Association of   globin gene quadruplication and heterozygous   thalassemia in patients with thalassemia intermedia

Sollaino, Maria Carla; Paglietti, Maria Elisabetta; Perseu, Lucia; Giagu, Nicolina; Loi, Daniela; Galanello, Renzo

doi:10.3324/haematol.2009.005728

Cited by 52 publications

(40 citation statements)

References 24 publications

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“…Contrary to the beneficial effect demonstrated by coinheritance of a-and b-thalassemia, inheritance of excess a-globin genes worsens the a-like/b-like globin chain imbalance and results in a more severe clinical phenotype. [67][68][69] This observation further emphasizes that the number of functional a-globin genes has a clear direct effect on the clinical severity of patients with b-thalassemia. …”

Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 76%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

118

120

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The thalassemias, together with sickle cell anemia and its variants, are the world’s most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

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Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 76%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

118

120

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“…Finally, a critical problem in b-thalassemia carrier screening is the identification of silent bthalassemia or the triple-quadruple a-gene arrangement, which by interacting with typical b-thalassemia may result in the clinical features of mild or severe b-thalassemia (thalassemia intermedia or major) Thein et al 1984;Kulozik et al 1987;Ristaldi et al 1990;Harteveld et al 2008;Sollaino et al 2009;Faa et al 2010). Silent b-thalassemia (normal HbA 2 b-thalassemia type 1) shows normal hematological features and HbA 2 level and may be identified solely by globin chain synthesis analysis or b-globin gene analysis (Kattamis et al 1979;Gonzalez-Redondo et al 1989;Galanello et al 1994).…”

Section: Carrier Detectionmentioning

confidence: 99%

The Prevention of Thalassemia

Cao

Kan

2013

Cold Spring Harbor Perspectives in Medicine

193

157

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The thalassemias are among the most common inherited diseases worldwide, affecting individuals originating from the Mediterranean area, Middle East, Transcaucasia, Central Asia, Indian subcontinent, and Southeast Asia. As the diseases require long-term care, prevention of the homozygous state constitutes a major armament in the management. This article discusses the major prevention programs that are set up in many countries in Europe, Asia, and Australia, often drawing from the experience in Sardinia. These comprehensive programs involve carrier detections, molecular diagnostics, genetic counseling, and prenatal diagnosis. Variability of clinical severity can be attributable to interactions with a-thalassemia and mutations that increase fetal productions. Special methods taht are currently quite expensive and not widely applicable are preimplantation and preconception diagnosis. The recent successful studies of fetal DNA in maternal plasma may allow future prenatal diagnosis that is noninvasive for the fetus.

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“…TI may result from defective production of b-globin chains due to b-globin gene defects, or from the increased production of α-globin chains, resulting from a triplicate or quadruplicate α-genotype associated with b-thalassemia heterozygosity, the latter situation leading to a milder form of TI. [2][3][4][5] The excess free α-chains have been demonstrated to precipitate within the erythroid precursors as hemichromes (HMC), forming large inclusion bodies. 6 In turn HMC alter the membrane clustering band 3 and enhance the deposition of opsonin autologous immunogobulins and C3 fragments.…”

Section: Introductionmentioning

confidence: 99%

Thalassemic erythrocytes release microparticles loaded with hemichromes by redox activation of p72Syk kinase

Ferru

Pantaleo

Carta³

et al. 2013

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o ndifferent genetic and clinical status provided new insights into the pathogenic role of circulating MP and possible interventions to control their amount in thalassemia. MethodsUnless otherwise stated, all materials were obtained from Sigma-Aldrich, St. Louis, MO, USA. Additional information about the methods are provided in the Online Supplementary Data. Treatment of red blood cellsVenous blood was drawn from 12 healthy individuals, eight non-splenectomized TI patients and six splenectomized TI patients. All subjects provided written, informed consent before entering the study. The study was approved by the local Ethics Committee and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.Clinical analyses were performed by routine laboratory tests at the Policlinico Hospital (Milan, Italy). Blood anti-coagulated with heparin was stored in citrate-phosphate-dextrose with adenine (CPDA-1) prior to its use. RBC were washed three times with phosphate-buffered saline (PBS: 137mM NaCl, 2.7mM KCl, 8.1mM K 2 HPO 4 , 1.5mM KH 2 PO 4 , pH 7.4) containing glucose 5 mM to obtain packed RBC.To stimulate HMC formation, RBC from healthy donors were suspended at a hematocrit of 30% and incubated with different concentrations (0, 0.25, 0.5, 1, 1.5, 2 mM) of phenylhydrazine at 37 °C for 4 h. To test the antioxidant effect in MP release we incubated 200 μM of 2-mercaptoethanol in the presence of 1 mM phenylhydrazine. When necessary, RBC were pretreated with Syk kinase inhibitors (10 μM Syk inhibitors II and 10 μM Syk inhibitors IV, Calbiochem, Darmstadt, Germany), for 1 h at 37 °C in the dark. Each reaction was terminated by three washes with PBS-glucose. For all protocols described, untreated controls were processed identically except that the stimulant/inducer was omitted from the incubation. Red blood cell membrane preparationStandard hypotonic membranes were prepared, as previously described, 20 and stored frozen at -80°C until use. Membrane protein content was quantified using the DC Protein assay (Biorad, Hercules, CA, USA). Analysis of microparticlesThe MP in plasma were analyzed by flow cytometry using a modification of a previously described method:22 25 μL of plasma diluted 1:1 with PBS-glucose 5mM were analyzed using anti-CD41 (BD, Franklin Lakes, NJ, USA) and anti-glycophorin-A (Dako, Denmark), both diluted 1:10. Assay of hemichromesHMC were quantified by measuring heme absorbance (Abs) using the following equation:HMC= -133xAbs577 -114xAbs630 + 233xAbs560, and expressed as nMoles/mL of solubilized membranes. 23 Microparticle isolationTo induce MP release in vitro, RBC from each volunteer and phenylhydrazine-treated RBC in PBS (30% hematocrit) were incubated as previously described. 24 Electrophoresis and immunoblottingMembrane and MP proteins were solubilized in Laemmli buffer 25 under reducing [2% (w/v) dithiothreitol] or non-reducing conditions at a volume ratio of 1:1. Sodium dodecylsulfate polyacrylamide gel electropho...

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Association of globin gene quadruplication and heterozygous thalassemia in patients with thalassemia intermedia

Cited by 52 publications

References 24 publications

α-Globin as a molecular target in the treatment of β-thalassemia

α-Globin as a molecular target in the treatment of β-thalassemia

The Prevention of Thalassemia

Thalassemic erythrocytes release microparticles loaded with hemichromes by redox activation of p72Syk kinase

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