Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019045 (hemoglobinopathies)
2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The repeated purine-pyrimidine motif (AT)xTy at the region -530bp 5' to the beta-globin gene is regarded as the binding site for BP1, a transcriptionally repressive nuclear protein. In present study, the rearrangement patterns of the -530 motif in the Chinese population, including 43 patients with various hemoglobinopathies and part of their relatives (34), as well as 20 hematologically normal individuals, were investigated with the method of ds-DNA cycle sequencing. The results showed that the -530 motif in Chinese people had three major variation types-(AT)8T5, (AT)7T7 and (AT)9T5. Besides, a novel rearrangement type, (AT)10T3, was found in a hematologically normal family. Furthermore, the analysis of haplotype between the beta-globin structural loci and the -530 motif rearrangement indicated that linkage disequilibrium existed between three mutant beta-globin genes (i.e., IVS-II-654(C-->T), CD41-42(-4bp) and HbE), and three -530 motif rearrangement types (i.e., (AT)8T5, (AT)7T7 and (AT)9T5)7 respectively.
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PMID:[A study of the variation of the (AT)xTy motif-530bp 5' to the beta-globin gene in the Chinese population]. 908 21

We studied two members of an African American family with erythrocytosis. An abnormal hemoglobin variant with an electrophoretic pattern on cellulose acetate similar to Hb J was identified. The oxygen dissociation curve using whole blood was biphasic, dramatically left-shifted, and hyperbolic. Sequence analysis of DNA from the proband showed heterozygosity for a T-->A change at the first position of codon 145 in the beta-globin gene which results in the substitution of an asparagine residue for normal tyrosine. The second cycle of C-terminal amino acid sequence analysis of a mixture of alpha- and beta-globin chains showed tyrosine, aspartic acid, and small amounts of asparagine. Collectively, these results indicate the existence of a mutation at codon 145 of the beta-globin gene which encodes for asparagine instead of tyrosine, and that asparagine then undergoes a partial posttranslational deamidation to aspartic acid. This amino acid substitution corresponds to Hb Osler, which is a high oxygen affinity hemoglobin variant, initially described to be caused by a substitution of Tyr-->Asp at beta 145. Posttranslational amino acid modification may constitute an important component in the pathophysiology of hemoglobinopathies.
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PMID:Hb Osler [beta 145(HC2)Tyr-->Asp] results from posttranslational modification. 910 Dec 80

Electrophoresis at alkaline and acid pH values is the most widely used method for screening for hemoglobinopathies in the clinical laboratory. Nevertheless, the method does not provide definitive diagnostic information for a number of hemoglobins. New automated DNA sequencing techniques make it possible to definitively identify mutations which cause hemoglobinopathies. Moreover these techniques take about the same time as it takes to perform hemoglobin electrophoresis and globin chain electrophoresis. Although the reagent cost is somewhat higher, the results are definitive.
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PMID:Sequence-based diagnosis of hemoglobinopathies in the clinical laboratory. 913 1

The chemical identification of variant hemoglobins was largely overtaken by DNA analysis during the last decade, despite remarkable improvement and automation of individual procedures in conventional chemistry. DNA diagnosis has proved more versatile, covering both variant hemoglobin and thalassemia mutations, less labor-demanding, and easier to learn. Protein chemistry is now reserved for some special problems such as post-translational modification (this problem would be covered much better by mass spectrometry), biosynthesis and stability, and pathologic physiology of selected abnormal hemoglobins. After introduction of DNA analysis during mid 1980's, the number of blood samples referred to our laboratory rapidly increased, mainly because of thalassemia traits in the differential diagnosis of microcytic anemia. Our experience during the past forty years and the present strategy for the rapid presumptive diagnosis of hemoglobinopathies and precise identification of mutations are briefly summarized.
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PMID:[Diagnosis of hemoglobinopathies]. 962 95

Proteins involved in repression of the human beta-globin gene may be useful in the treatment of sickle cell anemia, in conjunction with therapy to reactivate fetal globin genes. If there is a reciprocal elevation of gamma-globin expression upon repression, this approach could be useful in additional hemoglobinopathies. We previously showed that repression of the beta-globin gene appears to be mediated through two DNA sequences, silencers I and II, and identified a protein termed BP1 which binds to both silencer sequences. In this study, we cloned two cDNAs encoding proteins which bind to an oligonucleotide in silencer I containing a BP1 binding site. These cDNAs correspond to HMG-I and HMG-Y, isoforms regarded as architectural proteins. We demonstrate that binding of HMG-I(Y) to this oligonucleotide causes bending/flexure of the DNA. HMG-I(Y) also binds to a second oligonucleotide containing a BP1 binding site located in a negative control region upstream of the delta-globin gene, suggesting a role for HMG-I(Y) in repression of adult globin genes. Expression studies revealed that HMG-I(Y) is ubiquitously expressed in human tissues that do not express beta-globin, being present in 48 of 50 tissues and six hematopoietic cell lines examined. Furthermore, HMG-I(Y) expression is down-regulated during differentiation of primary erythroid cells. We present a model in which HMG-I(Y) alters DNA conformation to allow binding of repressor proteins, and in which the relative amount of HMG-I(Y) helps to determine the repressive state of the beta-globin gene.
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PMID:Binding of HMG-I(Y) elicits structural changes in a silencer of the human beta-globin gene. 988 3

The occurrence of point mutation alpha-thalassaemia and of complex combinations of haemoglobin defects is underestimated. Haemoglobinopathies, the most frequent monogenic recessive autosomal disorder in man, occur predominantly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now confronted with a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near future because of the endogamous growth of the ethnical minorities and the lack of prevention. We describe an Afghan family in which both partners of a consanguineous relationship are carriers of a beta- as well as an alpha-thalassaemia determinant. The combination of defects was revealed by the in vitro measurement of the beta/alpha biosynthetic ratio and was characterised at the DNA level. The molecular defects involved are the Cd5(-CT), a Mediterranean beta zero-thalassaemia mutation, and the alpha 2(zero/+)-thalassaemia AATA(-AA) polyadenylation defect. The alpha-thalassemia defect is a rare RNA-processing mutant described only twice before in heterozygous form in Asian-Indian patients. The mutation suppresses the expression of a alpha 2 gene and reduces the expression of the less efficient, 3' located alpha 1 gene as well, inducing a near alpha zero-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the children who, in addition to being homozygous for the alpha-thalassaemia point mutation, is also a carrier of the beta zero-thalassaemia defect. A previously described homozygous case of the alpha (zero/+)-thalassaemia condition, caused by a similar polyadenylation defect, was characterised by a severe HbH disease. However, the patient described here present at 7 years of age with severe caries, like his beta-thalassaemia homozygous brother but without hepatosplenomegaly, haemolysis or severe anaemia. The haematological analysis revealed 9.5 g/dl Hb; 5.4 x 10(12)/I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 pg MCH and 6.2% of HbA2. The biosynthetic ratio beta:alpha was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodies. The parents reported no complications during pregnancy, at birth, or in the neonatal period in rural Afghanistan. We presume therefore that the counterbalancing effect induced by the co-existing beta-thalassaemia defect could have modified a potentially severe perinatal HbH disease into a strongly hypochromic but well compensated 'alpha zero-like heterozygous' thalassaemia phenotype. The risk of a severe HbH disease, could have been easily missed in this family which was referred because of a child affected with beta-thalassaemia major.
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PMID:A complex haemoglobinopathy diagnosis in a family with both beta zero- and alpha (zero/+)-thalassaemia homozygosity. 1019 99

This article describes the laboratory investigation of an unusual hemoglobinopathy involving hemoglobin (Hb) S, HbSG(Philadelphia), and alpha-thalassemia-2 in a patient whose phenotype was HbSC by alkaline electrophoresis. Findings of a mean corpuscular volume of 62 fL and microcytes on the blood smear were inconsistent with HbSC disease. The patient's clinical course over several years had been mildly symptomatic. Testing in our hospital laboratory using isoelectric focusing and cation-exchange high-performance liquid chromatography to separate hemoglobins showed an unknown variant. Additional studies, including globin chain electrophoresis, reverse-phase high-performance liquid chromatography, and polymerase chain reaction-based DNA analysis were performed at reference laboratories, which reported the following findings: HbG(Philadelphia) associated with alpha-thalassemia-2, HbS and HbG(Philadelphia), and the alpha-globin deletions defining the -alpha3.7/-alpha3.7 genotype. The hemoglobin molecular defects, alpha-thalassemia-2, and the pattern of inheritance are discussed.
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PMID:Laboratory recognition of a rare hemoglobinopathy: hemoglobins SS and SG(Philadelphia) associated with alpha-thalassemia-2. 1050 56

beta Thalassemia (Thal) mutations were studied in DNA from 80/159 patients with hemolytic anemia and high levels of Hb A2 by the amplification refractory mutation system technique (ARMS-PCR). This method detects point mutations and insertions or deletions of just a few nucleotides in the beta globin gene by the polymerase chain reaction of allele-specific priming. In 43/80 patients with different clinical presentations of beta Thalassemia and 37/80 compound heterozygous for hemoglobinopathies and beta Thalassemia the most frequent mutation found was the -29 (of African origin), followed by the CD39 (of Mediterranean origin) and in a lower frequency also was found the -88, the IVSI-6 and the IVSI-110. We conclude that this technique is an useful approach in determining the beta thalassemia mutations in population surveys, because it allows to make a differential diagnosis between beta Thalassemia minor and individuals with high levels of Hb A2. It helps to clarify the diagnosis of patients with structural hemoglobinopathies that also presents high levels of Hb A2.
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PMID:[Detection of beta thalassemia by the technique of refractory amplification of mutation systems (ARMS-PCR)]. 1053 53

The promoter region of adult beta globin genes in humans and other mammals contains conserved regions of pivotal importance for their regulated tissue specific expression. These include the CACCC and CAAT motifs. The CACCC motif is duplicated in humans and other mammals. The human delta-globin gene lacks these conserved regions and its expression in normal individuals is about 3% that of the beta globin gene. Previous studies have shown that the introduction of the beta-globin CACCC or CAAT can activate the delta-globin gene promoter, but the effect of the distal CACCC element has not yet been tested. In the present study, using site-specific mutagenesis, we have introduced the consensus sequence for the distal and proximal CACCC motif and the CAAT box alone or in combination in the wild-type delta-globin gene promoter. The resulting mutants, as well as the wild type (wt) delta- and beta-globin gene promoters, have been analyzed in a transient expression assay in Cos7, K562, and MEL cell lines. The results show that the CACCC boxes can increase the transcription efficiency of the delta-globin gene promoter in both erythroid and non-erythroid cell systems. The contribution of the two CACCC elements is almost equal in the non-erythroid (Cos7) and erythroid embryonic-fetal cell lines (K562), while the proximal CACCC element is more active in adult erythroid cells (MEL). Nonetheless, duplication of this element does not appear to affect the efficiency of the promoter synergistically. Furthermore, to assess the competitive ability of the delta globin promoter containing the proximal or distal CACCC consensus sequences over the wt beta globin gene promoter, we have carried out transient expression experiments using DNA constructs in which the delta and beta globin gene promoters are linked in cis and are sharing a single enhancer (competitive transient expression). The results show that both CACCC elements are able to activate the delta globin gene promoter in Cos7 and K562 cells, although to a different extent, whereas only the proximal CACCC element is effective in increasing the transcription efficiency in MEL cells. These findings are in agreement with the more severe clinical phenotype produced by the beta-thalassemia mutations affecting the proximal CACCC box as compared with those within the distal CACCC box. The Erythroid Kruppel Like Factor (EKLF) is a nuclear protein restricted to erythroid cells which specifically bind the CACCC box sequence and activate the beta-globin gene. In the present study we carried out transactivation experiments of the mutagenized delta-globin gene promoter by introducing an EKLF expressing construct in erythroid cells. Constructs containing the proximal but not those bearing the distal CACCC element are transactivated. Our results indicate that the proximal CACCC box and, to a lesser extent, also the distal box have a role in the regulated stage specific expression of a beta-like globin gene, and show that the insertion of a single CACCC motif in the delta-globin gene promoter is sufficient to increase its activity. Nevertheless only the delta globin gene promoter containing the proximal CACCC element is able to compete with the wt beta globin gene promoter in the adult erythroid environment. These findings have potential relevance for the future prospective treatment of inherited hemoglobinopathies based on the conversion of the low functioning delta-globin gene into a high functioning beta-like globin gene.
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PMID:Activation of the delta-globin gene by the beta-globin gene CACCC motif. 1057 45

The aim of this study was to determine the prevalence of GB virus C (GBV-C) infection in pediatric patients receiving multiple blood transfusions in Turkey where HBV and HCV infections are common. Sera of a total of 148 children, of whom 85 had cancer and 63 hemoglobinopathies, were tested for GBV-C RNA and HCV RNA by RT-PCR and for antibodies to HBV and HCV. Demographic and clinical information as well as laboratory results were recorded for the patients (81 boys, 67 girls, aged 1-19 years). HBsAg positivity was found in 23 (15.5%) patients, HBV DNA positivity in 12 (8.1%), HCV RNA positivity in 9 (6.7%), and GBV-C RNA positivity in 4 (2.7%). There was no significant difference in the GBV-C RNA positivity between patients with cancer (3.2%) and patients with hemoglobinopathies (2.4%) (p > 0.05). GBV-C RNA was found in 4 (3.1%) out of 127 patients who had received transfusions, but it was not found in any of 21 patients who had not received transfusions. However, there was no relationship between GBV-C RNA positivity and the number of transfusions. Two of the patients with GBV-C RNA had high levels of ALT (ALT > 40 IU). In these two patients, neither HBV DNA nor HCV RNA were detected by PCR, and serological tests were also negative for these agents. We concluded that pediatric patients who had multiple transfusions in Turkey are at risk of being infected with GBV-C, in addition to HBV and HCV. Investigation of GBV-C RNA in patients with high ALT levels in the absence of other viral markers may be useful.
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PMID:Prevalence of GB virus C/hepatitis G virus infection in pediatric patients receiving multiple transfusions in Southern Turkey. 1077 Jun 80


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