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1.
Proc Natl Acad Sci U S A ; 117(27): 15620-15631, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32576689

RESUMO

Repulsive guidance molecules (RGMs) are cell surface proteins that regulate the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. They control fundamental biological processes, such as migration and differentiation by direct interaction with the Neogenin (NEO1) receptor and function as coreceptors for the bone morphogenetic protein (BMP)/growth differentiation factor (GDF) family. We determined crystal structures of all three human RGM family members in complex with GDF5, as well as the ternary NEO1-RGMB-GDF5 assembly. Surprisingly, we show that all three RGMs inhibit GDF5 signaling, which is in stark contrast to RGM-mediated enhancement of signaling observed for other BMPs, like BMP2. Despite their opposite effect on GDF5 signaling, RGMs occupy the BMP type 1 receptor binding site similar to the observed interactions in RGM-BMP2 complexes. In the NEO1-RGMB-GDF5 complex, RGMB physically bridges NEO1 and GDF5, suggesting cross-talk between the GDF5 and NEO1 signaling pathways. Our crystal structures, combined with structure-guided mutagenesis of RGMs and BMP ligands, binding studies, and cellular assays suggest that RGMs inhibit GDF5 signaling by competing with GDF5 type 1 receptors. While our crystal structure analysis and in vitro binding data initially pointed towards a simple competition mechanism between RGMs and type 1 receptors as a possible basis for RGM-mediated GDF5 inhibition, further experiments utilizing BMP2-mimicking GDF5 variants clearly indicate a more complex mechanism that explains how RGMs can act as a functionality-changing switch for two structurally and biochemically similar signaling molecules.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Ligadas por GPI/metabolismo , Fator 5 de Diferenciação de Crescimento/metabolismo , Proteína da Hemocromatose/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 2/ultraestrutura , Moléculas de Adesão Celular Neuronais/ultraestrutura , Cristalografia por Raios X , Proteínas Ligadas por GPI/ultraestrutura , Fator 5 de Diferenciação de Crescimento/ultraestrutura , Proteína da Hemocromatose/ultraestrutura , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Proteínas do Tecido Nervoso/ultraestrutura , Domínios Proteicos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Transdução de Sinais
2.
Toxicology ; 441: 152525, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32540480

RESUMO

There is considerable interest in gene and environment interactions in neurodegenerative diseases. The HFE (homeostatic iron regulator) gene variant (H63D) is highly prevalent in the population and has been investigated as a disease modifier in multiple neurodegenerative diseases. We have developed a mouse model to interrogate the impact of this gene variant in a model of paraquat toxicity. Using primary astrocytes, we found that the H67D-Hfe(equivalent of the human H63D variant) astrocytes are less vulnerable than the WT-Hfe astrocytes to paraquat-induced cell death, mitochondrial damage, and cellular senescence. We hypothesized that the Hfe variant-associated protection is a result of the activation of the Nrf2 antioxidant defense system and found a significant increase in Nrf2 levels after paraquat exposure in the H67D-Hfe astrocytes than the WT-Hfe astrocytes. Moreover, decreasing Nrf2 by molecular or pharmaceutical manipulation resulted in increased vulnerability to paraquat in the H67D-Hfe astrocytes. To further elucidate the role of Hfe variant genotype in neuroprotection mediated by astrocytes, we added media from the paraquat-treated astrocytes to differentiated SH-SY5Y neuroblastoma cells and found a significantly larger reduction in the viability when treated with WT-Hfe astrocyte media than the H67D-Hfe astrocyte media possibly due to higher secretion of IL-6 observed in the WT-Hfe astrocytes. To further explore the mechanism of Nrf2 protection, we measured NQO1, the Nrf2-mediated antioxidant, in primary astrocytes and found a significantly higher NQO1 level in the H67D-Hfe astrocytes. To consider the translational potential of our findings, we utilized the PPMI (Parkinson's Progression Markers Initiative) clinical database and found that, consistent with the mouse study, H63D-HFE carriers had a significantly higher NQO1 level in the CSF than the WT-HFE carriers. Consistent with our previous reports on H63D-HFE in disease, these data further suggest that HFE genotype in the human population impacts the antioxidant defense system and can therefore alter pathogenesis.


Assuntos
Proteína da Hemocromatose/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Feminino , Genótipo , Proteína da Hemocromatose/efeitos dos fármacos , Proteína da Hemocromatose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Paraquat/toxicidade
4.
PLoS One ; 15(4): e0232125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324809

RESUMO

BACKGROUND: Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. MATERIALS AND METHODS: We evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 µg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy. RESULTS: These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. CONCLUSIONS: ID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.


Assuntos
Anemia Ferropriva/epidemiologia , Grupos Étnicos/classificação , Ferritinas/sangue , Proteína da Hemocromatose/genética , Transferrina/análise , Adulto , Idoso , Anemia Ferropriva/genética , Anemia Ferropriva/metabolismo , Canadá/epidemiologia , Estudos Transversais , Grupos Étnicos/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Prevalência , Estados Unidos/epidemiologia
6.
PLoS One ; 14(12): e0226821, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856248

RESUMO

The homeostatic iron regulator protein HFE is involved in regulation of iron acquisition for cells. The prevalence of two common HFE gene variants (H63D, C282Y) has been studied in many cancer types; however, the impact of HFE variants, sex and HFE gene expression in lung cancer has not been studied. We determined the prevalence of HFE variants and their impact on cancer phenotypes in lung cancer cell lines, in lung cancer patient specimens, and using The Cancer Genome Atlas (TCGA) database. We found that seven out of ten human lung cancer cell lines carry the H63D or C282Y HFE variant. Analysis of lung cancer specimens from our institute (Penn State Hershey Medical Center) revealed a sex and genotype interaction risk for metastasis in lung adenocarcinoma (LUAD) patients; H63D HFE is associated with less metastasis in males compared to wild type (WT) HFE; however, females with the H63D HFE variant tend to develop more metastatic tumors than WT female patients. In the TCGA LUAD dataset, the H63D HFE variant was associated with poorer survival in females compared to females with WT HFE. The frequency of C282Y HFE is higher in female lung squamous cell carcinoma (LUSC) patients of TCGA than males, however the C282Y HFE variant did not impact the survival of LUSC patients. In the TCGA LUSC dataset, C282Y HFE patients (especially females) had poorer survival than WT HFE patients. HFE expression level was not affected by HFE genotype status and did not impact patient's survival, regardless of sex. In summary, these data suggest that there is a sexually dimorphic effect of HFE polymorphisms in the survival and metastatic disease in lung cancer.


Assuntos
Carcinoma/genética , Proteína da Hemocromatose/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
7.
Nutrients ; 11(10)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658725

RESUMO

Iron deficiency (ID), anemia, iron deficiency anemia (IDA) and excess iron (hemoconcentration) harm maternal-fetal health. We evaluated the effectiveness of different doses of iron supplementation adjusted for the initial levels of hemoglobin (Hb) on maternal iron status and described some associated prenatal determinants. The ECLIPSES study included 791 women, randomized into two groups: Stratum 1 (Hb = 110-130g/L, received 40 or 80mg iron daily) and Stratum 2 (Hb > 130g/L, received 20 or 40mg iron daily). Clinical, biochemical, and genetic information was collected during pregnancy, as were lifestyle and sociodemographic characteristics. In Stratum 1, using 80 mg/d instead of 40 mg/d protected against ID on week 36. Only women with ID on week 12 benefited from the protection against anemia and IDA by increasing Hb levels. In Stratum 2, using 20 mg/d instead of 40 mg/d reduced the risk of hemoconcentration in women with initial serum ferritin (SF) ≥ 15 µg/L, while 40 mg/d improved SF levels on week 36 in women with ID in early pregnancy. Mutations in the HFE gene increased the risk of hemoconcentration. Iron supplementation should be adjusted to early pregnancy levels of Hb and iron stores. Mutations of the HFE gene should be evaluated in women with high Hb levels in early pregnancy.


Assuntos
Anemia Ferropriva , Ferro/administração & dosagem , Ferro/uso terapêutico , Complicações Hematológicas na Gravidez , Adulto , Anemia Ferropriva/tratamento farmacológico , Anemia Ferropriva/prevenção & controle , Suplementos Nutricionais , Feminino , Ferritinas/sangue , Proteína da Hemocromatose/genética , Hemoglobinas/análise , Humanos , Gravidez , Complicações Hematológicas na Gravidez/tratamento farmacológico , Complicações Hematológicas na Gravidez/prevenção & controle , Cuidado Pré-Natal , Espanha , Resultado do Tratamento , Adulto Jovem
8.
Saudi Med J ; 40(9): 887-892, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31522215

RESUMO

OBJECTIVES: To evaluate any association between the frequency of hereditary hemochromatosis (HFE) gene mutation (H63D and C282Y) and iron overload in beta-thalassemia major (BTM) patients. METHODS: The case-control study was conducted from June 2016 to February 2018. Blood samples from 204 BTM patients and 204 normal controls were taken from the Sundas Foundation Blood Bank. These samples were analyzed for serum ferritin assay and HFE mutation. Ferritin level was measured on the ARCHITECT 1000SR. Both patient and control samples were analyzed for mutations using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Serum ferritin levels for all patients were greater than 1000ng/mL. The p.H63D mutation was observed in 23 (11.3%) cases, out of which 19 cases were heterozygous for p.H63D and 4 cases were homozygous. In control samples, 4 cases (2%) were found heterozygous for the p.H63D, and no homozygous mutation was found. Significantly high serum ferritin levels were found in BTM patients with the H63D mutation (p=0.00). In the case of p.C282Y, neither homozygous nor heterozygous mutation was found in patients or in controls. CONCLUSION: H63D polymorphism is associated with iron overload in BTM patients. Larger-scale research is required to give an elaborated view of the association of the HFE mutation with iron overload in these patients and to confirm our conclusion.


Assuntos
Ferritinas/sangue , Proteína da Hemocromatose/genética , Hemocromatose/sangue , Talassemia beta/sangue , Adulto , Transfusão de Sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Comorbidade , Feminino , Hemocromatose/epidemiologia , Hemocromatose/genética , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/genética , Masculino , Mutação , Paquistão/epidemiologia , Prevalência , Reação Transfusional , Talassemia beta/epidemiologia , Talassemia beta/genética
9.
J Pak Med Assoc ; 69(8): 1170-1175, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431773

RESUMO

Hapcidin is the central regulator of iron homeostasis in the body. Primarily it is extracted from urine. Hepcidin is a 25 amino acid long chain peptide. Inflammation or iron overload greatly stimulate production of hepcidin by hepatocytes. Recent evidences have revealed that mutations in the human haemochromatosis (HFE) gene lead to deficiency of hepcidin which is responsible for iron overload and contributing to haemochromatosis. Moreover, hepcidin plays a key role in different types of anaemia, mainly anaemia of inflammation in which concentration of hepcidin increases up to 100 folds. Its contribution to renal disease, heart diseases, cancer and obesity-related disorders are also observed. On the other hand, its role is quite inevitable in understanding metastasis in certain cancers. By understanding the mechanism of hepcidin and its pathological roles in blood and iron diseases could lead to new therapies.


Assuntos
Hepatócitos/metabolismo , Hepcidinas/metabolismo , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Neoplasias/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Proteína da Hemocromatose/genética , Homeostase , Humanos
10.
Semin Liver Dis ; 39(4): 476-482, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31330553

RESUMO

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.


Assuntos
Inflamação/complicações , Distúrbios do Metabolismo do Ferro/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Exercício Físico , Proteína da Hemocromatose/genética , Hepatócitos/metabolismo , Homeostase , Humanos , Distúrbios do Metabolismo do Ferro/terapia , Mutação , Flebotomia
13.
Biofactors ; 45(4): 583-597, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132316

RESUMO

HFE-hemochromatosis is a disease characterized by a systemic iron overload phenotype mainly associated with mutations in the HFE protein (HFE) gene. Osteoarthritis (OA) has been reported as one of the most prevalent complications in HFE-hemochromatosis patients, but the mechanisms associated with its onset and progression remain incompletely understood. In this study, we have characterized the response to high iron concentrations of a primary culture of articular chondrocytes isolated from newborn Hfe-KO mice and compared the results with that of a similar experiment developed in cells from C57BL/6 wild-type (wt) mice. Our data provide evidence that both wt- and Hfe-KO-derived chondrocytes, when exposed to 50 µM iron, develop characteristics of an OA-related phenotype, such as an increased expression of metalloproteases, a decreased extracellular matrix production, and a lower expression level of aggrecan. In addition, Hfe-KO cells also showed an increased expression of iron metabolism markers and MMP3, indicating an increased susceptibility to intracellular iron accumulation and higher levels of chondrocyte catabolism. Accordingly, upon treatment with 50 µM iron, these chondrocytes were found to preferentially differentiate toward hypertrophy with increased expression of collagen I and transferrin and downregulation of SRY (sex-determining region Y)-box containing gene 9 (Sox9). In conclusion, high iron exposure can compromise chondrocyte metabolism, which, when simultaneously affected by an Hfe loss of function, appears to be more susceptible to the establishment of an OA-related phenotype.


Assuntos
Condrócitos/metabolismo , Compostos Férricos/farmacologia , Proteína da Hemocromatose/genética , Hemocromatose/metabolismo , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Osteoartrite/metabolismo , Agrecanas/genética , Agrecanas/metabolismo , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Diferenciação Celular , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Ferritinas/genética , Ferritinas/metabolismo , Regulação da Expressão Gênica , Hemocromatose/complicações , Hemocromatose/genética , Hemocromatose/patologia , Proteína da Hemocromatose/deficiência , Humanos , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoartrite/etiologia , Osteoartrite/genética , Osteoartrite/patologia , Oxirredutases/genética , Oxirredutases/metabolismo , Cultura Primária de Células , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Proteína da Região Y Determinante do Sexo , Transdução de Sinais
14.
Ann Hepatol ; 18(2): 354-359, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31056361

RESUMO

INTRODUCTION AND AIM: Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS: We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS: In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163µg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS: Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.


Assuntos
Proteína da Hemocromatose/genética , Hemocromatose/genética , Anticorpos Anti-Hepatite C/sangue , Hepatite C Crônica/epidemiologia , Mutação , Adulto , Idoso , Alabama/epidemiologia , Alanina Transaminase/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Ferritinas/sangue , Predisposição Genética para Doença , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/epidemiologia , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Fenótipo , Prevalência , Medição de Risco , Fatores de Risco
15.
Ter Arkh ; 91(4): 118-121, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31094485

RESUMO

Hereditary hemochromatosis (HH) is a disease with an autosomal recessive hereditary type, stipulated by the genetic defect that leads to a high intestinal absorption of iron and primary accumulation in the parenchymal cells of the liver and other organs. This is the most common hereditary disease among White population, the frequency is about 1 case per 250 people. The prevalence of HH is inhomogeneous, people from countries in Northern Europe, especially Scandinavian, are more susceptible to this disease. Mutations of the HFE gene account for approximately 90% of HH cases. In HH excess iron deposits mainly in the cytoplasm of parenchymal cells of various organs and tissues: in the liver, pancreas, endocrine glands, skin and joints. The clinical picture of HH is characterized by the classical triad development: cirrhosis of the liver, diabetes mellitus (DM) and hyperpigmentation. HH may also manifest itself as various endocrinopathies (hypofunction of hypophysis, adrenal glands, thyroid gland, arthropathy, cardiomyopathy). Diagnostics of HH is based on the determination of the iron metabolism values: serum iron, transferrin saturation, the amount of ferritin, the genetic tests, liver biopsy data are used to confirm the diagnosis. Despite the fact that HH is a well-studied disease, in some cases it is complicated to diagnose it. Developed posthemorrhagic anemia in a patient is one of such reasons when the iron metabolism test is not informative.


Assuntos
Anemia , Hemocromatose/diagnóstico , Sobrecarga de Ferro/diagnóstico , Ferro/metabolismo , Europa (Continente) , Hemocromatose/genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Sobrecarga de Ferro/complicações , Proteínas de Membrana/genética
16.
Mol Immunol ; 112: 40-50, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078115

RESUMO

The classical HLA class I genes (HLA Ia) were extensively studied because of their implication in clinical fields and anthropology. Less is known about worldwide genetic diversity and linkage disequilibrium for non-classical HLA class I genes (HLA Ib) and HLA pseudogenes. Notably, HLA-H, which is deleted in a fraction of the population, remains scarcely explored. The aims of this study were 1/ to get further insight into HLA-H genetic diversity and into how this variability potentially affects its expression and 2/ to define HLA Ib worldwide allelic diversity and linkage. Exome sequence data from the 1000 Genomes Project were used to define second field HLA-A, -E, -F, -G and -H typing using PolyPheMe software. Allelic and two-loci haplotype frequencies were estimated using Gene[Rate] software both at worldwide and continental levels. Eleven novel HLA-H alleles identified in exome data were validated by NGS performed on 25 genomic DNA samples from the same cohort. Phylogenetic analysis and frequency distribution of HLA-H alleles revealed three clades, each predominantly represented in Admixed American, European and East Asian populations, African populations and South Asian populations. Among these eleven novel alleles, two potentially encode complete transmembrane HLA proteins. We confirm the high LD between HLA-H and -A, and between HLA-H and -G, and show the three genes have distinct worldwide allelic distribution. Conversely, HLA-E and HLA-F both showed little LD, displayed restricted allelic diversity and practically no difference in their distribution across the planet. Our work thus reveals an unexpectedly high HLA-H genetic diversity, with alleles highly represented in Asia possibly encoding a functional HLA protein. Functional implication of these results remains to be explored, both in physiological and pathological contexts.


Assuntos
Variação Genética/genética , Antígenos HLA-DQ/genética , Haplótipos/genética , Proteína da Hemocromatose/genética , Alelos , Ásia , Grupo com Ancestrais do Continente Asiático/genética , Frequência do Gene/genética , Genes MHC Classe I/genética , Humanos , Desequilíbrio de Ligação/genética , Filogenia
17.
Dis Markers ; 2019: 4864370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984307

RESUMO

Background: Influence of TMPRSS6 A736V and HFE (C282Y and H63D) polymorphisms on serum hepcidin-25 levels and iron status parameters in end-stage renal disease (ESRD) patients stratified according to gender has not been previously investigated. In addition, we aimed to evaluate the diagnostic accuracy of the parameters to separate iron-deficiency anemia (IDA) from anemia of chronic disease. Materials and Methods: Iron status parameters and genetic analysis were performed in 126 ESRD patients and in 31 IDA patients as the control group. Results: ESRD patients had significantly higher ferritin and hepcidin-25 (<0.001) relative to IDA patients. Cut-off values with the best diagnostic accuracy were found for hepcidin ≥9.32 ng/mL, ferritin ≥48.2 µg/L, transferrin saturation ≥16.8%, and MCV ≥81 fL. Interaction between gender and HFE haplotypes for the hepcidin-25 and ferritin levels in ESRD patients (p = 0.005, partial eta squared = 0.09; p = 0.027, partial eta squared = 0.06, respectively) was found. Serum transferrin was influenced by the combined effect of gender and TMPRSS6 A736V polymorphism in ESRD patients (p = 0.002, partial eta squared = 0.07). Conclusion: Our findings could contribute to the further investigation of mechanisms involved in the pathophysiology and important gender-related involvement of the TMPRSS6 and HFE polymorphisms on anemia in ESRD patients.


Assuntos
Anemia Ferropriva/genética , Proteína da Hemocromatose/genética , Hepcidinas/sangue , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Adulto , Idoso , Anemia Ferropriva/sangue , Feminino , Ferritinas/sangue , Humanos , Ferro/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Transferrina/análise
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 618-622, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998180

RESUMO

OBJECTIVE: The explore the molecular basis of iron-overload in Tibet nationality population of Tibet. METHODS: The inpatients with iron-overload in our department from Dec. 1st 2014 to Jul.31st 2016 were enrolled in this study. Abdominal MRI and the mutation sites C282Y and H63D in HFE exon were examined. For HFE mutation-negative patients, the non-HFE mutation was detected, including 5 HJV mutations of G320V, p.Q312X, p.D249H, p.I281T, p.C321X and 2 TFR2 mutations: (Y250X, I238M), and 2 SLC40A1 mutations: (V162del, N144H). RESULTS: Among 113 iron overload patients, only one showed homozygous p.H63D mutation, and one showed heterozygosis p.H63D mutation. In 73 patients accepted non-HFE gene detection, only one was heterozygosis p.D249N mutation in HJV, and one was heterozygosis p.I238M mutation in TFR2. CONCLUSION: Currently, the pathogenic gene for Tibetan iron-overload has not yet been found.


Assuntos
Sobrecarga de Ferro , Genótipo , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I , Humanos , Mutação , Tibet
19.
Future Med Chem ; 11(7): 743-769, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30945556

RESUMO

Members of the type II transmembrane serine proteases (TTSP) family play a vital role in cell growth and development but many are also implicated in disease. Two of the well-studied TTSPs, matriptase and hepsin proteolytically process multiple protein substrates such as the inactive single-chain zymogens pro-HGF and pro-macrophage stimulating protein into the active heterodimeric forms, HGF and macrophage stimulating protein. These two proteases also have many other substrates which are associated with cancer and tumor progression. Another related TTSP, matriptase-2 is expressed in the liver and functions by regulating iron homoeostasis through the cleavage of hemojuvelin and thus is implicated in iron overload diseases. In the present review, we will discuss inhibitor design strategy and Structure activity relationships of TTSP inhibitors, which have been reported in the literature.


Assuntos
Benzamidinas/química , Inibidores de Serino Proteinase/química , Tiazóis/química , Benzamidinas/metabolismo , Descoberta de Drogas , Proteínas Ligadas por GPI/metabolismo , Proteína da Hemocromatose/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Proteínas de Membrana/antagonistas & inibidores , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Serina Endopeptidases/metabolismo , Serina Proteases/metabolismo , Inibidores de Serino Proteinase/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
20.
PLoS One ; 14(3): e0214196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913256

RESUMO

Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ.


Assuntos
Ferritinas/sangue , Proteína da Hemocromatose/genética , Homozigoto , Modelos Biológicos , Transferrina/metabolismo , Adulto , Substituição de Aminoácidos , Austrália , Feminino , Hemocromatose/sangue , Hemocromatose/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto
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