HBB

..The -158GgammaT and the (AT)9(T)5alleles were found to be associated with increased levels of HbF in beta-thal carriers, but not in wild-type subjects...

..Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area...

Our previous studies on the human beta globin gene cluster revealed the presence of intergenic transcripts throughout the locus, and demonstrated that transcription of the locus control region (LCR) initiates within an ERV9 endogenous ..

..Further studies are needed to validate this hypothesis and determine whether XmnI or another closely linked variant modulates severity and HbF levels in patients with beta(0)-thalassemia/HbE disease...

..We conclude that the CH haplotypes are useful genetic determinants for beta-thalassemia major and intermedia patients, while the 3'HS1 (+179 C>T) mutation may have functional consequences in gamma-globin genes expression...

..We conclude that a mammalian enhancer can cooperate with adjacent sequences to create an efficient replicator module...

..Refining the expectations for allele and trait frequency change for Jamaica and other similar populations is an area for future study...

..These results imply that GATA-1 is sufficient to direct chromatin structure reorganization within the beta-globin LCR and an erythroid pattern of gene expression in the absence of other hematopoietic transcription factors...

..Most epigenetic and chromatin structural features did not undergo transitions at the presumed borders of the globin domain where the insulator factor CTCF interacts, raising questions about the function of the borders...

..Taken together, these results suggest that the formation of the ACH is dependent on a largely intact LCR structure. We propose that the ACH indeed is an extension of the LCR holocomplex...

..The 5'HS5 insulator operates in adult as well as in embryonic murine erythroid cells. The insulator has no significant stimulatory effects of its own. These results indicate that 5'HS5 can function as a chromatin insulator in vivo...

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..These data are important in understanding the role of malaria in the selection and maintenance of the sickle cell gene...

..The rapid decay in LD upstream of the HbC allele demonstrates the large effect the ss-globin hotspot has in mitigating the effects of positive selection on linked variation...

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The normal expression of human beta globin is critically dependent upon the constitutively high stability of its encoding mRNA...

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..These results provide the first evidence that nuclear matrix association dynamically mediates the looping of the beta-globin locus to achieve transcriptional control...

..We propose that quasi-palindromic sequences may form stable mini- hairpins or cruciforms in the HS4 region and might play a role in regulating beta-globin gene expression by affecting the binding of transcription factors...

..These observations demonstrate that the phenotype observed in the LCR-inverted locus was in part attributable to placing the HS5 insulator between the LCR HS enhancers (HS1 to HS4) and the promoter of the beta-globin gene...

..Thus, a novel frameshift cd53 (-T) mutation may lead to mild thalassemia intermedia even though there is no statistically significant difference in beta-globin messenger RNA (mRNA) level between six heterozygotes and six normal subjects...

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..We conclude that multiple interactions between the LCR and the beta-globin gene are required to maintain the appropriate spatial configuration in vivo...

..Our data reveals that in the majority of these Hb E-beta-thalassemia patients, it is very hard to predict the clinical phenotype of the patients from the beta-globin mutations and these secondary genetic modifiers...

..Lack of protective polymorphisms may contribute to morbidity and mortality during outbreaks of malaria in the highlands...

..Multiplexed ARMS for ethnic-specific beta-thalassemia mutations from the original newborn screening dried blood specimens is a rapid and efficient approach for diagnostic confirmation...

..Degradation of the downstream cleavage product by Xrn2 results in transcriptional termination, as envisaged in the torpedo model...

..In addition, a large selection of the 3' non-coding regions of rabbit and human globulin mRNAs (both the alpha and beta globin mRNAs) are 85% homologous, demonstrating that this region is significantly conserved in evolution.

..Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature...

..disease, resulting from one or more of a total of more than 200 different mutations in the beta-globin gene (HBB)...

..We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia...

..Surprisingly, HS5 functions as an enhancer blocker in embryonic erythroid cells. We conclude that HS5 is a developmental stage-specific border in erythroid cells...

..This frameshift mutation produced a termination codon at the position of the new 21st codon. Mutations that lead to premature termination of beta-globin synthesis appear to be among the common causes of beta 0-thalassemia in man...

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..Nucleotide diversity at synonymous sites in the sample is 0.14%, suggesting an average age of sequence divergence of approximately 450,000 years, consistent with that expected for a neutrally evolving human nuclear locus...

..Prevention programs based on molecular diagnosis of heterozygous carriers and/or patients require the use of reliable mutation scanning methods in at-risk populations...

..Our results indicate that each hypersensitive site in the human beta-globin LCR has distinct structural features and suggest that HS2 plays a pivotal role in LCR organization at embryonic and fetal stages of globin gene expression...

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..These data establish the potential of using a gamma-globin lentiviral vector for gene therapy of beta-thalassemia...

Beta-thalassemia is caused by the reduced (beta) or absent (beta) synthesis of the beta globin chains of the hemoglobin tetramer. Three clinical and hematological conditions of increasing severity are recognized, i.e...

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..anubis) pre- and posttreatment...

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..6%, HbA1 1.7%, HbA2 1.7%, beta globin gene mutation CD17, A-->T/IVS-II-654, C-->T). The patient's HLA typing was A 24,11, B 58,35 and DRB1 03,15...

..of eutherian mammals exhibits a propensity for recombinational exchange with the closely linked beta-globin gene (HBB) and has been independently converted by the HBB gene in multiple lineages...

..g., BALB/c) in response to hydrogen peroxide stress has been shown to be correlated with the type of hemoglobin beta chain (Kruckeberg, W.C., et al. (1987) Blood 70, 909-914)...

..In 30 mM Asp (pH 3.0) or 20 mM Asp (pH 3.1) resolution of these two peptides is fully restored. Isoelectric, amphoteric buffers thus seem to represent a novel, powerful buffer system able to offer high resolution and high selectivity...

Allelic variation in the mouse beta globin gene complex (Hbb) produces structurally different beta globins in different mouse strains...

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..These findings provide evidence that a domain of active chromatin is formed by spreading from an enhancer to a target gene and can be blocked by a nucleosome-free gap in an insulator...

..An analysis of cis-acting regulatory regions showed varied sequence haplotypes associated with some frequent beta-thalassemia mutations in this Eastern Indian population...

..The relationship of these measurements of transgenic globin expression to a possible binary model of globin LCR action and to mimicry from red blood cell loss due to transgenic globin imbalances are discussed...

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..Hb), transferred trough a recessive autosomal mechanism, due to a reduced or else defective synthesis of beta globin sequences...

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..We therefore conclude that, although the GATA site in 5'HS1 is critical for efficient epsilon-globin gene expression, hypersensitive site formation per se is independent of 5'HS1 function, if any, in definitive erythroid cells...

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..Different types of beta globin gene mutations were analyzed using reverse dot blotting (RDB) method...

To prepare monclonal antibody (mAb) against both hemoglobin A2 (HbA2) and hemglobin A (HbA), this antiboy can bind to delta globin chain and beta globin chain, but not to gamma globin chain.

..Haplotype analyses indicated that the unusual form of the beta-globin gene deletion and gamma-globin gene triplication in cis were linked to halotype [+ - - - - - -]...

..The parents had no history of hemolysis. The paternity of the child was confirmed by DNA analysis...

..To assess the clinical significance of the interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians...

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..Using a human beta-globin transgenic mouse line in a beta-thalassemia diseased model generated with a lentiviral-mediated approach, we investigate the stable therapeutic effect on a common thalassemia syndrome...

..A PXE phenotype without mutations in ABCC6 has been described in Greek and Italian patients presenting with beta thalassemia. We attempted to determine the incidence of beta thalassemia in a cohort of French patients with PXE...

..The cluster shows a massive overrepresentation of a non-LTR retrotransposon, CR1, which accounts for 16% of the DNA. We suggest that the locus is a preferred site for CR1 insertion...

..A genetic boundary between northern and southern Han Chinese was not evident in the present study...

..These results suggest that primary structural elements--and the spatial organization of these elements--are important for function of the beta-globin LAR...

..for a large deletion, which has a 5' breakpoint at position -4279 from the cap site of the beta-globin gene (HBB) with the 3' breakpoint located in a L1 family of repetitive sequences at an unknown distance from the beta-globin ..

..Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype...

beta-thalassemia major can be caused by homozygosity or compound heterozygosity for beta-globin gene mutations (HBB gene). Most cases are inherited from parents who both have diseased alleles of the HBB gene...

..The humanized IVSI-110 mouse model accurately recapitulates the splicing defect found in comparable beta-thalassemia patients. This mouse model is available as a platform for testing strategies for the restoration of normal splicing...

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..The higher yield of these mice has facilitated physiological and therapeutic studies of sickle cell anemia...

..To estimate the additional number of affected individuals based on the prevalence of sickle-cell syndromes among relatives of index cases...

..It also provides an innovative strategy for the treatment of many disease conditions, including sickle cell anemia and beta-thalassemia...

..These mice have hemolytic anemia, 10% irreversibly sickled cells in their peripheral blood, reticulocytosis, and other phenotypic features of SCA...

..We focused on the role of the silencer II region located upstream of the beta-globin gene, which along with its cognate binding protein BP1, negatively regulates beta-globin transcription...

..This amplification method is rapid, sensitive and simple, and also has application research that is important for the prenatal diagnosis of sickle cell disease...

..Therefore, activation of the expression of the Epo receptor gene and activation of the erythroid differentiation program are two independent events in normal hematopoiesis...

..6 pg, MCHC: 33.5%, HbA(2): 5.3%, HbF: 0% and HbA: 85.4%. The boy was found to be compound heterozygote for beta globin gene mutations (HBB:c.92 + 5G > C/HBB:c.93-2A > C). The mutation HBB:c.93-2A > C was inherited from his father...

..PNA-induced gene expression strategy also may have implications in gene therapy of other diseases such as genetic diseases, cancer and infectious diseases...

..The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s)...

..These cells may be useful for identifying transcription factors that reactivate gamma-globin synthesis or screening gamma-globin inducers for the treatment of sickle cell disease or beta-thalassemia...

..This is the first study of the deletions involved in deltabeta-thal in Iranian patients. Our study highlights the importance of detecting these mutations for prenatal diagnosis carrier detection and genotype/phenotype prediction...

..These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a gamma-globin lentiviral vector...

..The best method for desorbing bound protein was found to be an electrophoretic step consisting in driving sodium dodecylsulphate micelles from the cathodic reservoir...

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..We considered that the results of PCR correlated with the character of HIV as infectivity...

..The altered expression of structural and nonstructural genes may play important roles in the mediation of myocarditis development and perhaps other pathological processes in the heart...

..The low toxicity exerted by compounds 9 and 24 in all of the assays investigated suggests that these new HDAC inhibitors should be considered for personalized therapy of selected patients with beta(0) thalassemia...

..We investigated the G-CSF effect in a thalassemic mouse model (HBB(th-3)) as compared with a normal strain (C57BL/6), in terms of safety, mobilization efficacy, and distribution of ..

..We conclude that hnRNP A1 is able to direct unspliced globin pre-mRNA into a nuclear compartment where it is recognised by Rev and then transported to the cytoplasm...

Hyoscine N-butyl bromide (HBB) acts by inhibiting cholinergic transmission in the abdomino-pelvic parasympathetic ganglia, thus relieving spasm in the smooth muscles of gastrointestinal, biliary, urinary tract and female genital organs, ..

..The modified transgenes are the first to transfer intronic elements that potentiate LCR activity and are designed to facilitate correction of hemoglobinopathies using single copy vectors...

..Inhibition of in vivo pathology by either of the methods described above will demonstrate athe efficacy of these strategies and will provide a foundation for genetic therapy of sickle cell disease in humans. ..

..Furthermore, important information to develop novel Hb F inducers will be disclosed by this study. ..

..These studies will provide a solid foundation for subsequent clinical trials in human patients with this devastating disease. ..

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..With this model, based on the genotype and analysis of the mRNA stability, we aim to predict the potential success of gene therapy given a specific mutation. ..

..The proposed research comprises a crucial step in evaluating the promise of developmentally silenced globin genes for individuals with beta-thalassemia and sickle cell anemia. ..

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..The proposal will also examine the question of whether or not developmental stage-specific transcription factor binding to the beta/epsilon-globin gene enhancer differentially contributes to chicken beta-globin gene switching. ..

..These experiments provide a comprehensive approach to understanding the regulation of beta-globin locus chromatin structure and potential applications to development of gene therapy strategies. ..

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..This research seeks to understand how these defective gene products are destroyed and how this information might be used to develop new treatments for this debilitating disease. ..

..3) To confirm that the most effective oligonucleotides identified in Specific Aims 1 and 2 are effective in erythroid cells from patients with thalassemia. ..

..to identify and characterize DNA sequences and trans-acting factors that regulate the expression of the human beta globin gene complex, especially those involved in the switch from gamma to beta synthesis in late fetal life...