante revelou diferença estatisticamente significativa, tendo o alelo selvagem maior atividade da PON1 que alelo mutante; para o polimorfismo PON1c.192Q>R observou-se entre os alelos selvagem e mutante diferenças significativas para as variáveis bioquímicas VLDL-C (p=0,0267) e triglicérides (p=0,0127). Nos HbSC verificou-se diferença estatística significativa para o PON1c.192Q>R e concentração de hemoglobina (p=0,0459), hematócrito (p=0,0225) e contagem de linfócitos típicos (p=0,0364). Para o PON1c.55L>M observou-se diferença significativa com a idade (p=0,0139), plaquetas (p=0,0109), creatinina (p=0,0329) e PCR (p=0,0141). Observou-se associação entre atividade da PON1 e esplenectomia (p=0,001); para hemeoxigenase e ferro sérico (p=0,023); e para vitamina C observamos correlação com colesterol HDL (p=0,037). Há correlação entre glutationa e vitamina C (p=0,035).Conclusões: Os polimorfismos estudados podem estar agindo sinergicamente com a hemoglobina variante S e assim influenciar na gravidade da doença, necessitando de outros estudos para validar estes resultados, uma vez que algumas destas investigações foram realizadas pela primeira vez neste grupo de indivíduos.
Patients with sickle cell disease (SCD) has continued oxidative stress (OS), which is resulting from ineffective antioxidant systems, characterized by production of reactive oxygen species (ROS) of multifactorial origin, mainly generated by the hemolytic process. Objective: To investigate polymorphism related to oxidative stress in hereditary hemochromatosis HFE gene (c.282C>Y, c.63H>D c.65S and D>C), haptoglobin (HP), glutathione S-transferase (GST) (GSTT1 and GSTM1) and paraoxonase (PON1) (c.55L>M and c.192Q>R), in association with the hematological and biochemical data, serum levels of vitamin C, paraoxonase 1, transferrin receptor and clinical manifestations of SCD patients. Methods. The sample included 153 individuals with SCD (HbSS and HbSC) and 196 healthy children. The profile of hemoglobin was determined by HPLC. The HFE gene polymorphisms, HP, GST, PON1, the presence of alpha thalassemia 3.7 Kb, 4.2 Kb and haplotypes of the beta gene cluster were investigated by PCR and PCR-RFLP. The lipid profile, liver, renal function, inflammation and iron metabolism was performed by spectrophotometric techniques. Serum levels of vitamin C, soluble transferrin receptor and total hemeoxigenase were investigated by ELISA. Results: The GST Mu null genotype was more frequent in both groups and both polymorphisms were in Hardy-Weinberg equilibrium. In the HbSS observed significant differences in the parameters of leukocytes (p = 0.0452) and segmented neutrophils (p = 0.0224) and event STA (p = 0.0423). Individuals with SCD had differences for urea (p = 0.0288) and ferritin (p = 0.0316). Evaluating the Haptoglobin gene in individuals with SCD found a significant difference for reticulocyte count (p = 0.0167), serum ferritin (p = 0.0493); typical lymphocyte count (p = 0.0422) and LDH (p = 0.0181); in the HbSS were found differences for creatinine (p = 0.0178) and ALT (p = 0.0127). For the HFE gene was found significant differences were observed between wild and mutant alleles for the polymorphism c.63H> D and platelet count (p = 0.0311) in individuals with SCD; for polymorphism c.65S> C were differences were statistically significant for hemoglobin (p = 0.0044) and hematocrit (p = 0.0078). In the HBSC observed significant differences in MCV (p = 0.0032), MCH (p= 0.0010) and typical lymphocytes (p = 0.0242). Among subjects HbSS were observed significant differences between alleles and platelets (p = 0.0078). For mutation c.65S> C showed significant differences in the parameters of hemoglobin (p=0.0265) and hematocrit (p=0.0407) in HbSS individuals, and hemoglobin (p=0.0051) and hematocrit (p=0.0060) in subjects HbSC. The analysis of the clinical history of individuals with SCD and polymorphism c.63H> D there was a significant difference for splenomegaly, OR = 3.38 (0.93 -12.22) and p = 0.0402. In HbSS individuals significant difference was found between alleles c.63H> D and infection, with OR = 0.29 (0.07 -1.18) p = 0.0455. For the PON1 gene, The activity assessment of PON1 in the individuals DF with wild and mutant genotypes showed statistically significant differences, the wild-type allele showed higher PON1 activity than the mutant allele; for the biochemical parameters to polymorphism PON1c.192Q> R and the values of VLDL-C (p = 0.0267) and triglycerides (p = 0.0127). In HbSC there was a statistically significant difference for PON1c.192Q> R and hemoglobin (p = 0.0459), hematocrit (p = 0.0225) and typical lymphocyte count (p = 0.0364). For PON1c.55L> M there was significant difference with age (p = 0.0139), platelets (p = 0.0109), creatinine (p = 0.0329) and CRP (p= 0.0141). There was an association between PON1 activity and splenectomy (p = 0.001) for hemeoxigenase and serum iron (p = 0.023), and vitamin C showed a correlation with HDL cholesterol (p = 0.037). There is a correlation between glutathione and vitamin C (p=0.035) Conclusions: The polymorphisms could be acting synergistically with this hemoglobin variant S, and influence the severity of disease, have been necessary further studies to validate these results, since some of these investigations were performed for the first time in this group of individuals.
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Santos, Paulo Caleb Júnior de Lima. "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." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-04022011-110402/.
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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, em relação aos de genótipo selvagem. Para os pacientes, 72,5% (37/51) apresentaram ao menos 1 alteração no gene HFE e 11 foram identificados como homozigotos para a mutação p.C282Y. Uma mutação não descrita na literatura (p.V256I) foi identificada no gene HFE e a modelagem molecular (análises de ligação e estrutural) detectou que a mutação não reduziu a afinidade entre as proteínas HFE e β2-microglobulina. No sequenciamento dos éxons dos genes HJV e HAMP foram identificadas as alterações já descritas: HJV p.E302K, HJV p.A310G, HJV p.G320V e HAMP p.R59G. Para o gene TFR2, foram identificados 3 polimorfismos já descritos (p.A75V, p.A617A e p.R752H). No gene SLC40A1 foram observados 6 polimorfismos (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704 e rs11568346) e 1 alteração não descrita previamente na literatura (p.G204S). As conclusões foram: 1- em relação aos doadores de sangue, a presença dos alelos HFE 282Y e HFE 63D foi associada ao maior aporte de ferro nos homens que não doaram sangue anteriormente. 2.1- Para os pacientes com sobrecarga de ferro, a mutação p.C282Y em homozigose, ou em heterozigose composta com a p.H63D, foi a mais frequente alteração encontrada (33,3%). 2.2- O diagnóstico molecular de hemocromatose juvenil (HJ) no Brasil (HJV p.G320V em homozigose) foi relatado. As mutações funcionais HJV p.E302K e HAMP p.R59G foram identificadas, sendo possível que estas alterações possam estar contribuindo para consequências fenotípicas juntas as outras mutações em regiões intrônicas ou regulatórias dos genes. 2.3- Mutações funcionais nos genes TFR2 e SLC40A1 não foram identificadas.Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption, which leads to a progressive accumulation of iron in the body. The aims were: 1- to assess the frequency of HFE gene mutations (p.C282Y, p.H63D and p.S65C) and to identify their relationship to iron status in blood donors; 2- to search in primary iron overload patients: 2.1- HFE, 2.2- HJV and HAMP, 2.3- TFR2 and SLC40A1 gene mutations. Blood donors (n=542) were recruited from Hemocentro of Santa Casa Hospital, Sao Paulo, Brazil. The study included 51 patients with transferrin saturation ≥ 50% (women) and ≥ 60% (men) and absence of secondary causes. The genotypes for HFE mutations were evaluated by PCR-RFLP. Subsequent bidirectional sequencing for each gene was performed using the Genetic Analizer sequencer 3500XL®. The frequencies of HFE 282Y, HFE 63D and HFE 65C alleles were 2.1, 13.6 and 0.6% in blood donors, respectively. The first time male donors carrying heterozygous genotype for the p.C282Y mutation had higher transferrin saturation values; and men carrying HFE 63DD and 63HD genotypes had higher serum ferritin concentrations when compared to the wild genotype. Thirtyseven (72.5%) out of the 51 patients presented at least one HFE mutation and 11 were identified as homozygous for the mutation p.C282Y. One novel mutation (p.V256I) in the HFE gene was indentified and molecular modeling (free energy and structural analysis in silico) showed that p.V256I mutation did not reduce the affinity binding between HFE and β2-microglobulin. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Sequencing in the TFR2 gene observed 3 polymorphisms (p.A75V, p.A617A e p.R752H); and sequencing in the SLC40A1 gene identified 6 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704 e rs11568346) and 1 p.G204S non-described mutation. The conclusions were: 1- for blood donors, the presence of HFE 282Y and HFE 63D alleles were associated with alterations on iron status only in first time male blood donors. 2.1- For patients with iron overload, the p.C282Y mutation in homozygous or in compound heterozygous with p.H63D, was the most frequent molecular change found (33.3%). 2.2- The molecular diagnosis of Juvenil Hemochromatosis (JH) in Brazil (homozygous genotype for the HJV p.G320V) was reported. The HJV p.E302K and HAMP p.R59G functional mutations were found and, it is conceivable that they may be contributing to phenotypic consequences together to other mutations in intronic or regulatory regions. 2.3- Functional mutation in the TFR2 and SLC40A1 genes were not identified.
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Estevão, Isabeth da Fonseca. "Frequência dos mutantes C282Y e H63D do gene HFE e sua influência no metabolismo do ferro e na expressão da beta talassemia heterozigota /." São José do Rio Preto : [s.n.], 2007. http://hdl.handle.net/11449/92482.
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Resumo: A beta talassemia é um dos mais freqüentes distúrbios genéticos no mundo. Estima-se que 1,5% a 3% da população mundial seja portadora do traço talassêmico. Esses portadores geralmente são oligo ou assintomáticos e têm uma expectativa de vida semelhante à dos não portadores. Entretanto, níveis elevados de ferritina sérica têm sido observados em alguns estudos comparativos entre beta talassemia heterozigota e não portadores e, alguns indivíduos, que nunca foram transfundidos, apresentam sinais clínicos e laboratoriais de sobrecarga de ferro. A fisiopatologia dessa complicação continua em discussão. Vários pesquisadores têm sugerido um efeito modulador da mutação do gene da beta globina e mutações em genes codificadores de proteínas relacionadas ao metabolismo do ferro. Mutações no gene HFE são as mais freqüentemente associadas à hemocromatose hereditária. O objetivo do presente trabalho foi avaliar a freqüência das mutações C282Y e H63D no gene HFE em portadores de beta talassemia heterozigota e analisar sua influência no metabolismo do ferro. Foram estudados 162 portadores de beta talassemia heterozigota, residentes na cidade de São Carlos ou região, caucasóides e, acompanhados no serviço de Hematologia. O diagnóstico de traço talassêmico foi confirmado em todos por meio do eritrograma e da quantificação da Hb A2 e Hb fetal por HPLC. O metabolismo do ferro foi avaliado pelas dosagens de ferro sérico, capacidade total de ligação do ferro, ferritina e saturação da transferrina e, a análise molecular das mutações no gene HFE, pela técnica de PCR-RLFP. Foram realizadas análises de correlação linear de Pearson por idade e gênero entre hemoglobina... (Resumo completo, clicar acesso eletrônico abaixo)Abstract: Beta thalassemia is one of the most frequent genetic disorder in the world. It is estimated that 1.5% to 3% of the world population is a thalassemia carrier. These individuals are generally slightly symptomatic or asymptomatic and they have a life expectancy similar to those who are non-carriers. However, high levels of serum ferritin have been observed in some comparative studies between heterozygous for beta thalassemia and non-carriers, and some individuals that were never transfused, present clinic and laboratories signs of iron overload. The physiopathology of this disease continues in discussion. Several researchers have suggested a modulator effect from the mutation of the beta globin gene and mutations in genes related with the iron metabolism. Mutations of the gene HFE are the most frequently associated to the hereditary hemochromatosis. The aim of this study was evaluate the frequency of C282Y and H63D mutations in the HFE gene in beta thalassemia carriers, and analyze its influence in the iron metabolism. 162 beta thalassemia carriers, Caucasoid, residing in the city of Sao Carlos or region and accompanied in the Hematology service were studied. The diagnostic of thalassemia trait was confirmed in every one through a complete erythrogram and quantification of Hb A2 and Hb fetal by HPLC. The iron metabolism was evaluated by serum iron, total iron-binding capacity, serum ferritin and percent saturation of transferring. The molecular analysis of the mutations in the HFE gene was made by PCR-RLFP. There were made analysis of linear Pearson' correlation, by age and gender, among hemoglobin, Hb A2, VCM and among reticulocytes count and the values of saturation of transferrin and serum ferritin.
Orientador: Claudia Regina Bonini Domingos
Coorientador: Antonio José Manzato
Banca: Celso Carlos de Campos Guerra
Banca: Paula Rahal Liberatore
Mestre
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Saliou, Philippe. "Hémochromatose HFE : influence de facteurs génétiques et non génétiques sur l'expression phénotypique." Thesis, Brest, 2014. http://www.theses.fr/2014BRES0101/document.
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L’hémochromatose HFE est une maladie du métabolisme du fer liée au gène HFE dont la principale mutation est C282Y. L’objectif général de ce travail était d’étudier l’influence de facteurs génétiques et non génétiques sur l’expression phénotypique de patients atteints d’hémochromatose HFE. Cette étude prospective incluait les patients C282Y/C282Y etC282Y/H63D inclus en protocole de saignées entre janvier 2004 et décembre 2011 au centre de santé brestois de l’EFS-Bretagne. Dans un premier temps, nous avons étudié l’influence du génotype C282Y/H63D sur la survenue d’une surcharge en fer. Nous avons confirmé que le variant H63D doit être considéré comme un facteur de susceptibilité dont l’expression est liée à la présence de co-facteurs responsables d’une hyper ferritinémie. Ensuite, nous avons étudié le rôle des grossesses et de l’alimentation sur l’expression phénotypique du génotype C282Yhomozygote. Nous avons montré qu’il existe bien une différence d’expressivité clinique liée au sexe chez les patients C282Y/C282Y. Cependant, nos données n’ont pas confirmé l’effet protecteur typiquement attribué aux grossesses pour expliquer la plus lente accumulation de fer chez les femmes. Cette étude a également mis en évidence une association modérée entre la consommation d’aliments riches en fer et le degré de surcharge en fer des patients C282Yhomozygotes traités par phlébotomies. Ce travail contribue à mieux comprendre l’hétérogénéité phénotypique observée dans l’hémochromatose HFE. La finalité est de pouvoir repérer précocement les sujets les plus à risque de développer les surcharges en fer les plus sévères et par conséquent des complications cliniquesHFE hemochromatosis is a disorder of iron metabolism related to the HFE gene whose mainmutation is C282Y. The overall aim of this study was to investigate the influence of genetic and non genetic factors on phenotypic expression of patients with HFE hemochromatosis. This prospective study included the C282Y/C282Y and C282Y/H63D patients enrolled in a phlebotomy program between 2004 and 2011 in a blood centre of western Brittany (Brest, France). First, weassessed the weight of the C282Y/H63D genotype in the occurrence of iron overload. We confirmed that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors responsible for hyper ferritinemia. Then we investigated the effect of pregnancies and iron-rich diet on phenotypic expressivity of the C282Y/C282Y genotype. We have shown that there is a difference in clinical expression related to gender in C282Y/C282Ypatients. However our findings did not confirm that pregnancies protect against iron accumulationin women. This study established a moderate link between dietary iron intake and the degree of iron overload in HFE hemochromatosis patients who come to medical attention. This work contributes to a better understanding of the phenotypic heterogeneity observed in HFE hemochromatosis. The purpose is to identify precociously subjects the most at risk of developing iron overload and therefore clinical complications
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Vieira, Fatima Mendonça Jorge. "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." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5133/tde-24012013-170707/.
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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 (8,3% versus 1,77%, odds ratio 5,02, IC [95%] = [4,1%; 14,8%], p=0,0001) e H63D (27,5% versus 14,05, odds ratio 2,32, IC [95%] = [19,7%; 36,4%], p=0,0004) em relação à população grupo controle. A hepatite C estava presente em 41,7% dos pacientes e estava associada à ingestão de álcool em 71,7% dos casos. Conclusões: As mutações HFE e a expressão clínica da hemocromatose hereditária podem contribuir isoladamente para o desencadeamento da PCT, independente-mente da presença de outros fatores precipitantes; o que torna a pesquisa das mutações HFE um exame necessário nos pacientes com PCT. Nos pacientes homozigotos para C282Y e heterozigotos compostos (C282Y/H63D) a flebotomia é o tratamento de primeira escolha. A porfiria cutânea tardia pode ser um marcador cutâneo para a hemocromatose e o dermatologista pode auxiliar no seu diagnóstico e tratamento precoce.Background: Porphyria cutanea tarda (PCT) is the most common form of porphyria and is characterized by the decreased activity of the uroporphyrinogen decarboxylase enzyme. Several reports associated HFE gene mutations of hereditary hemochromatosis with PCT worldwide, although up to date only one study has been conducted in Brazil. Objective: Study the association between porphyria cutanea tarda and C282Y and H63D mutations in the HFE gene of hereditary hemochromatosis. Identify the association with alcoholism, hepatitis C, hepatitis B and HIV infection and relate them with the presence or absence of the HFE gene mutations and study retrospectively the therapeutic response to chloroquine. Methods: Ambispective study in the period from 2003 to 2012 to detect the C282Y and H63D mutations in 60 patients with porphyria cutanea tarda. The family history, alcoholism, hepatitis C, hepatitis B and HIV were investigated. HFE mutations were held with real-time PCR. The therapeutic response was assessed using the urinary porphyrins (24h urine), the iron profile (serum iron, ferritin and transferrin saturation) and the liver enzymes, before and after biochemical remission. Results: The frequency of alleles of the mutations were significantly higher in patients with PCT for C282Y (8.3% vs. 1.77%, odds ratio 5.02, CI [95%] = [4.1%; 14.8%], p = 0.0001) and H63D (27.5% vs. 14.05, odds ratio 2.32, CI [95%] = [19.7% and 36.4%], p = 0.0004) in relation to group control population. Hepatitis C was found in 41.7% of the patients and was associated with the ingestion of alcohol in 71.7% of cases. Conclusions: The HFE mutations and clinical expression of hereditary hemochromatosis can contribute in an isolated manner to the outbreak of PCT, independently of the existence of other precipitating factors. This makes the search for HFE mutations necessary in patients with PCT. In patients who are homozygous for C282Y and compound heterozygotes (C282Y/H63D) phlebotomy is the treatment of first choice. Porphyria cutanea tarda can be a cutaneous marker for hemochromatosis and the dermatologist can help in its diagnosis and early treatment.
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HOFFMAN-GLEMANE, HEDOUIN SABINE. "Hemochromatose idiopathique diagnostiquee au decours d'une yersiniose." Amiens, 1989. http://www.theses.fr/1989AMIEM021.
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Praline, Julien. "Génétique des formes sporadiques de sclérose latérale amyotrophique." Thesis, Tours, 2009. http://www.theses.fr/2009TOUR3139/document.
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La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative d’évolution toujours fatale. Dans les formes sporadiques (SLAS), l’étiologie demeure inconnue et l’hypothèse d’une participation génétique dans le cadre d’un modèle de maladie complexe est envisagée. Notre travail porte sur deux gènes de susceptibilité dans la SLAS : le gène de l’Apolipoprotéine E (APOE) et le gène impliqué dans l’hémochromatose familiale de type 1 (HFE). Notre première étude confirme sur une population de 1482 patients atteints de SLA sporadique le lien entre allèle ε4 et la forme bulbaire de la maladie mais uniquement chez les hommes. Nous proposons une explication physiopathologique faisant intervenir le récepteur aux androgènes, particulièrement exprimé au niveau des motoneurones bulbaires. Notre deuxième étude sur 244 patients et 302 contrôles ne retrouve pas l’association entre le polymorphisme H63D et le risque de SLA sporadique notée dans d’autres populations. En revanche, l’allèle Y du polymorphisme C282Y semble exercer un effet protecteur vis-à-vis de la SLA. Ces données sont discutées dans le contexte de l’hypothèse physiopathologique du stress oxydantAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The cause of sporadic cases (SALS) remains unknown but a genetic participation in a model of complex disease is suspected. Our work concerns two susceptibility genes for SALS: Apolipoprotein E gene (APOE) and the gene involved in familial hemochromatosis (HFE). Our first study including 1482 patients with SALS confirms a link between ε4 allele and bulbar-onset of the disease, only in men. We suggest a pathophysiological explanation with a role for the androgen receptor which is particularly abundant in motor neurons of the brainstem. Our second study about 244 patients and 302 controls did not find any association between the H63D polymorphism and SLAS, which has previously been showed. However, the Y allele of the C282Y polymorphism seems to exert a protective effect against SALS. We discuss these data within the pathophysiological hypothesis of oxidative stress in ALS
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LOPEZ, JEAN-PHILIPPE. "Etude comparative des parametres biologiques et morphologiques au cours de l'evolution d'une hemochromatose genetique." Lille 2, 1994. http://www.theses.fr/1994LIL2M141.
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