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1.
Ann Hematol ; 98(12): 2661-2671, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31495903

RESUMO

Haemoglobin (Hb) H-constant spring (CS) alpha thalassaemia (- -/-αCS) is the most common type of nondeletional Hb H disease in southern China. The CRISPR/Cas9-based gene correction of patient-specific induced pluripotent stem cells (iPSCs) and cell transplantation now represent a therapeutic solution for this genetic disease. We designed primers for the target sites using CRISPR/Cas9 to specifically edit the HBA2 gene with an Hb-CS mutation. After applying a correction-specific PCR assay to purify the corrected clones followed by sequencing to confirm the mutation correction, we verified that the purified clones retained full pluripotency and exhibited a normal karyotype. This strategy may be promising in the future, although it is far from representing a solution for the treatment of HbH-CS thalassemia now.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Hemoglobinas Anormais , Células-Tronco Pluripotentes Induzidas/metabolismo , Talassemia alfa , Hemoglobinas Anormais/genética , Hemoglobinas Anormais/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Talassemia alfa/genética , Talassemia alfa/metabolismo , Talassemia alfa/terapia
2.
Ann Hematol ; 98(9): 2045-2052, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31243572

RESUMO

Thalassemia has a high prevalence in Thailand. Oxidative damage to erythroid cells is known to be one of the major etiologies in thalassemia pathophysiology. Oxidative stress status of thalassemia is potentiated by the heme, nonheme iron, and free iron resulting from imbalanced globin synthesis. In addition, levels of antioxidant proteins are reduced in α-thalassemia and ß-thalassemia erythrocytes. However, the primary molecular mechanism for this phenotype remains unknown. Our study showed a high expression of miR-144 in ß- and α-thalassemia. An increased miR-144 expression leads to decreased expression of nuclear factor erythroid 2-related factor 2 (NRF2) target, especially in α-thalassemia. In α-thalassemia, miR-144 and NRF2 target are associated with glutathione level and anemia severity. To study the effect of miR-144 expression, the gain-loss of miR-144 expression was performed by miR inhibitor and mimic transfection in the erythroblastic cell line. This study reveals that miR-144 expression was upregulated, whereas NRF2 expression and glutathione levels were decreased in comparison with the untreated condition after miR mimic transfection, while the reduction of miR-144 expression contributed to the increased NRF2 expression and glutathione level compared with the untreated condition after miR inhibitor transfection. Moreover, miR-144 overexpression leads to significantly increased sensitivity to oxidative stress at indicated concentrations of hydrogen peroxide (H2O2) and rescued by miR-144 inhibitor. Taken together, our findings suggest that dysregulation of miR-144 may play a role in the reduced ability of erythrocyte to deal with oxidative stress and increased RBC hemolysis susceptibility especially in thalassemia.


Assuntos
Eritrócitos/metabolismo , MicroRNAs/biossíntese , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Regulação para Cima , Talassemia alfa/metabolismo , Talassemia beta/metabolismo , Eritrócitos/patologia , Feminino , Glutationa/biossíntese , Glutationa/genética , Hemólise , Humanos , Peróxido de Hidrogênio/metabolismo , Células K562 , Masculino , MicroRNAs/genética , Fator 2 Relacionado a NF-E2/genética , Talassemia alfa/genética , Talassemia alfa/patologia , Talassemia beta/genética , Talassemia beta/patologia
3.
Hemoglobin ; 43(1): 38-41, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30915867

RESUMO

To evaluate the iron metabolism and oxidative status in patients with Hb H disease, we investigated 43 patients with Hb H disease, including eight deletional Hb H disease patients and 35 nondeletional Hb H disease patients and 20 healthy controls. The levels of hematological parameters, serum ferritin, hepcidin, superoxide dismutase (SOD), malondialdehyde (MDA) and total antioxidant capacity (TAC), were examined. We found higher serum ferritin levels and lower hepcidin, MDA and TAC levels in Hb H disease patients than in controls. The hepcidin level in Hb H disease patients was positively correlated with MDA and TAC levels but not with serum ferritin and SOD levels. The patients with nondeletional Hb H disease showed higher serum ferritin and Hb H concentrations than those patients with deletional Hb H disease. However, no statistically significant differences in SOD, MDA and TAC levels were found in patients with deletional and nondeletional Hb H disease. Oxidative stress and antioxidant defense were related to hepcidin levels. Our study indicated that hepcidin might be an important parameter for monitoring the iron metabolism and oxidative status of Hb H disease patients.


Assuntos
Ferro/metabolismo , Oxirredução , Estresse Oxidativo , Talassemia alfa/metabolismo , Adolescente , Antioxidantes/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Índices de Eritrócitos , Feminino , Humanos , Fígado/metabolismo , Masculino , Talassemia alfa/sangue
4.
Hematology Am Soc Hematol Educ Program ; 2018(1): 353-360, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504332

RESUMO

The α-thalassemia trait, associated with deletions removing both α-globin genes from 1 chromosome (genotype ζ αα/ζ--), is common throughout Southeast Asia. Consequently, many pregnancies in couples of Southeast Asian origin carry a 1 in 4 risk of producing a fetus inheriting no functional α-globin genes (ζ--/ζ--), leading to hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS). Expression of the embryonic α-globin genes (ζ-globin) is normally limited to the early stages of primitive erythropoiesis, and so when the ζ-globin genes are silenced, at ∼6 weeks of gestation, there should be no α-like globin chains to pair with the fetal γ-globin chains of Hb, which consequently form nonfunctional tetramers (γ4) known as Hb Bart's. When deletions leave the ζ-globin gene intact, a low level of ζ-globin gene expression continues in definitive erythroid cells, producing small amounts of Hb Portland (ζ2γ2), a functional form of Hb that allows the fetus to survive up to the second or third trimester. Untreated, all affected individuals die at these stages of development. Prevention is therefore of paramount importance. With improvements in early diagnosis, intrauterine transfusion, and advanced perinatal care, there are now a small number of individuals with BHFS who have survived, with variable outcomes. A deeper understanding of the mechanism underlying the switch from ζ- to α-globin expression could enable persistence or reactivation of embryonic globin synthesis in definitive cells, thereby providing new therapeutic options for such patients.


Assuntos
Transfusão de Sangue Intrauterina , Hemoglobinas Anormais , Hidropisia Fetal , Assistência Perinatal/métodos , Talassemia alfa , Hemoglobinas Anormais/genética , Hemoglobinas Anormais/metabolismo , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Hidropisia Fetal/metabolismo , Hidropisia Fetal/terapia , Talassemia alfa/diagnóstico , Talassemia alfa/genética , Talassemia alfa/metabolismo , Talassemia alfa/terapia
5.
Br J Haematol ; 179(2): 256-265, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28699687

RESUMO

Studying different sickle cell genotypes may throw light on the pathogenesis of sickle cell disease (SCD). Here, the clinical profile, red cell sickling and K+ permeability in 29 SCD patients (15 patients with severe disease and 14 with a milder form) of HbA/S-Oman genotype were analysed. The super sickling nature of this Hb variant was confirmed. The red cell membrane permeability to K+ was markedly abnormal with elevated activities of Psickle , Gardos channel and KCl cotransporter (KCC). Results were consistent with Ca2+ entry and Mg2+ loss via Psickle stimulating Gardos channel and KCC activities. The abnormal red cell behaviour was similar to that in the commonest genotype of SCD, HbSS, in which the level of mutated Hb is considerably higher. Although activities of all three K+ transporters also correlated with the level of HbS-Oman, there was no association between transport phenotype and disease severity. The super sickling behaviour of HbS-Oman may obviate the need for solute loss and red cell dehydration to encourage Hb polymerisation, required in other SCD genotypes. Disease severity was reduced by concurrent α thalassaemia, as observed in other SCD genotypes, and represents an obvious genetic marker for prognostic tests of severity in young SCD patients of the HbA/S-Oman genotype.


Assuntos
Eritrócitos Anormais/metabolismo , Hemoglobina A/genética , Hemoglobinas Anormais/genética , Heterozigoto , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Potássio/metabolismo , Talassemia alfa , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Masculino , Pessoa de Meia-Idade , Permeabilidade , Índice de Gravidade de Doença , Talassemia alfa/genética , Talassemia alfa/metabolismo
6.
Stem Cell Res ; 20: 80-83, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28395745

RESUMO

The thalassemias are a group of genetic disorders characterized by a deficiency in the synthesis of globin chains. In this study the MUi009-A human induced pluripotent stem cell line was successfully generated from peripheral blood CD34+ haematopoietic progenitors of a 32year old male who had coinherited a homozygous ß°-thalassemia mutation at codon 41/42 (-TCTT) and a heterozygous α-thalassemia 4.2 deletion. The MUi009-A cell line exhibited embryonic stem cell characteristics with consistent pluripotency marker expression and the capability of differentiating into the three germ layers. The cell line may provide a tool for drug testing and gene therapy studies.


Assuntos
Reprogramação Celular , Células-Tronco Pluripotentes Induzidas/citologia , Talassemia alfa/patologia , Adulto , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Análise Mutacional de DNA , Corpos Embrioides/metabolismo , Corpos Embrioides/patologia , Deleção de Genes , Genótipo , Heterozigoto , Humanos , Cariótipo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Masculino , Microscopia de Fluorescência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Talassemia alfa/genética , Talassemia alfa/metabolismo
7.
Stem Cell Res ; 20: 84-87, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28395746

RESUMO

Hemoglobin Constant Spring (HbCS, HBA2: c.427T>C) is a common nondeletional α-thalassemia resulting from a nucleotide substitution at the termination codon of the HBA2 gene. Homozygosity for HbCS is characterized with mild anemia, jaundice, and splenomegaly. In this study, the human induced pluripotent stem cell line MUi017-A was successfully generated from peripheral blood CD34+ hematopoietic progenitors of a 52year old female with homozygous HbCS. The MUi017-A cell line exhibited embryonic stem cell characteristics with consistent expression of specific pluripotency markers and the capability of differentiating into the three germ layers. The cell line may be used for the disease modeling.


Assuntos
Reprogramação Celular , Hemoglobinas Anormais/genética , Células-Tronco Pluripotentes Induzidas/citologia , Antígenos CD34/metabolismo , Sequência de Bases , Diferenciação Celular , Linhagem Celular , Análise Mutacional de DNA , Corpos Embrioides/metabolismo , Corpos Embrioides/patologia , Feminino , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Homozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Cariótipo , Microscopia de Fluorescência , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Talassemia alfa/genética , Talassemia alfa/metabolismo , Talassemia alfa/patologia
8.
Ann Hematol ; 95(8): 1329-32, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27256348

RESUMO

OBJECTIVES: This study was conducted to assess bone mineral density (BMD) and bone mineral content (BMC) of patients with hemoglobin H (HbH) disease. METHODS: BMD and BMC were measured by dual energy X-ray absorptiometry of the lumbar spines and femur neck in 21 patients with Hb H disease over the age of 10 years. An association of BMD with sex, age, hemoglobin, calcium, phosphorus, and serum ferritin level was also evaluated. RESULTS: Prevalence of BMD below the expected range for age in the lumbar spine and femur neck region in patients with HbH disease were 33.3 and 14.3 %, respectively. Lumbar BMD was significantly lower in the patients compared to healthy individuals (median (min-max) 0.725 (0.595-0.924) vs. 1.061 (0.645-1.238), P < 0.001)). There was no significant relationship between BMD in the lumbar and femur neck with any of the evaluated variables (P value >0.05). CONCLUSION: Data regarding bone density in HbH disease is limited; osteoporosis as a common complication of ß-thalassemia intermedia syndrome should be considered even in HbH which shows its prevalence is less than ß-thalassemia intermedia.


Assuntos
Densidade Óssea , Colo do Fêmur/metabolismo , Vértebras Lombares/metabolismo , Talassemia alfa/metabolismo , Absorciometria de Fóton , Adolescente , Adulto , Criança , Comorbidade , Estudos Transversais , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Osteoporose/metabolismo , Prevalência , Adulto Jovem , Talassemia alfa/epidemiologia
9.
Hum Mol Genet ; 25(21): 4787-4803, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28173139

RESUMO

ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harboring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells. The mechanisms that underlie selective neuronal vulnerability and neurodegeneration in the central nervous system upon Atrx mutation or deletion are unknown. To interrogate the cellular specificity of Atrx for its retinal neuroprotective functions, we employed a combination of temporal and lineage-restricted conditional ablation strategies to generate five different conditional knockout mouse models, and subsequently identified a non-cell-autonomous requirement for Atrx in bipolar cells for inhibitory interneuron survival in the retina. Atrx-deficient retinal bipolar cells exhibit functional, structural and molecular alterations consistent with impairments in neuronal activity and connectivity. Gene expression changes in the Atrx-null retina indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of ATRX in the forebrain and retina may contribute to similar neuropathological processes underlying cognitive impairment and visual dysfunction in ATR-X syndrome.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/genética , Animais , Cromatina , Modelos Animais de Doenças , Interneurônios/metabolismo , Masculino , Retardo Mental Ligado ao Cromossomo X/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mutação , Neurônios/metabolismo , Proteínas Nucleares/genética , Retina/metabolismo , Células Bipolares da Retina/metabolismo , Proteína Nuclear Ligada ao X/metabolismo , Talassemia alfa/metabolismo
10.
Am J Hematol ; 90(8): 737-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26017030

RESUMO

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.


Assuntos
DNA Helicases/genética , Células-Tronco Hematopoéticas/patologia , Taxa de Mutação , Síndromes Mielodisplásicas/genética , Proteínas Nucleares/genética , Talassemia alfa/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Análise de Sobrevida , Proteína Nuclear Ligada ao X , Talassemia alfa/metabolismo , Talassemia alfa/mortalidade , Talassemia alfa/patologia
12.
Hum Mol Genet ; 24(7): 1824-35, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25452430

RESUMO

ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences the expression level of specific genes; however, deposition of H3.3 at transcribed genes is currently thought to occur independently of ATRX. We focused on a set of genes, including the autism susceptibility gene Neuroligin 4 (Nlgn4), that exhibit decreased expression in ATRX-null cells to investigate the mechanisms used by ATRX to promote gene transcription. Overall TERRA levels, as well as DNA methylation and histone modifications at ATRX target genes are not altered and thus cannot explain transcriptional dysregulation. We found that ATRX does not associate with the promoter of these genes, but rather binds within regions of the gene body corresponding to high H3.3 occupancy. These intragenic regions consist of guanine-rich DNA sequences predicted to form non-B DNA structures called G-quadruplexes during transcriptional elongation. We demonstrate that ATRX deficiency corresponds to reduced H3.3 incorporation and stalling of RNA polymerase II at these G-rich intragenic sites. These findings suggest that ATRX promotes the incorporation of histone H3.3 at particular transcribed genes and facilitates transcriptional elongation through G-rich sequences. The inability to transcribe genes such as Nlgn4 could cause deficits in neuronal connectivity and cognition associated with ATRX mutations in humans.


Assuntos
DNA Helicases/metabolismo , Regulação da Expressão Gênica , Guanina/metabolismo , Retardo Mental Ligado ao Cromossomo X/metabolismo , Proteínas Nucleares/metabolismo , Transcrição Genética , Talassemia alfa/metabolismo , Animais , Cromatina/genética , Cromatina/metabolismo , DNA Helicases/genética , Metilação de DNA , Quadruplex G , Histonas/metabolismo , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/embriologia , Retardo Mental Ligado ao Cromossomo X/genética , Camundongos , Camundongos Knockout , Mutação , Proteínas Nucleares/genética , Fases de Leitura Aberta , Regiões Promotoras Genéticas , Proteína Nuclear Ligada ao X , Talassemia alfa/embriologia , Talassemia alfa/genética
13.
Methods Mol Biol ; 1170: 229-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24906316

RESUMO

Mitosis and meiosis are essential processes that occur during development. Throughout these processes, cohesion is required to keep the sister chromatids together until their separation at anaphase. Cohesion is created by multiprotein subunit complexes called cohesins. Although the subunits differ slightly in mitosis and meiosis, the canonical cohesin complex is composed of four subunits that are quite diverse. The cohesin complexes are also important for DNA repair, gene expression, development, and genome integrity. Here we provide an overview of the roles of cohesins during these different events as well as their roles in human health and disease, including the cohesinopathies. Although the exact roles and mechanisms of these proteins are still being elucidated, this review serves as a guide for the current knowledge of cohesins.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Meiose , Mitose , Animais , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/genética , Cromátides/genética , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/análise , Proteínas Cromossômicas não Histona/genética , Segregação de Cromossomos , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Síndrome de Lange/genética , Síndrome de Lange/metabolismo , Síndrome de Lange/patologia , Ectromelia/genética , Ectromelia/metabolismo , Ectromelia/patologia , Humanos , Hipertelorismo/genética , Hipertelorismo/metabolismo , Hipertelorismo/patologia , Retardo Mental Ligado ao Cromossomo X/genética , Retardo Mental Ligado ao Cromossomo X/metabolismo , Retardo Mental Ligado ao Cromossomo X/patologia , Talassemia alfa/genética , Talassemia alfa/metabolismo , Talassemia alfa/patologia
14.
Zhonghua Xue Ye Xue Za Zhi ; 35(5): 419-23, 2014 May.
Artigo em Chinês | MEDLINE | ID: mdl-24857212

RESUMO

OBJECTIVE: To investigate the incidence and the gene mutation frequencies and patterns of α-thalassemia in preschool children in Chongqing city. METHODS: Cluster random sampling was used. A total of 1057 preschool children in three areas of Chongqing were screened by using routine blood test and hemoglobin electrophoresis analysis. Molecular analysis carried out for all the samples. RESULTS: Of the 1057 samples, 55 cases were diagnosed as being carriers of α-thalassemia, which included 80 allele genes. Therefore, the frequency of α-thalassemia carriers in Chongqing was 5.20%. Of the 55 α-thalassemia carriers, five different deletions of α-thalassemia were identified, the three most common deletion types and proportions were 54.55% for the -α(3.7) deletion, 18.18% for --(SEA) deletion, and 9.08% for the -α(4.2) deletion, respectively; eight types of nondeletion defects were determined, containing one case of Hb Quong Sze and seven novel mutations of a-globin gene. Furthermore, 24 cases of α-Triplication were detected with the α-Triplication carrier rate of 2.55%. In addition, in this study we also found two cases of abnormal hemoglobin disorders occurred on α-globin gene, Hb J-Wenchang-Wuming and Hb Arya. Hb Arya was characterized in the Chinese population for the first time confirmed by literature retrieval. CONCLUSION: In this study, we have clarified the carrier frequency and molecular spectrum of α-thalassemia in Chongqing, and we first reported the carrier incidence of α-Triplication in Chongqing. The materials obtained from this study would be of valuable reference for genetic counseling and the examination instruction of children in this area.


Assuntos
Talassemia alfa/epidemiologia , Grupo com Ancestrais do Continente Asiático , Pré-Escolar , China/epidemiologia , Humanos , Incidência , Mutação , Prevalência , alfa-Globinas/metabolismo , Talassemia alfa/metabolismo
15.
Hemoglobin ; 38(3): 165-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24601859

RESUMO

Studies dealing with rheological red blood cell (RBC) behavior in sickle cell trait carriers are scarce. Moreover, the association with α-thalassemia (α-thal), which also modifies erythrocyte behavior, has not always been taken into account. We analyzed erythrocyte deformability by means of a shear stress diffractometer, along with hematological and biochemical parameters (glucose and plasma lipids), given their possible influence on erythrocyte deformability, in 14 sickle cell trait carriers and 23 healthy controls. Nine patients were also α-thal carriers and five were not. Among the thalassemia carriers, eight were heterozygous and one was homozygous. When compared with controls, sickle cell trait carriers showed no differences for any of the biochemical parameters analyzed (p > 0.05), but significantly lower hemoglobin (Hb) (p = 0.003), mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) (p < 0.001) levels, although no differences in erythrocyte deformability were observed at any of the shear stresses tested (p > 0.05). When comparing sickle cell trait carriers, with and without α-thal, no differences in erythrocyte deformability were observed (p > 0.05), in spite of the former showing lower MCV and MCH (p < 0.05) levels. Carriers of α-thal had lower Hb S [ß6(A3)Glu → Val; HBB: c.20A > T] levels (p = 0.013) than non carriers. The existence of a compensating mechanism seems reasonable because, despite presenting lower erythrocyte indices, which could worsen erythrocyte deformability, this rheological property improves when the percentage of Hb S is lower.


Assuntos
Deformação Eritrocítica , Eritrócitos/metabolismo , Traço Falciforme/metabolismo , Talassemia alfa/metabolismo , Adulto , Substituição de Aminoácidos , Índices de Eritrócitos , Eritrócitos/patologia , Feminino , Hemoglobina Falciforme/genética , Hemoglobina Falciforme/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Traço Falciforme/genética , Traço Falciforme/patologia , Talassemia alfa/genética , Talassemia alfa/patologia
16.
Biochem Med (Zagreb) ; 24(1): 167-74, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24627726

RESUMO

Hemoglobin (Hb) Grey Lynn is a Hb variant caused by a substitution of Phe for Leu at position 91 of α1-globin chain, originally described in individual of unknown ethnic background. This article addresses the interaction of Hb Grey Lynn with a non-deletional α(+)-thalassemia found in Thailand, a hitherto un-described condition. The proband was adult Thai woman referred for investigation of mild anemia with Hb 90 g/L. Hb analyses using low pressure liquid chromatography raised a suspicion of abnormal Hb presence, which was failed to demonstrate by cellulose acetate electrophoresis and capillary electrophoresis. DNA sequencing identified a CTT (Leu) to TTT (Phe) mutation at codon 91 corresponding to the Hb Grey Lynn (Vientiane) [α91(FG3)Leu>Phe (α1) on α1-globin gene and a C deletion between codons 36 and 37 on α2-globin gene causing α(+)-thalassemia. As compared to those observed in a compound heterozygote for Hb Grey Lynn / α(0)-thalassemia reported previously, higher MCV (81.7 fL) and MCH (26.3 pg) values with a lower level of Hb Grey Lynn (19.7%) were observed in the proband. The normochromic normocytic anemia observed could be due to the interaction of Hb Grey Lynn with α(+)-thalassemia. The two mutations could be identified using PCR-RFLP and allele-specific PCR assays developed.


Assuntos
Deleção de Genes , Hemoglobinas Anormais/genética , Mutação Puntual/genética , Talassemia alfa/genética , Adulto , Sequência de Bases , Feminino , Hemoglobinas Anormais/metabolismo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Homologia de Sequência do Ácido Nucleico , Tailândia , Talassemia alfa/metabolismo
17.
J Clin Lab Anal ; 28(4): 261-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24577940

RESUMO

BACKGROUND: Iron overload is a major complication in patients with hemoglobin H (Hb H) disease and causes damage of tissues. METHODS: We investigated 26 Hb H patients and 75 controls to evaluate their oxidative stress and antioxidant statuses. RESULTS: There were significantly increased levels of superoxide anion in leucocytes, nitrite (NO2-), and malondialdehyde (MDA) in plasma, and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRx) and oxidized glutathione (GSSG) in erythrocytes, decreased levels of nitrate (NO3-) and vitamin C in plasma, and reduced glutathione (GSH) in erythrocytes, in addition to the abnormal iron status in the patients when compared with those in the controls. Meanwhile, levels of serum ferritin were positively correlated with serum iron, plasma MDA, and erythrocyte SOD in the patients. In addition, the activities of SOD were positively correlated with those of GPx and GRx, and the levels of GSSG and MDA, but negatively correlated with those of GSH. Furthermore, the levels of MDA were negatively correlated those of vitamin C. CONCLUSIONS: These results demonstrate the presence of oxidative stress and decreased levels of antioxidants; moreover, the related metabolic antioxidant pathway is active in Hb H patients with iron overload.


Assuntos
Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Redes e Vias Metabólicas , Estresse Oxidativo , Talassemia alfa/metabolismo , Talassemia alfa/patologia , Adolescente , Alanina Transaminase/sangue , Antioxidantes/metabolismo , Estudos de Casos e Controles , Creatina Quinase/sangue , Eritrócitos/enzimologia , Feminino , Ferritinas/sangue , Humanos , Ferro/sangue , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/complicações , Masculino , Malondialdeído/sangue , Superóxido Dismutase/metabolismo , Adulto Jovem , Talassemia alfa/sangue , Talassemia alfa/complicações
18.
Eur J Haematol ; 92(3): 237-43, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24168396

RESUMO

Chronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P < 0.05) association was observed, the following ones were confirmed upon correction for multiple comparisons: (i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.


Assuntos
Anemia Falciforme/sangue , Antígenos CD36/genética , Hemoglobina A/genética , Hemólise/genética , Óxido Nítrico Sintase Tipo III/genética , Molécula 1 de Adesão de Célula Vascular/genética , Alelos , Anemia Falciforme/genética , Criança , Eritrócitos/citologia , Feminino , Genótipo , Haplótipos , Hemoglobinas/metabolismo , Homozigoto , Humanos , Estudos Longitudinais , Masculino , Óxido Nítrico/metabolismo , Fenótipo , Talassemia alfa/metabolismo
19.
Mol Biol Rep ; 40(11): 6205-12, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24065537

RESUMO

Beta-thalassemia is the most frequent hereditary blood disorder in Tunisia because of its geographic localization and history. This pathology is characterized by a complex multisystem process with genetic and biochemical interactions. The aim of this work was to establish phenotype/genotype association through studying the distribution and the relationship between ß-thalassemia and α-thalassemia mutations and three polymorphic markers: the C → T polymorphism at -158 of the Gγ gene, the RFLP haplotype and the repeated sequence (AT)xTy in the ß globin silencer, in two groups of ß-thalassemia major and ß-thalassemia intermedia (TI) patients. Statistical analysis has shown that moderate expression seen in TI patients was significantly associated to ß(+) -87 (C → G), -30 (T → A) and IVSI-6 (T → C) mutations, haplotypes VIII, IX and Nb and to XmnI polymorphism. The regression analysis of combined genotypes (mutation/XmnI/RFLP haplotype) revealed that they contribute to justify 17.1 % of clinical expression diversity (p < 0.05). Among the studied genotypes the XmnI polymorphism seems to be the most determinant modulating factor, followed by the ß-thalassemia mutation and RFLP haplotype. Our findings highlight the heterogeneity of molecular background of ß-thalassemia that would be responsible of clinical variability.


Assuntos
Estudos de Associação Genética , Heterogeneidade Genética , Globinas beta/genética , Talassemia beta/diagnóstico , Talassemia beta/genética , Adolescente , Adulto , Criança , Pré-Escolar , Ordem dos Genes , Haplótipos , Hemoglobinas/genética , Hemoglobinas/metabolismo , Humanos , Pessoa de Meia-Idade , Mutação , Motivos de Nucleotídeos , Fenótipo , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Tunísia , Adulto Jovem , Talassemia alfa/genética , Talassemia alfa/metabolismo , Talassemia beta/sangue , gama-Globinas/genética
20.
Hum Pathol ; 44(10): 2199-203, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23954140

RESUMO

α-Thalassemia/mental retardation syndrome X-linked protein (ATRX) and death domain-associated protein (DAXX) genes are tumor suppressors whose mutations have been identified in sporadic pancreatic neuroendocrine tumors as well as in patients with MEN1. However, it is unknown whether ATRX and DAXX alterations are specific for pancreatic neuroendocrine tumor. In addition, the association of ATRX/DAXX protein loss with tumor cell proliferation has not been examined. We, therefore, immunostained ATRX and DAXX in 10 gastric, 15 duodenal, 20 rectal, 70 pancreatic, and 22 pulmonary neuroendocrine tumors with 15 nonneoplastic pancreases and 27 pancreatic adenocarcinomas to elucidate the site-specific roles of ATRX/DAXX abnormalities. At least 1 loss of ATRX and DAXX immunoreactivity was detected in all neuroendocrine tumor cases but not in any of nonneoplastic pancreatic tissues or pancreatic adenocarcinomas. The loss of DAXX protein was correlated with the Ki-67 index (ATRX, P = .904; DAXX, P = .044). The status of DAXX immunoreactivity correlated positively with World Health Organization histologic grade (P = .026). These results suggest that the status of ATRX or DAXX protein loss in neuroendocrine tumor differed among the organs in which these tumors arose, and these proteins may play site-specific roles in the development of these tumors.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Gastrointestinais/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/patologia , Retardo Mental Ligado ao Cromossomo X/patologia , Tumores Neuroendócrinos/patologia , Talassemia alfa/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Neoplasias Gastrointestinais/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Retardo Mental Ligado ao Cromossomo X/metabolismo , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Adulto Jovem , Talassemia alfa/metabolismo
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