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 purpose of this review is to give a general up-date of the most recent developments concerning polymorphisms within the beta-globin gene cluster. The first polymorphisms to be identified were mostly restriction fragment length polymorphisms. They were important markers both for their use as diagnostic tools and for anthropological investigations. Although they have been associated with specific patterns of globin gene expression in the hemoglobinopathies, none have been demonstrated to have any intrinsic functional significance. More recently, additional single nucleotide variations and microsatellite-like polymorphic simple sequence repeats have been identified which are frequently located in trans-acting protein binding segments and hence might affect regulatory processes.
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PMID:Sequence polymorphisms of potential functional relevance in the beta-globin gene locus. 881 12

We report an Asian Indian family in which two daughters have Hb Sun Prairie, a known unstable alpha 2-globin variant [codon 130, GCT-->CCT; alpha 2 130(H13)Ala-->Pro beta 2]. While the homozygous probands have chronic hemolysis-the same phenotype as previously reported, the heterozygous parents are asymptomatic with a thalassemia carrier phenotype, distinct from the chronic hemolytic state previously described in a heterozygote. Unlike the earlier cases in which family studies were not available, this family clearly exhibits autosomal recessive inheritance, unusual amongst variants within the same region of helix H. Globin chain biosynthesis ratios initially suggested a beta-thalassemic hemoglobinopathy-this was excluded by normal sequence analysis of both beta-globin genes. This case report further illustrates the complexity of phenotypes in the thalassemic hemoglobinopathies. It also demonstrates inversion of the alpha/beta-globin chain biosynthesis ratio, a phenomenon which had been noted in other alpha-globin variants and can be a confounding factor in the investigation of thalassemic hemoglobinopathies.
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PMID:Hb Sun Prairie: diagnostic pitfalls in thalassemic hemoglobinopathies. 881 13

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 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

A non-radioactive solid-phase minisequencing method for confirmation of abnormal hemoglobin variants causing sickle cell disease has been developed. In this method amplified 5'-biotinylated target sequences containing normal and mutation sites are immobilized onto streptavidin-coated microplates. Detection primers corresponding to target sequences are annealed immediately adjacent to the mutation site and single-step, hapten-labeled nucleotide primer extension reactions are performed. The incorporation of the labeled nucleotide is detected through immunological reaction with an enzyme-labeled anti-hapten conjugate and a substrate. The method enables confirmation of mutations of the beta-globin gene variants (Hbs S, C, E D-Punjab, O-Arab) and the alpha-globin gene variant (Hb G-Philadelphia). The test was evaluated using characterized dried blood spot specimens (n = 100) The advantages of the procedure are easy performance and objectiveness. The non-radioactive minisequencing assay will prove helpful for genotyping in neonatal screening for hemoglobinopathies and in prenatal and pre-implantational diagnostics.
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PMID:Multivariant confirmation of sickle cell disease using a non-radioactive minisequencing reaction. 902 25

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 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

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

A large English pedigree in which heterocellular hereditary persistence of fetal hemoglobin (HPFH) segregates is described. beta-globin cluster deletions and gamma gene promoter mutations associated with HPFH have been excluded. Of particular importance in this pedigree is the absence of any cosegregating hemoglobinopathy, thus allowing observation of the segregation pattern of this form of HPFH without the complicating effect of a beta-globin gene mutation. Information gained in this study confirms that the extent of elevation of hemoglobin (Hb) F and F cells varies between affected individuals. There are one example of incomplete penetrance and three examples of father-to-son transmission, thus excluding X-linked inheritance. Consistent with previous reports, the most likely mode of inheritance is autosomal codominant. Linkage studies using a beta-globin cluster microsatellite show no evidence of linkage to this chromosomal region implicating the presence of trans-acting regulatory factor(s). We have recently mapped one such locus to the chromosome 6q region in a very large Asian-Indian pedigree. Linkage to chromosome 6q in the English pedigree was excluded, thus indicating the presence of genetic heterogeneity in heterocellular HPFH.
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PMID:Genetic heterogeneity in heterocellular hereditary persistence of fetal hemoglobin. 920 80


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