Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated four members of a three-generation Dutch family for a suspected hemoglobinopathy. Chronic hemolysis and a moderate macrocytic normochromic anemia with slight morphological abnormalities of the red cells was observed in all four. Hemoglobin chain synthesis in vitro and separation of the globin chains by reversed phase high performance liquid chromatography revealed an abnormal beta-globin species in addition to the normal alpha and beta chains. The decreased amount of normal beta-globin and the low amount of unidentified protein suggested an unstable beta-globin variant. An abnormal band was detected by isoelectrofocusing. In one family member tested, the hemoglobin in an erythrocyte lysate had decreased heat stability. All carriers were positive in the isopropanol hemoglobin instability test. Treatment of erythrocytes with methylviolet gave rise to microgranular inclusions. Nucleotide sequencing of the polymerase chain reaction-amplified beta-globin gene revealed a heterozygous single base pair T-->C mutation at codon 75, which changes the normal CTG codon for leucine to a CCG codon for proline. This variant has previously been identified as Hb Atlanta or beta 75(E19)Leu-->Pro. The mutation creates a new Msp I restriction site, which was used to confirm the diagnosis in all four family members. A quantitative reverse transcriptase polymerase chain reaction procedure for determining the relative amounts of mRNA transcripts for the normal and abnormal globin chain showed a comparable stability for both transcripts.
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PMID:A Dutch family with Hb Atlanta [beta 75(E19)Leu-->Pro]. 893 61

The locus control region of the beta-globin gene is composed of four erythroid-specific hypersensitive sites. Hypersensitive site 2 has been shown to be a powerful enhancer and contains a tandem repeat sequence for the transcription factors AP1 and NFE2 (activating protein 1 and nuclear factor erythroid 2, respectively). The human NRF2 (NFE2 related factor 2) has been isolated by bacterial expression screening using this core sequence as a probe. p45-NFE2, NRF1, and NRF2 belong to the CNC ("cap 'n' collar") subfamily of the basic region-leucine zipper transcription factors, which exhibits strong homology at specific regions such as the "CNC" and the DNA binding and leucine zipper domains. Although the erythroid-specific p45-NFE2 has been implicated in globin gene regulation, p45-NFE2 null mice succumb to bleedings due to lack of platelets and those that survive exhibit only a mild anemia. To determine the function of NRF2, which we found to be widely expressed in vivo, we have characterized the genomic structure of the mouse NRF2 gene, disrupted the Nrf2 gene by homologous recombination in mouse embryonic stem cells (ES cells), and generated NRF2-/- mice. Homozygous mutant mice developed normally, were not anemic, reached adulthood, and reproduced. Our studies indicate that NRF2 is dispensable for mouse development.
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PMID:NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. 894 40

The inheritance of sickle-cell anemia upon the background of the major beta-globin gene cluster haplotypes has been associated with differing risks for major organ failure, and more recently with response to hydroxyurea treatment. Early identification of beta-globin haplotypes in individuals with sickle-cell anemia may be a clinically useful prognostic factor for severity of disease expression. This report describes the use of whole-blood spots on filter papers from newborn hemoglobinopathy screening for beta-globin gene cluster haplotyping by the polymerase chain reaction.
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PMID:Beta-globin haplotypes from blood spots for follow-up of newborn hemoglobinopathy screening. 898 Feb 65

beta-thalassaemia is one of the commonest autosomal recessive genetic diseases in the Singapore population. In the homozygous form, it results in a severe anaemia, requiring monthly transfusion for survival. Because of the less than satisfactory treatment available for the condition, prenatal diagnosis has always been an option for couples at-risk. The available method was globin chain analysis of foetal blood, obtained at 18 to 20 weeks of gestation. Affected pregnancies would then be diagnosed and require termination in the mid to late trimester. A relatively newer technique, chorionic villus sampling (CVS), allows foetal material to be obtained in the first trimester. However, analysis of the foetal tissue requires direct gene studies to be performed. The aim of this study was to evaluate the feasibility of this analysis in couples at-risk for beta-thalassaemia in Singapore. Sixteen couples who were at-risk for a child with beta-thalassaemia major were offered prenatal diagnosis. All of them opted for CVS as compared to foetal blood sampling. The mutations in the beta-globin gene in these couples at-risk were identified. Direct gene analysis was then performed on the foetal sample, using a variety of molecular techniques. These included reverse dot-blot hybridisation, allele-specific oligonucleotide hybridisation, restriction enzyme digests and direct analysis of amplified products. DNA profiling was done for each case to exclude definitively the possibility of maternal tissue contaminating the foetal sample. The results in all these cases were unequivocal. The procedure of CVS itself was uneventful in these 16 couples. Procedural-associated foetal loss was nil. Prenatal diagnosis in the first trimester allows early termination of an affected pregnancy with significantly less maternal morbidity and prenatal anxiety. It also results in greater patient acceptability of the procedure and plays a key role in the prevention of this devastating genetic disease.
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PMID:Early prenatal diagnosis of beta-thalassaemia in Singapore. 905 2

The beta-thalassemia syndromes are a heterogeneous group of genetic disorders characterized by reduced or absent expression of the beta-globin gene. To date, over 300 beta-thalassemia alleles have been characterized in or around the beta-globin region. Thalassemia major is severe anemia necessitating chronic blood transfusions, splenectomy, iron chelation therapy, and bone marrow transplantation. Usually thalassemia major results from homozygosity or compound heterozygosity for severe betaO- and/or beta+-thalassemia mutations. Thalassemia intermedia is a clinical diagnosis that describes a symptomatic but less severe condition than beta-thalassemia major. beta-thalassemia intermedia may arise from several different combinations of alpha- and/or beta-thalassemia mutations. Heterozygous beta-thalassemia is typically characterized by a mild microcytic hypochromic anemia without any significant clinical implications. In this report, we describe a 63-year-old Africian American woman with asymptomatic homozygous beta-thalassemia, who seems to carry 2 copies of the -29 mutation in the promoter region of the beta-globin gene. Her elevated hemoglobin F level of 83% was associated with heterozygosity for the Xmn I polymorphism upstream of the Ggamma-globin gene. Southern blot analysis at the alpha-globin locus did not show any deletion that would account for the mildness of her phenotype. Therefore, homozygosity for the -29 mutation along with the Xmn I polymorphism appears to confer an extremely mild beta-thalassemia phenotype. This observation has important implications in the prenatal diagnosis and genetic counseling of families segregating this type of genetic defect.
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PMID:Molecular basis of asymptomatic beta-thalassemia major in an African American individual. 905 61

Hemoglobin Constant Spring (HbCS) is the most common nondeletional alpha-thalassemic mutation and is an important cause of HbH-like disease in Southeast Asia. HbCS variants have an almost normal mean cell volume (MCV) and the anemia is more severe when compared with other alpha-thalassemic variants. We explored the pathobiology of HbCS red blood cells (RBCs) because the underlying cause(s) of this MCV "normalizing" effect of HbCS and the more severe anemia are not fully explained. HbCS containing RBCs are distinctly overhydrated relative to deletional alpha-thalassemia variants, and the derangement of volume regulation and cell hydration occurs early in erythroid maturation and is fully expressed at the reticulocyte stage. Furthermore, the membrane rigidity and membrane mechanical stability of HbCS containing RBCs is increased when compared with HbH and alpha-thalassemia-1 trait RBCs. In seeking the cause(s) underlying these cellular alterations we analyzed membranes from HbCS and deletional alpha-thalassemic variants and found that in addition to oxidized beta-globin chains, oxidized alpha cs-globin chains are also associated with the membranes and their skeletons in HbCS containing RBCs. We propose that the membrane pathology of HbCS variants is caused by combination of the deleterious effects induced by membrane-bound oxidized alpha cs- and beta-globin chains. The membrane alterations induced by alpha cs chains are more akin to those induced by beta A-globin chains than those induced by the alpha A-globin chains that accumulate in the beta-thalassemias. Thus, each globin chain, alpha cs, alpha A, beta A, appears to produce its own form of membrane perturbation.
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PMID:The unusual pathobiology of hemoglobin constant spring red blood cells. 905 61

Adeno-associated virus type 2 (AAV), a nonpathogenic human parvovirus, is gaining attention as a vector for potential use in human gene therapy. We and others have described AAV-mediated beta-globin gene transfer and expression in established human and murine erythroleukemia cell lines in vitro. However, successful AAV-mediated globin gene transduction of hematopoietic stem cells and long-term expression in vivo in progeny cells have not been documented. We report here that infection of murine hematopoietic bone marrow cells ex vivo with a recombinant AAV vector containing the genomic copy of a normal human globin gene followed by transplantation of these cells into lethally irradiated congenic mice resulted in efficient gene transfer into hematopoietic cells with long-term repopulating ability as detected by the presence of the human globin gene sequences in bone marrow and spleen in primary recipient mice for at least 6 months. Long-term expression of the human globin gene was also detected in bone marrow, but not in spleen, in primary recipient mice. Furthermore, in secondary-transplant experiments, we were also able to document the presence as well as expression of the transduced human globin gene in mouse bone marrow for up to 3 months. These results provide further support for potential use of the AAV-based vector system in gene therapy of human hemoglobinopathies in general and sickle-cell anemia and beta-thalassemia in particular.
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PMID:Adeno-associated virus type 2-mediated transduction of murine hematopoietic cells with long-term repopulating ability and sustained expression of a human globin gene in vivo. 906 Jun 72

The present report described the hematologic and molecular study of the second case of Hb D-Punjab associated with a beta zero-thalassemia found in Spain and the first case in which the mutations have been identified at molecular level. A family from India is studied, which is constituted by mother (I2) and 3 children (II1, II2 and II3). The molecular characterization of the hemoglobinopathy was made by electrophoretic and chromatographic techniques and confirmed by sequencing of the beta-globin gene. The mutation causer of the beta-thalassemia was studied by PCR-ARMS. The mother (I2) and one of her child (II2) are carriers of the gene for beta zero-thalassemia owing to the frameshift CD 8/9 mutation (+ G). Other of them (II1) is heterozygous for Hb D-Punjab without beta-thalassemia association. The third child (II3) knows a double heterozygote state for Hb D-Punjab/beta zero-thalassemia (hemoglobin D-thalassemia). In spite of the patient with hemoglobin D-thalassemia has 94.5% of Hb D, without Hb A, the hematologic picture belongs to thalassemia trait with moderate haemolytic anemia, intense microcytosis and hypochromia and numerous target cells. This hematologic picture discloses the mildness of the Hb D-Punjab, but the reliable responsible for the phenotype is the disbalance in the synthesis of globin chains, because of frameshift CD 8/9 mutation (+ G) beta zero-thalassemia mutation.
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PMID:[The association of beta zero-thalassemia and Hb D Punjab in a family of Indian origin. The second case reported in Spain]. 913 46

The pathophysiology and clinical severity of beta-thalassemia are related to the degree of alpha/non-alpha-chain imbalance. A triplicated alpha-globin gene locus can exacerbate effects of excess alpha-chains caused by a defective beta-globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the alpha alpha alpha(anti-3.7) allele and a mutation in the beta-globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytosis and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases). Different phenotypes were also evident in the presence of the same beta-thalassemia mutation: in one family, two individuals had the same alpha- and beta-globin genotypes but presented with different hematologic phenotypes. In addition, the complex interaction involving a triplicated alpha-globin gene, beta39- and delta+27-thalassemia mutations is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A2 and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical alpha- and beta-globin genotypes. Interaction with a triplicated alpha-gene can play a role in the clinical presentation of patients with defective beta-globin gene expression and should be considered in the diagnosis of atypical cases.
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PMID:Different hematological phenotypes caused by the interaction of triplicated alpha-globin genes and heterozygous beta-thalassemia. 920 3

Two population groups from Western India with a high prevalence of the beta(S) gene, one tribal (Valsad) and the other nontribal (Nagpur), were studied. The beta(S) gene frequency in both populations was similar (0.22 vs. 0.23), but not the clinical expression of sickle-cell anemia (SS): the sickle homozygotes in the tribal group appeared to have a mild clinical course, whereas the majority in the nontribal group exhibited a more severe clinical phenotype. Both tribal and nontribal SS patients had a similarly high mean hemoglobin (Hb)F expression (18.5% vs. 15.5%) and a high number of F cells (72.3% vs. 66.6%). DNA analysis of the beta-globin gene cluster region revealed that in these two populations, this portion of DNA was identical with and corresponded to the typical Arab-Indian haplotype. Nevertheless, in heterozygotes, the mean beta(S) expression was lower (27.9%) in the tribal as compared to the nontribal group (35.5%). The major epistatic factor distinguishing the milder presentation in tribals vs. a more severe manifestation in nontribals was the very high frequency (0.97) of the alpha-thalassemia gene in the former as compared to the latter (0.24). We conclude that the phenotypic expression of sickle-cell anemia, linked to the Arab-India haplotype and expressing similar levels of HbF and F cells, is not uniformly mild in India and that alpha-thalassemia is a powerful and additional epistatic factor in the Indian subcontinent.
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PMID:Effect of alpha-thalassemia on sickle-cell anemia linked to the Arab-Indian haplotype in India. 920 6


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