Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta-thalassemia (beta-thal) is present in 59% and 75% of patients with abnormal hemoglobin disorders in northwestern and central Mexico, respectively. In our Research Center, up until 1997, we reported the presence of 13 beta-thal alleles in 26 unrelated chromosomes (-28A>C; -87C>T; MET1VAL; IVS1, G>A, +1; IVS1, G>A, +5; IVS1, G>C, +5; IVS1, G>A, +110; IVS2, C>G, +745; GLU6FS; VAL11FS; GLN39TER; HBD/HBB 104 kb del; and HBD87/HBB116 fusion). Since then, 57 more beta-thal chromosomes have been identified by the amplification-refractory mutation system (ARMS) and DNA sequencing from 54 individuals with beta-thalassemia (seven compound heterozygotes, three with two beta-thal alleles, three with beta-thal and HbS, and one with beta-thal and HbD; and 47 beta-thal heterozygotes). Nine of the previously observed alleles were found, together with three new alleles: IVS2, G>A, +1; LYS17TER; and 4-bp del, 41/42CTTT. Moreover, a novel mutation was observed, HIS77FS, bringing to a total of 17 beta-thal alleles identified in our population. Six alleles constitute 78.3% of the observed alleles: five Mediterranean alleles (GLN39TER; IVS1, G>A, +1; IVS1, G>A, +110; HBD/HBB 104 kb del; and IVS1, G>A, +5) and one common in the Kurdish population (-28A>C). We note especially the presence in these families of -28A>C and VAL11FS, both of which have previously been considered private alleles. The observed spectrum of mutations is characteristic of populations with low frequencies of thalassemias. Because thalassemia is not a rare disease in Mexico, we emphasize its necessary consideration in the differential diagnosis of microcytic hypochromic anemia.
Blood Cells Mol Dis
PMID:Molecular spectrum of beta-thalassemia in the Mexican population. 1531 94

Cell-based therapies have potential widespread applications in clinical medicine, and methods for controlling the fate of transplanted cells are needed. We have previously described a means for directing the growth of genetically modified cells in vivo using a derivative of the thrombopoietin receptor, mpl, that is reversibly activated by a drug called a chemical inducer of dimerization (CID). Since Jak2 participates in signaling from a number of different cytokine receptors (including mpl), we tested whether direct activation of the JH1 domain of Jak2 would broaden the repertoire of hematopoietic lineages responsive to the CID. While the engineered Jak2 induced a significant rise in genetically modified red cells, as we have observed previously with mpl, it lacked mpl's ability to expand genetically modified platelets and failed to expand genetically modified granulocytes, B cells, or T cells. These findings identify a signaling molecule other than mpl that can function as a cell growth switch in vivo and demonstrate that signaling molecules used for in vivo selection need not be confined to receptors. The erythroid-restricted growth response suggests that CID-activated Jak2 may be well suited to gene therapy applications in sickle cell anemia or beta-thalassemia.
Mol Ther 2004 Sep
PMID:In vivo selection of genetically modified erythroid cells using a jak2-based cell growth switch. 1533 46

The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations.
Hum Mol Genet 2004 Oct 01
PMID:Thalassemia in Sri Lanka: a progress report. 1535 26

Hemoglobin E (HbE, beta26 Glu-->Lys) is the most common abnormal Hb variant in the world, and found in greatest frequency in Southeast (SE) Asia. In the United States, HbE is the third most prevalent variant (after HbS and HbC); and its now increasing frequency is due to immigration from SE Asia. HbE homozygotes present a benign clinical picture, but when HbE is coupled with beta0-thalassemia or HbS, variably severe hemoglobinopathies arise. To date, there are no transgenic animal models of HbE-related diseases. We report here the creation of transgenic mice expressing human HbE as a step toward creating animal models for HbE-related diseases. The betaE mice exhibit red blood cell hypochromia and target cells consistent with those observed in human patients exhibiting HbE trait. Furthermore, the transgenic HbE hemolysates contain increased amounts of Hb oxidation products.
Blood Cells Mol Dis
PMID:Generation of transgenic mice expressing human hemoglobin E. 1552 49

Analytical procedures have been developed for the detection and diagnosis of sickle cell disease in newborn babies by analyzing the hemoglobin extracted from dried blood spots on Guthrie cards using electrospray ionization mass spectrometry (ESI-MS). An essential requirement is the ability to reliably differentiate two globin chains whose molecular weights differ by only 1 Da such as adult hemoglobin (Hb A) and Hb C. This has been achieved by improving the accuracy and precision of the molecular weight determination to a fraction of a dalton. We report the potential of mass spectrometry for screening neonates for these debilitating diseases by presenting results from 147 blood spots that had been characterized by phenotypic methods and which include samples from 20 sickle cell disease, 1 beta-thalassemia major, 57 sickle cell trait, and 39 normal babies. In all cases, the mass spectrometric results agreed with the results obtained using conventional analytical practice with high-performance liquid chromatography (HPLC) and isoelectric focusing (IEF). We show that mass spectrometry is a viable technique for the diagnosis of newborns with sickle cell disease or homozygous beta0-thalassemia.
Blood Cells Mol Dis
PMID:The potential of electrospray ionization mass spectrometry for the diagnosis of hemoglobin variants found in newborn screening. 1552 50

Thalassemia is a disease caused by a variety of mutations affecting both the adult and embryonic alpha- and beta-globin loci. A mouse strain carrying an embryonic zeta-globin gene disrupted by the insertion of a PGK-Neo cassette displays an alpha-thalassemia-like syndrome. Embryonic survival of this zeta-null mouse is variable and strongly influenced by genetic background, the 129/SvEv mouse strain displaying a more severe phenotype than C57BL/6. We have identified two modifying loci on C57BL/6 chromosomes 2 and 5, which affect the penetrance of embryonic lethality in the 129/SvEv mouse. Through this work, we were able to observe an interesting effect on somatic recombination events in thalassemic embryos. We show that these events can occur on multiple chromosomes in very early embryonic cells, prior to their allocation to the germline. Our results demonstrate that somatic recombination events can be transmitted to subsequent generations.
Hum Mol Genet 2005 Mar 01
PMID:zeta-/- Thalassemic mice are affected by two modifying loci and display unanticipated somatic recombination leading to inherited variation. 1564 44

Hemoglobin (Hb) C (alpha2beta(2)6Glu-Lys) is a variant Hb found mainly in West Africa where individuals carrying both Hb C and Hb S (alpha2beta(2)6Glu-Val) usually have a disease similar to sickle cell disease. The Hb C molecule has reduced solubility leading to crystal formation and hemolytic anemia. We report a hitherto undescribed interaction of Hb C and Hb Malay (alpha2beta(2)19Asn-Ser) in a Thai individual. She was a 24-year-old pregnant woman with moderate anemia who had the following hematologic data; Hb 8.9 g/dl, Hct 30.0%, MCV 81.0 fl, MCH 24.1 pg, MCHC 29.7 g/dl, RDW 17.1% and instead of Hb crystal a marked number of target cell in peripheral blood was observed. Hb analysis revealed 22.5% Hb Malay, 64.6% Hb C and 4.5% Hb A2. Globin gene analyses demonstrated that she carried the betaC mutation (beta6: GAG-AAG) in trans to the betaMalay mutation (beta19: AAC-AGC). Hematologic data of the patient were compared to those of the compound heterozygote for Hb C and Hb E (alpha2beta(2)26Glu-Lys) found in 5 other unrelated Thai pregnant women and 11 pregnant women with Hb C heterozygote with or without co-inheritance of alpha-thalassemia who had much lower Hb C levels and the non-pregnant women with Hb C heterozygote and a compound Hb E/Hb Malay syndrome. Different genotype-phenotype correlations observed in these Thai patients with Hb C disorders are illustrated.
Blood Cells Mol Dis
PMID:Compound heterozygote states for Hb C/Hb Malay and Hb C/Hb E in pregnancy: a molecular and hematological analysis. 1598 9

Accelerated apoptosis of erythroid progenitors is a characteristic of beta-thalassemia which presents a significant barrier to definitive therapeutic approaches utilizing induction of endogenous fetal globin gene expression. gamma-globin gene expression may not be inducible in, or may not be able to rescue, erythroid cells in which programmed cell death is initiated early in erythroblast development. In this report, short-chain fatty acid derivatives (SCFADs) which induce fetal globin gene expression were tested for their ability to promote proliferation and survival of erythroid progenitors cultured from beta-thalassemic subjects, and of cytokine-dependent erythroid cell lines. Certain SCFADs promoted thalassemic Bfu-e growth and cytokine-independent growth and survival of erythroid cell lines. A 40-80% increase in erythroid Bfu-e colony number was observed in cultures established with any of five mitogenic SCFADs, compared to control or butyrate-treated cultures from the same subjects. Immunoblot analysis demonstrated that these same SCFADs also regulated the expression of specific protein inhibitors of apoptosis. Anti-apoptotic ratios of the proteins Bcl-xL/Bcl-xS in thalassemic Bfu-e were increased by 30-120% with exposure to the SCFDs, compared to the ratios in the same cells cultured under control conditions. Similar anti-apoptotic increases in Mcl-1L/Mcl-1S ratios were induced by the SCFADs. These findings suggest that select fetal globin-inducing SCFADs which enhance proliferation of beta-thalassemia progenitors may enhance survival of these progenitors by altering levels of Bcl-family protein members. This combination of effects should enhance erythroid cell survival in the beta-thalassemia syndromes, allowing fetal globin gene expression to be induced more effectively than currently available, growth-suppressing, fetal globin-inducing agents, such as the butyrates or chemotherapeutic agents.
Blood Cells Mol Dis
PMID:Enhancement of growth and survival and alterations in Bcl-family proteins in beta-thalassemic erythroid progenitors by novel short-chain fatty acid derivatives. 1609 82

Infrared (IR) spectroscopy has made important contributions to the arena of hematology in the past decade. The normal physiology and pathologic modifications of the three cellular elements in blood, i.e., leukocytes, erythrocytes and platelets, have been thoroughly investigated by this recently emerged optical tool. By revealing subtle alterations in the structures of macromolecules in these blood cells, IR spectroscopy has become an ideal complementary analytical tool to conventional biochemical assays used to diagnose various common hematological disorders. Such traditional assays include molecular structure measurements that determine erythrocyte membrane fluidity and conformational changes, lipid profiling of platelet membranes, as well as assays of leukocyte proliferation and differentiation. IR spectroscopic-based techniques can be used to analyze DNA alterations, secondary structural changes in proteins, and to profile cellular lipids. From a molecular and biomedical perspective, IR spectroscopy has been explored for the diagnosis and prognosis of leukemia and beta-thalassemia, to predict drug sensitivity and resistance in chemotherapy patients, and more recently to examine apoptotic processes in blood cells. These studies have shown great promise in the early identification of drug-resistant patients and the early diagnosis of hematological disorders, especially malignancies. Furthermore, IR spectroscopic-based investigations will enable specific mechanisms underlying hematological disorders to be elucidated by revealing the molecular changes in the blood cells at a very early pathogenesis stage.
Blood Cells Mol Dis
PMID:Molecular and chemical characterization of blood cells by infrared spectroscopy: a new optical tool in hematology. 1612 19

Plasma CCL18/PARC, a member of the CC chemokine family, has been found to be several ten-fold increased in symptomatic Gaucher type I patients. Elevated plasma chitotriosidase levels are a well-known abnormality in Gaucher patients, however, its diagnostic use is limited by the frequent genetic deficiency in the protein. Like the situation in Gaucher disease, lipids accumulate in macrophages of patients suffering from beta-thalassemia, and, in both conditions, increased chitotriosidase levels occur. We here report that plasma CCL18/PARC is also significantly increased in patients with beta-thalassemia major (range 76.8-4977.8, median=650.8 ng/ml, n=36 and control range 10-72, median=33 ng/ml n=36 respectively, P<0.001). The CCL18/PARC levels are lower than in Gaucher patients (range 174.8-10798.7, median 2538.2 ng/ml, n=28, P<0.001). In our cohort of beta-thalassemic patients, CCL18/PARC showed a significant negative correlation to iron chelation therapy and a significant positive correlation to ferritin and chitotriosidase levels, the latter only in the patients with the wild type genotype for the enzyme. Our study demonstrates that beta-thalassemic patients have increased CCL18/PARC levels that could be of value in monitoring iron overload and compliance to therapy.
Blood Cells Mol Dis
PMID:Elevated plasma chemokine CCL18/PARC in beta-thalassemia. 1613


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