Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019045 (hemoglobinopathies)
 2,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The stage selector protein (SSP) is a heteromeric complex involved in preferential expression of the human gamma-globin genes in fetal-erythroid cells. We have previously identified the ubiquitous transcription factor CP2 as a component of this complex. Using the protein dimerization domain of CP2 in a yeast two-hybrid screen, we have cloned a novel gene, NF-E4, encoding the tissue-restricted component of the SSP. NF-E4 and CP2 coimmunoprecipitate from extract derived from a fetal-erythroid cell line, and antiserum to NF-E4 ablates binding of the SSP to the gamma promoter. NF-E4 is expressed in fetal liver, cord blood, and bone marrow and in the K562 and HEL cell lines, which constitutively express the fetal globin genes. Enforced expression of NF-E4 in K562 cells and primary erythroid progenitors induces endogenous fetal globin gene expression, suggesting a possible strategy for therapeutic intervention in the hemoglobinopathies.
Mol Cell Biol 2000 Oct
PMID:Induction of human fetal globin gene expression by a novel erythroid factor, NF-E4. 1100 62

Clinical phenotypes associated with abnormal globin chain biosynthesis may result in thalassemia (deficient quantity) or hemolytic anemia (abnormal hemoglobins). However, the phenotypic expression of hyperunstable hemoglobin variants often includes features of thalassemia, along with variable peripheral hemolysis. Hemoglobinopathies caused by highly unstable beta-chain variants have a dominant thalassemia-like phenotype, in which carriers have a clinical expression of thalassemia intermedia, but highly unstable alpha-globin variants are usually only phenotypically apparent when they interact with other alpha-thalassemia mutations. In a child with clinical and hematological features consistent with beta-thalassemia intermedia, DNA analysis excluded any beta-globin gene mutations but characterized a novel deletion cd37(C2)Pro>0 (Hb Heraklion) in the alpha1 globin gene, in trans to a common Mediterranean nondeletion alpha-thalassemia mutation (alpha(Hph)alpha). The deletion of proline at alpha37(C2) is predicted to result in severe instability of the variant hemoglobin, which on interaction with a synthesis-deficient alpha-thalassemia mutation causes a relatively severe dyserythropoietic anemia, representing an alternative phenotype associated with highly unstable alpha-chain variants. Hb Heraklion is the fourth highly unstable alpha-globin variant that we have observed in patients from Greece and Albania. Two variants involve the alpha2-globin gene: Hb Agrinio (alpha29(B10)Leu>Pro) and Hb Adana (alpha59(E8)Gly>Asp), and two the alpha1-gene: Hb Aghia Sophia (alpha62(E11)Val>0) and (Hb Heraklion a37(C2)Pro>0). Each has been observed on interaction with a different alpha-thalassemia mutation and the phenotypes associated with these highly unstable alpha-variants are presented.
Blood Cells Mol Dis 2000 Aug
PMID:Distinct phenotypic expression associated with a new hyperunstable alpha globin variant (Hb heraklion, alpha1cd37(C2)Pro>0): comparison to other alpha-thalassemic hemoglobinopathies. 1104 28

The severe hemoglobinopathies, including beta-thalassemia major and sickle cell anemia, are candidate diseases for a genetic treatment based on the transfer of a regulated globin gene in autologous hematopoietic stem cells. Two years ago, May et al reported that an optimized beta-globin transcription unit containing multiple proximal and distal regulatory elements harbored by a recombinant lentiviral vector could efficiently integrate into murine hematopoietic stem cells and express therapeutic levels of the human beta-globin gene. Here, we review the advantages afforded by lentivirus-mediated globin gene transfer and recent studies based on this strategy.
Curr Opin Mol Ther 2002 Oct
PMID:Therapeutic globin gene delivery using lentiviral vectors. 1243 53

Reverse allele specific oligonucleotide assays provide a robust method for the molecular characterization of high-mutation spectrum disorders. Commercial test have been developed for human leukocyte antigens class I and class II regions of human chromosome 6, the cystic fibrosis transmembrane conductance regulator at 7q31 and strains of human Hepatitis B and C virus. In their most developed form, these assays rely upon highly multiplexed PCR reactions containing biotinylated primers providing a substrate for nonradioactive detection systems. Sophisticated reverse dot-blot technology involves mechanized covalent attachment of activated primary amine-conjugated oligonucleotides to carboxylated nylon membranes or bovine serum albumin. Subsequent to line or dot printing, membranes are stored or sold dry in preparation for hybridization. Circular spots or lines are visualized colorimetrically after hybridization through the use of streptavidin horseradish peroxidase incubation followed by development using tetramethylbenzidine and hydrogen peroxide, or via chemiluminescence after incubation with avidin alkaline phosphatase conjugate and a luminous substrate susceptible to enzyme activation, such as CSPD, followed by exposure to x-ray film. The entire procedure from blood specimen receipt to result usually requires less than 1 day. Because of the simplicity, speed, and generally high sensitivity and specificity, large numbers of individuals can be rapidly screened using this technology. Rapid turnaround is often required in prenatal diagnosis of cystic fibrosis, beta-thalassemia and hemoglobinopathies, giving this technology has special applicability in those genetic diseases. Commercial instruments are available which automate the hybridization and color development. In addition, scanning software can capture the probe reactivity pattern and interpret it in terms of a genotype.
Expert Rev Mol Diagn 2003 Mar
PMID:Origin and utility of the reverse dot-blot. 1264 92

In the present paper, we demonstrate the erythroid cell membrane unique properties in a previously characterized case of hemoglobin-H disease, associated with congenital dyserythropoietic anemia type-I features. In order to explain the patient's cell membrane distortions and the high affinity for the various intracellular inclusions, we studied its composition and structure in comparison to other anemic and non-anemic cases. Red cells from peripheral blood were fractionated into cellular, membrane and protein extracts. Membrane attached immunocomplexes were separated and collected by immunoprecipitation. The subcellular fractions were analyzed by SDS-PAGE electrophoresis and immunoblotted against a variety of erythroid-specific antibodies. The protein composition of the membrane was characterized by immunogold electron microscopy. In the membrane of the CDA-associated case, we identified sialic acid and protein deficiencies, formation of protein crosslinkings, excesses of bound globin and immunoglobulins and aberrant peptides. In contrast to the typical hemoglobin-H disease, the ghost-bound globin exhibited preferential attachment to the skeletal proteins than the band 3 and the skeleton-bound globin consisted not only of beta- but also of alpha-globin chains. Another hallmark, probably associated with the CDA defect, was the participation of glycophorins in the membrane-bound immunocomplexes and the pathological clustering of the latter in the membrane. This study strongly suggests that the result of the combinatorial effects on the diseased membrane created a unique profile, quite distinct from the one observed in several typical hemoglobinopathies. Our observations shed light into critical membrane alterations leading to hemolysis in the novel CDA-associated disease and probably into the CDA-I or CDA-I-like diseases.
Blood Cells Mol Dis
PMID:Defective organization of the erythroid cell membrane in a novel case of congenital anemia. 1266 86

Although the endocrine pancreas appears to play an important role in the pathophysiology of sickle cell disease, very little is known about the morphologic changes in this tissue. Our study was initiated to delineate the microscopic features of the endocrine pancreas in a large autopsy series of sickle cell hemoglobinopathies. From more than 650 cases archived at the Centralized Pathology Unit for Sickle Cell Disease (Mobile, AL), 224 autopsy cases were identified for review of clinical and gross autopsy findings and/or for microscopic studies, including histochemical stains (trichrome, reticulin, iron), and immunohistochemical stains (insulin, glucagon, somatostatin, and pancreatic polypeptide). The gross examinations were recorded as unremarkable in 65% of the autopsies. In childhood and adolescence (< or = 18 years), pancreas weights (50.76 +/- 5.16SE gm) were significantly greater (p < 0.0001) than age-matched controls (30.42 +/- 3.59SE gm). In adulthood, pancreas weights (108.34 +/- 5.29SE gm) were not significantly different from controls (110 gm). Microscopic findings included vascular congestion (48%), edema (65%), siderosis (31%), and nesidioblastosis (76%), which included islet cell dispersion (53%), hyperplasia (23%), and hypertrophy (25%). Analysis by age groups suggested that islet cell dispersion/hyperplasia persists unchanged, whereas diameters of compact islets tend to increase with age. These findings may be related to local tissue hypoxia and/or increased metabolic energy needs in sickle cell disease.
Pediatr Pathol Mol Med
PMID:Nesidioblastosis in sickle cell disease. 1267 39

The switch from embryonic to fetal then to adult hemoglobin synthesis is a unique phenomenon during early human development. Fetal hemoglobin (Hb F) is known to interfere with polymerization of Hb S in erythrocytes. Several pharmacologic agents such as 5-azacytidine, myleran, hydroxyurea, erthropoietin, and butyrates enhance fetal hemoglobin production and have been used in hemoglobinopathy patients to ameliorate severe pain episodes and reduce severe anemia. Among these, hydroxyurea is the agent of choice because of its safety and ease of administration. One of the primary cellular mechanisms involved in pharmacologic induction of Hb F synthesis is rapid regeneration of erythroid precursors following the cytoreduction phase of certain pharmacologic agents. Molecular mechanisms involving changes in chromatin structure and/or transcription factor binding have been demonstrated for gamma gene induction by butyrate. Identifying the proteins involved in gamma gene activation by various compounds may offer a new strategy for gene therapy to cure hemoglobinopathy disorders.
Pediatr Pathol Mol Med
PMID:Pharmacologic induction of fetal hemoglobin synthesis: cellular and molecular mechanisms. 1267 46

The hemoglobin disorders of beta-thalassemia and sickle cell disease together constitute the most prevalent of human monogenic diseases. Although palliative therapies and curative allogeneic stem cell transplantation therapy have been developed for these disorders, many patients still suffer significant morbidity and early mortality. Therefore, development of alternative treatment based on a gene therapy approach continues to be a worthwhile endeavor. Several laboratories have recently achieved major progress towards this goal. Using lentiviral vectors to obtain high-level expression of relatively complex globin gene cassettes, therapeutic correction of several murine models of both beta-thalassemia and sickle cell disease has been achieved. These breakthroughs, coupled with recent significant developments in the ability to select and expand genetically modified stem cells in vivo, have greatly advanced the possibility of gene therapy for the hemoglobin disorders in the near future. These advances, together with recent information regarding safety issues of retroviral gene transfer, are reviewed here.
Curr Opin Mol Ther 2003 Oct
PMID:Update on gene therapy for hemoglobin disorders. 1460 20

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
Blood Cells Mol Dis
PMID:Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. 1463 44

Reactivation of fetal hemoglobin (HbF) expression using pharmacological agents represents a potential strategy for the therapy of beta-thalassemia, sickle cell disease, HbE and other beta-hemoglobinopathies. However, the drugs currently available have low efficacy and specificity and are associated with high toxicity. We describe the development of stable cellular genomic reporter assays (GRAs) based on the green fluorescence protein (EGFP) gene under the Ggamma-globin promoter in the intact human beta-globin locus. We show that human erythroleukemic cell lines stably transfected with a Ggamma-EGFP beta-globin locus construct can maintain a uniform basal level of EGFP expression over long periods of continuous culture and that induction of EGFP expression parallels the induction of the endogenous globin genes. We compared the EGFP-induction potency of a number of chemotherapeutic agents, including histone deacetylase inhibitors and DNA-binding agents. We show that hydroxyurea and butyrate result in moderate levels of induction (70-80%) but with an additive inductive effect. Among the DNA-binding agents tested, cisplatin was the most potent inducer of HbF expression, (442+/-32%), a level which is comparable to hemin (764+/-145%). These results indicate that cellular GRAs containing Ggamma-EGFP-modified beta-globin locus constructs can be used to develop novel inducers of HbF synthesis for the therapy of beta-hemoglobinopathies.
Hum Mol Genet 2004 Jan 15
PMID:Cellular genomic reporter assays for screening and evaluation of inducers of fetal hemoglobin. 1464 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>