Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a two-step strategy to alter any mouse locus repeatedly and efficiently by direct positive selection. Using conventional targeting for the first step, a functional neo gene and a nonfunctional HPRT minigene (the "socket") are introduced into the genome of HPRT- embryonic stem (ES) cells close to the chosen locus, in this case the beta-globin locus. For the second step, a targeting construct (the "plug") that recombines homologously with the integrated socket and supplies the remaining portion of the HPRT minigene is used; this homologous recombination generates a functional HPRT gene and makes the ES cells hypoxanthine-aminopterin-thymidine resistant. At the same time, the plug provides DNA sequences that recombine homologously with sequences in the target locus and modifies them in the desired manner; the plug is designed so that correctly targeted cells also lose the neo gene and become G418 sensitive. We have used two different plugs to make alterations in the mouse beta-globin locus starting with the same socket-containing ES cell line. One plug deleted 20 kb of DNA containing the two adult beta-globin genes. The other replaced the same region with the human beta-globin gene containing the mutation responsible for sickle cell anemia.
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PMID:Deletion and replacement of the mouse adult beta-globin genes by a "plug and socket" repeated targeting strategy. 793 10

Two human hemoglobins designed to inhibit the polymerization of sickle hemoglobin (Hb S; alpha 2 beta S2) have been produced. Mutations that disrupt the ability of Hb S to form polymers were introduced into the normal human beta-globin gene by site-specific mutagenesis. These mutations affect the axial and lateral contacts in the sickle fiber. The recombinant hemoglobin designated anti-sickling hemoglobin 1 (Hb AS1) contains the mutations beta 22 glutamic acid to alanine and beta 80 asparagine to lysine. Hb AS2 has the same beta 22 glutamic acid to alanine mutation combined with beta 87 threonine to glutamine. Human alpha- and beta AS-globin genes were separately fused downstream of beta-globin locus control region sequences and these constructs were coinjected into fertilized mouse eggs. Transgenic mouse lines that synthesize high levels of each anti-sickling hemoglobin were established and anti-sickling hemoglobins were purified from hemolysates and characterized. Both AS hemoglobins bind oxygen cooperatively and the oxygen affinities of these molecules are in the normal range. Delay time experiments demonstrate that Hb AS2 is a potent inhibitor of Hb S polymerization; therefore, locus control region beta AS2-globin gene constructs may be suitable for future gene therapy of sickle cell disease.
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PMID:Recombinant human hemoglobins designed for gene therapy of sickle cell disease. 793 4

In Saudi Arabia two major forms of sickle cell anaemia (SCA) have been identified, a benign SCA is reported mainly in the Eastern province and a severe form is reported in other parts of the country. Multiple factors including associated alpha-thalassaemia, elevated Hb F and glucose-6-phosphate dehydrogenase (G-6PD) deficiency have often been reported as modifying the clinical presentation of the disease. However, these factors do not completely explain the amelioration in the clinical manifestations in SCA. More recently interest has been directed toward the investigations of the regions surrounding the beta-globin genes. Using restriction endonucleases extensive polymorphism has been identified and different haplotypes have been encountered. We initiated studies in the different regions of Saudi Arabia. Our studies on the Saudi population from different regions of the country using Hinc II and Hind III showed that the beta-globin gene haplotype ++-++ is associated with a mild sickle cell anaemia, while ----+ is associated with the severe form of the disease. Xmn I polymorphic site 5' to the G gamma gene and 7.6 kb Hpa I fragments 3' to the beta-globin gene are also associated mainly with the mild disease. This paper presents and compares the two major forms of SCA in Saudi population and relates it to the genetic heterogeneity.
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PMID:The relationship of the genetic heterogeneity of sickle cell gene to clinical manifestations. 809 5

Bone marrow transplantation (BMT) is the only treatment currently available which can cure thalassaemia and sickle cell anaemia. However, it is not without risk and the complications of graft failure, GVHD, veno-occlusive disease, interstitial pneumonitis and infections, together with the toxicity of the conditioning therapy result in a transplant-related mortality in children of 10-20%. For the survivors, long-term sequelae include chronic GVHD, endocrinopathies and an increased incidence of secondary malignancies. The decision to offer BMT to a patient with a haemoglobinopathy must be based on a knowledge of the relative risks of transplant and conventional therapy. However, in sickle cell anaemia, a subset of patients with particularly severe disease can be identified at an early age when the risks associated with BMT are at their lowest. In thalassaemia, chelation therapy can delay the onset of organ damage due to hypertransfusion but is unlikely to prevent it entirely. The results of BMT in children without organ impairment are excellent and BMT must now be considered a real alternative to conventional treatment. Gene therapy is an exciting prospect for the future but recent progress in retroviral gene transfer has been hindered by poor infection efficiencies and expression levels in the target cells. The identification of the positive regulatory elements of both the alpha- and beta-globin genes may resolve some of these problems. Finally, alternative gene delivery systems are being investigated, but the introduction of gene therapy for the haemoglobinopathies into clinical practice may need to await successful gene targeting and replacement.
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PMID:Bone marrow transplant for the haemoglobinopathies: past, present and future. 835 16

As a preliminary step to preimplantation diagnosis of sickle cell disease in unfertilized eggs or 8-cell embryos of heterozygous parents, we established quality control for detection of the mutant and normal alleles of the beta-haemoglobin gene using single buccal cells. Efficient polymerase chain reaction (PCR) amplification of a 680 base pair sequence of the beta-globin gene spanning the site of the sickle cell mutation was obtained for 79 per cent of single heterozygous cells. In 71 per cent of cases, both alleles were detected. With this current efficiency, we predict that a clinical preimplantation diagnosis at the 8-cell embryo stage could be carried out safely and reliably for a couple at risk of transmitting sickle cell disease to their children.
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PMID:Detection of both the normal and mutant alleles in single cells of individuals heterozygous for the sickle cell mutation--prelude to preimplantation diagnosis. 844 70

In Kenya and most of Eastern Africa, sickle haemoglobin (HbS) is the pre-dominant beta-globin chain abnormality; homozygous sickle cell disease, (SCA), is the predominant form of sickle cell disease. Although the prevalence of sickle cell trait (SCT) in Kenya was known, the magnitude of SCA was yet to be established. We performed a national survey in all hospitals from November 1987 to May 1990 and found 3605 cases with SCA. Age was recorded for 2821 patients. Seventy-seven per cent of these patients were below the age of fifteen. The oldest patient was a 50-year-old female. The paediatric to adult ratio was 3:1. More than 80% of the patients were of Luo or Luhya ethnic origin (Luo 58.4%, Luhya 23.9%). There was a discrepancy between SCT rate (SCTr) and the percentage distribution of SCA patients per province. The Kambes of the Mijikenda group in the Coast Province with the highest SCTr (35%) constituted only 8.5%, but the Luos with a SCTr of 28%, 58% of the total SCA patient population in Kenya. We found reports of SCA in the Somali and Turkana, in whom no SCT had been found previously.
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PMID:Survey of sickle disease in Kenya. 847 Feb 99

At the present time, about 3.5 million people from Turkey, Greece, Italy, the Middle East, Africa and Asia are living in Germany. They are potential carriers of beta-thalassaemia and haemoglobinopathies such as sickle cell disease. These diseases are new for most of us and represent a challenge to physicians, taking care of these patients. Not only do we have to learn about the clinical problems of homozygous patients and how to handle them, we also have to become acquainted with the problems related to the heterozygous carrier stage. The large number of asymptomatic pregnant carriers of beta-globin anomalies is a particular challenge for obstetricians. They need to identify carriers through haemoglobin electrophoresis screening, inform the carrier about the meaning of being a carrier, screen the woman's partner, refer for genetic counselling and suggest and explain prenatal diagnosis in case the partner is also a carrier. There is as yet no cure for thalassaemia and sickle cell disease, except for bone marrow transplantation in a few selected cases. Therefore, prenatal diagnosis presents a valuable method of preventing severe chronic diseases. Screening does not only allow genetic counselling, the information gained has also clinical implications for carriers of beta-thalassaemia. In this paper a summary is given of the pathophysiological and clinical features of thalassaemia and sickle cell disease and molecular biology methods to diagnose thalassaemias and sickle cell disease are discussed. In addition, a screening programme for pregnant women from countries at risk is suggested to enable physicians to give optimal care and initiate prenatal diagnosis.
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PMID:[Monitoring pregnant patients from risk countries with sickle cell disease and thalassemia. Clinical aspects, screening and prenatal diagnosis]. 849 63

Very different fetal hemoglobin levels among adult sickle cell anemia patients suggest genetic modulation of gamma-globin gene expression. In sickle cell anemia, different fetal hemoglobin levels are associated with distinct beta-globin gene haplotypes. Haplotype may be a marker for linked DNA that modulates gamma-globin gene expression. From 295 individuals with sickle cell anemia, we chose for detailed studies 53 patients who had the highest or the lowest fetal hemoglobin levels and 7 patients whose fetal hemoglobin levels were atypical of their haplotype. In these individuals, we examined portions of the beta-globin gene locus control region hypersensitive sites two and three, an (AT)x(T)y repeat 5' to the beta-globin gene, a 4-bp deletion 5' to the A gamma T gene, promoters of both gamma-globin genes, 5' flanking region of the G gamma-globin gene, and A gamma-globin gene IVS-II. Of the regions we studied all polymorphisms were always haplotype-linked and no additional mutations were present. This suggested that variations in these areas are uncommon mechanisms of fetal hemoglobin modulation in sickle cell anemia. Whereas unexamined cis-acting sequences may regulate gamma-globin gene transcription, trans-acting factors may play a more important role.
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PMID:Fetal hemoglobin in sickle cell anemia: relation to regulatory sequences cis to the beta-globin gene. Multicenter Study of Hydroxyurea. 860 54

The ability to generate stable high-titer vectors that give rise to high levels of expression of transduced globin genes in erythroid cells is a prerequisite for effective retroviral-mediated globin gene therapy. The human beta-globin gene with its immediate flanking sequences does not contain all the regulatory elements necessary for regulated high-level and position-independent expression in erythroid cells. The regulatory element known as the beta-globin locus control region (BetaLCR) can provide a linked Beta-globin gene with these properties. However, addition of BetaLCR sequences to a retrovirus carrying a beta-globin gene increases its genetic instability. We have developed a new generation of retroviral vectors in which a human gamma-globin gene is placed under the control of the alphaLCR, the major regulatory element of the alpha-globin gene cluster. We demonstrate that these retroviruses are genetically stable in producer cell lines and can be produced at high titers that exceed 5 x 10(6) colony-forming units (CFU)/mL. In addition, we show that the transduced gamma-globin gene can be expressed in the adult erythroid environment of mouse erythroleukemia (MEL) cells at a level comparable to that of a single endogenous Betamaj-globin gene. These retroviruses can also transduce primary murine bone marrow progenitor cells as efficiently as retroviruses that carry the neomycin resistance (neor) gene. This new generation of globin retroviral vectors may prove useful for gene therapy of human beta-globin gene disorders such as sickle cell disease and beta-thalassemia.
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PMID:Production of genetically stable high-titer retroviral vectors that carry a human gamma-globin gene under the control of the alpha-globin locus control region. 863 Apr 19

The beta gene cluster haplotypes, alpha gene status, Hb F level and hematological parameters have been characterized in 154 unrelated Guadeloupe patients with sickle cell disease: 112 with sickle cell anemia, 26 with SC disease, 15 with Hb S-beta-thalassemia, and one patient with Hb S in association with the hereditary persistence of fetal hemoglobin. Fourteen haplotypes in 16 combinations were found, the three major African haplotypes were present on 92% of all chromosomes: 73% Benin, 11% Bantu, 8% Senegal. Among SS patients, 57% were Benin homozygotes, one patient was a Senegal homozygote, one patient was a Bantu homozygote, and all the others were heterozygous. The A gamma T chain was observed on seven chromosomes and about 5% of the analyzed beta S chromosomes exhibited atypical haplotypes. The common haplotype beta C was found in all patients with SC disease. An interesting feature was the high frequency (44%) of deletional alpha-thalassemia among SS patients. Two patients have an alpha-gene globin triplication. The DNA haplotypes and alpha-gene status have been correlated with hematological parameters in these patients. The anthropological aspect of these data is interesting as the haplotypes of the beta-globin gene throw light on the slave trade from the various parts of Africa to the Caribbean Islands in particular, and North America in general.
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PMID:beta S haplotypes, alpha-globin gene status, and hematological data of sickle cell disease patients in Guadeloupe (F.W.I.). 874 33


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