Home About us Contact
|
Home About us Contact | ||
|
|
||
Globin Chains (globin + chain)
Selected Abstracts,-Globin gene cluster haplotypes and HbF levels are not the only modulators of sickle cell disease in LebanonEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2003A. Inati Abstract: Sickle cell disease (SCD) is an inherited autosomal recessive disorder of the , -globin chain. Despite the fact that all subjects with SCD have the same single base pair mutation, the severity of the clinical and hematological manifestations is extremely variable. This study examined for the first time in Lebanon the correlation between the clinical manifestation of SCD and the , -globin gene haplotypes. The haplotypes of 50 patients diagnosed with SCD were determined using polymerase chain reaction amplification of fragments containing nine polymorphic restriction sites around and within the ,,G,,A,,,,,,,, -globin gene complex. Most reported haplotypes were found in our population with the Benin haplotype as the most prevalent one. When the patients were divided according to their HbF levels into three groups (Group A: HbF < 5%, Group B: HbF between 5 and 15%, and Group C: HbF > 15%), surprisingly, the highest levels of HbF were associated with the most severe clinical cases. Our findings suggest that fetal hemoglobin levels are important but not the only parameters that affect the severity of the disease. In addition, the high levels of HbF in patients with CAR haplotypes did not seem to ameliorate the severity of symptoms, suggesting that genetic factors other than haplotypes are the major determinants of increased HbF levels in Lebanon. [source] A novel beta-delta globin gene fusion, anti-Lepore Hong Kong, leads to overexpression of delta globin chain and a mild thalassaemia intermedia phenotype when co-inherited with ,0 -thalassaemiaBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2007Chi-Chiu So Summary Anti-Lepore haemoglobins (Hb) are rare ,, fusion variants that arise from non-homologous crossover during meiosis, resulting in a ,,,,,, configuration. A novel anti-Lepore mutation (anti-Lepore Hong Kong) was found in two Chinese families with raised Hb A2. Direct sequencing revealed a crossover within a 54-bp region spanning the junction of cap site (CAP) and exon 1, which predicted the production of normal , -globin. Determination of ,/, -mRNA ratios by quantitative real-time polymerase chain reaction demonstrated downregulation of the , gene in cis due to the interposed ,, fusion gene. Although heterozygotes have normal red cell indices and are clinically silent, compound heterozygotes with ,0 mutation in trans produce a mild thalassaemia intermedia phenotype with a markedly raised Hb A2 level that may mimic clinically mild Hb E- ,+ -thalassaemia. Awareness of the presence of anti-Lepore Hong Kong will help to resolve diagnostic problems in regions with significant prevalence of globin disorders. [source] An interplay of alleviating mutations in the clinical phenotype of ,-thalassaemia intermediaINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 6 2004A. NADKARNI Summary Prediction of a , -thalassaemia major phenotype from the , -genotype is generally relatively straightforward. However, despite the ability to accurately define the , -thalassaemia mutations, prediction of a , -thalassaemia intermedia phenotype from the genotype sometimes remains problematic and this has important implications in genetic counselling and prenatal diagnosis. We report a 11-year-old Indian male child with a thalassaemia intermedia phenotype. , -Globin gene analysis of the family showed that he was a compound heterozygote with the ,88 (C,T) ,+ -mutation and the IVS1 nt 130 (G,C) ,0 -mutation. Both these mutations are rare among Indians. The propositus was also found to be heterozygous for the XmnI polymorphism and had a normal , -genotype. In this family interplay of two alleviating mutations (a milder promoter mutation along with a gene for raised HbF) might have synergistically compensated for lack of globin chains in the patient. Hence, the nature of the , -genotype as well as the knowledge of the presence or absence of alleviating factors will help the clinician to decide whether early commencement of a regular transfusion regime is necessary. [source] Disorders of the synthesis of human fetal hemoglobinIUBMB LIFE, Issue 2 2008Laura Manca Abstract Fetal hemoglobin (HbF), the predominant hemoglobin in the fetus, is a mixture of two molecular species (,2G,2 and ,2A,2) that differ only at position 136 reflecting the products of two nonallelic ,-globin genes. At the time of birth, HbF accounts for ,70% of the total Hb. The G,:A, globin ratio in the HbF of normal newborn is 70:30 whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a ,- to ,-globin gene switch. Alterations of these ratios are indicative of a molecular defect at the level of the HbF synthesis. Qualitative hemoglobinopathies due to G, and A, chain structural variants, and quantitative hemoglobinopathies affecting the synthesis of HbF such as ,-thalassemias, duplications, triplications, and even sextuplications of the ,-globin genes, which may be detected in newborn blood lysates, have been described. Moreover, several pathological and nonpathological conditions affecting the ,-globin gene cluster, such as ,-thalassemia, sickle cell disease, ,,-thalassemia, and hereditary persistence of HbF syndromes, are characterized by the continued synthesis of ,-globin chains in the adult life. Studies of these natural mutants associated with increased synthesis of HbF in adult life have provided considerable insight into the understanding of the control of globin gene expression and Hb switching. © 2008 IUBMB IUBMB Life, 60(2): 94,111, 2008 [source] Hemoglobin Kenya composed of ,- and (A,,)-fusion-globin chains, associated with hereditary persistence of fetal hemoglobinAMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009Ibifiri Wilcox Hb Kenya is made up of two normal ,-globin chains and two A,,-fusion globin chains. The latter are the product of an A,,-hybrid globin gene formed as a result of misalignment during meiosis and nonhomologous crossing over. It is associated with a deletion of 22.7 kb including the ,-globin gene, between the A,- and ,-globin genes. Hb Kenya is found in Kenyans and Ugandans. Heterozygotes have moderately increased Hb F, and this mutation has been known as an (A,,)+ hereditary persistence of fetal hemoglobin (HPFH). Compound heterozygotes for Hb Kenya/Hb S are thought to be asymptomatic, but reports of long term follow-up of these patients are lacking. The correct identification of Hb Kenya is sometimes problematic. In cation exchange high performance liquid chromatography, Hb Kenya elutes in similar position as Hb A2, Hb Lepore, Hb E, and several other variant hemoglobins. Definitive diagnosis that is necessary for proper patient management is best done by DNA-based gap-PCR tests. Am. J. Hematol, 2009. © 2008 Wiley-Liss, Inc. [source] Non-Hodgkin disease in ,-thalassemia majorAMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2006Zaher K. Otrock Abstract Thalassemia is a spectrum of diseases characterized by the decrease or absence of globin chains. The occurrence of lymphoma in thalassemia has rarely been reported, and our review of the English literature revealed only four cases. Because anemia is always masked by regular transfusions in thalassemic patients, physicians discover a hidden malignancy late in the course of the disease. We hereby report the case of a thalassemic patient developing non-Hodgkin disease and discuss the possibility of a link between the two disease entities. This case is intended to alert physicians of the possibility of a malignancy in thalassemia patients. Am. J. Hematol. 81:62,64, 2006. © 2005 Wiley-Liss, Inc. [source] Embryonic and fetal globins are expressed in adult erythroid progenitor cells and in erythroid cell culturesPRENATAL DIAGNOSIS, Issue 7 2001Elizabeth T. Lau Abstract The understanding of human hemoglobin ontogeny during development is of biological and clinical importance. Molecular and immunocytological techniques were used to study the expression of embryonic zeta (,), epsilon (,), and fetal gamma (,) globin genes in newborn cord blood, peripheral blood from men, pregnant and non-pregnant women, and in vitro mononuclear cell cultures. We have shown that embryonic and fetal globin mRNA and peptides are expressed in cultured erythroid cells and in circulating blood cells from newborns, adult non-pregnant women and from men. The findings suggest that during erythroid cell differentiation in newborns and adults, there is a transient recapitulation of sequential globin chain expression as found during embryonic and fetal development. Furthermore, these findings underscore the need for caution in using embryonic and fetal globin chains as markers to identify erythroid cells of fetal origin in maternal circulation for prenatal diagnosis. Copyright © 2001 John Wiley & Sons, Ltd. [source] Effect of coenzyme Q10 as an antioxidant in ,-thalassemia/Hb E patientsBIOFACTORS, Issue 1-4 2005Ruchaneekorn W. Kalpravidh Abstract Thalassemia is a group of genetic disorders resulting from different mutations in the globin gene complex and leading to an imbalance in globin synthesis. Unmatched globin chains are less stable and susceptible to oxidation. Patients with ,-thalassemia/HbE are prone to increased oxidative stress as indicated by increased lipid peroxidation product, malondialdehyde (MDA), partly because of the presence of iron in the form of heme and hemichromes released from excess globin chains and excess iron deposition in various tissues. The level of antioxidant such as glutathione is markedly decreased while activities of antioxidant enzymes including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) are increased. We have recently found that the levels of coenzyme Q10 (CoQ10) are also very low in thalassemia. We therefore evaluated the oxidative stress and the antioxidants in these patients before and after supplementation with 100 mg CoQ10 daily for 6 months. The results showed that the plasma level of CoQ10 significantly increased and the oxidative stress decreased as the level of MDA declined. The administration of CoQ10 led to significant improvement of biochemical parameters of antioxidant enzymes. The antioxidant supplementation will be beneficial for thalassemia patients as adjunct therapy to increase their quality of life. [source] Phenylhydrazine as a partial model for ,-thalassaemia red blood cell hemodynamic propertiesBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2008Yuval Ramot Summary ,-Thalassaemia is a congenital haemoglobinopathy, associated with red blood cells (RBC) anomalies, leading to impairment of their flow-affecting properties, namely, RBC deformability, self-aggregability, and adherence to endothelial cells (EC). Treatment of normal RBC with phenylhydrazine (PHZ) causes selective association of oxidized ,-globin chains with the membrane skeleton, leading to reduced RBC deformability, characteristic of ,-thalassaemia. PHZ has thus been used to mimic phenotypes of ,-thalassaemia RBC. The present study was undertaken to further elucidate the suitability of PHZ-treated RBC as a model for ,-thalassemic RBC, by comparing the aggregability and adhesiveness of PHZ-treated RBC to those of RBC from thalassaemia intermedia (TI) patients, using image analysis of RBC under flow. In addition, the externalization of phosphatidylserine (PS), a mediator of RBC/EC interaction, was determined. It was found that PHZ caused enhanced RBC adhesiveness to extracellular matrix, similar to TI-RBC. Furthermore, in both conditions, the enhanced adhesiveness was mediated by PS translocated to the RBC surface. In contrast, PHZ treatment completely abolished RBC aggregability, while TI-RBC aggregability was slightly elevated. It is proposed that PHZ-treated RBC resemble ,-thalassaemia RBC in their deformability and adhesiveness, but not in their aggregability, and thus can be used as a limited model for ,-thalassaemia RBC phenotypes. [source] Genomic organisation and regulation of murine alpha haemoglobin stabilising protein by erythroid Kruppel-like factorBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2007Janelle R. Keys Summary Alpha haemoglobin stabilising protein (AHSP) binds free , -globin chains and plays an important role in the protection of red cells, particularly during , -thalassaemia. Murine ASHP was discovered as a GATA-1 target gene and human AHSP is directly regulated by GATA-1. More recently, AHSP was rediscovered as a highly erythroid Kruppel-like factor (EKLF) -dependent transcript. We have determined the organisation of the murine AHSP gene and compared it to orthologs. There are two CACC box elements in the proximal promoter. The proximal element is absolutely conserved, but does not bind EKLF as it is not a canonical binding site. In rodents, the distal element contains a 3 bp insertion that disrupts the typical EKLF binding consensus region. Nevertheless, EKLF binds this atypical site by gel mobility shift assay, specifically occupies the AHSP promoter in vivo in a chromatin immunoprecipitation assay, and transactivates AHSP through this CACC site in promoter,reporter assays. Our results suggest EKLF can occupy CACC elements in vivo that are not predictable from the consensus binding site inferred from structural studies. We also propose that absence of AHSP in EKLF-null red cells exacerbates the toxicity of free , -globin chains, which exist because of the defect in , -globin gene activation. [source] | |||||||||||||