Coinheritance of the different copy numbers of α-globin gene modifies severity of β-thalassemia/Hb E disease

Sripichai, Orapan; Munkongdee, Thongperm; Kumkhaek, Chutima; Svasti, Saovaros; Winichagoon, Pranee; Fucharoen, Suthat

doi:10.1007/s00277-007-0407-2

Cited by 49 publications

(39 citation statements)

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“…For example, co-inheritance of α-thalassemia in β-thlassemia/Hb E is associated with milder clinical symptom whereas co-inheritance of triplicated α-globin gene leads to more severe anemia. [25][26][27] Similarly, coinheritance of α-thalassemia in β-thalassemic mice was also found to ameliorate the thalassemic phenotype, as the reduction of α-globin expression yielded more balanced globin chains. 28 Moreover, the reduction of α-globin expression by short-interfering RNA (siRNA) in murine thalassemic primary erythroid cultures was able to restore α:β-globin mRNA ratios to the balanced wild type levels resulting in the detectable phenotypic correction, 29 indicating a potential therapeutic application in the treatment of β-thalassemia.…”

Section: Discussionmentioning

confidence: 96%

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

Srinoun¹,

Svasti²,

Chumworathayee³

et al. 2009

Haematologica

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Background β-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate β-globin chain production. The excessive unbound α-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis. Design and MethodsIn vitro globin chain synthesis in reticulocytes from different types of thalassemic mice was performed. The effect of imbalanced globin chain synthesis was assessed from changes of red blood cell properties including increased numbers of red blood cells vesicles and apoptotic red blood cells, increased reactive oxygen species and decreased red blood cell survival. ResultsThe α/β-globin chain ratio in β -thalassemic mice, 1.26±0.03, was significantly higher than that of wild type mice, 0.96±0.05. The thalassemic mice show abnormal hematologic data and defective red blood cell properties. These values were improved significantly in doubly heterozygous thalassemic mice harboring 4 copies of human β E -globin transgene, with a more balanced globin chain synthesis, 0.92±0.05. Moreover, transgenic mice harboring 8 extra copies of the human β E -globin transgene showed inversely imbalanced α/β-globin synthesis ratio, 0.83±0.01, that resulted in a mild β-thalassemia phenotype due to the excessive β-globin chains. The degree of ineffective erythropoiesis also correlated with the degree of imbalanced globin chain synthesis. Bone marrow and splenic erythroid precursor cells of β -thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice. ConclusionsImbalanced α/β-globin chain as a consequence of either reduction or enhancement of β-globin chain synthesis can cause abnormal red blood cell properties in mouse models.Key words: thalassemia, transgenic mice, ineffective erythropoiesis, globin chain synthesis. mice. Haematologica 2009;94:1211-1219. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Srinoun K, Svasti S, Chumworathayee W, Vadolas J, Vattanaviboon P, Fucharoen S, and Winichagoon P. Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

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Section: Discussionmentioning

confidence: 96%

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

Srinoun¹,

Svasti²,

Chumworathayee³

et al. 2009

Haematologica

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“…In largescale prospective studies, all patients with coinherited a-thalassemia displayed a milder phenotype, older age at presentation, smaller splenic and hepatic sizes, normal physical and sexual maturation, and significantly reduced transfusion requirements. 59,[62][63][64][65][66] Furthermore, in HbE b-thalassemia patient cohorts, the frequency of a-thalassemia is significantly lower than in the normal matched population, and it is extremely rare to find patients with 2 a-globin gene deletions (2/aa or 2a/2a). 64,66 These observations suggest that individuals with HbE b-thalassemia who coinherit only 2, rather than the normal 4, a-globin genes have a very mild phenotype and are rarely brought to medical attention.…”

Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 99%

“…59,[62][63][64][65][66] Furthermore, in HbE b-thalassemia patient cohorts, the frequency of a-thalassemia is significantly lower than in the normal matched population, and it is extremely rare to find patients with 2 a-globin gene deletions (2/aa or 2a/2a). 64,66 These observations suggest that individuals with HbE b-thalassemia who coinherit only 2, rather than the normal 4, a-globin genes have a very mild phenotype and are rarely brought to medical attention. 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.…”

Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 99%

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

Mettananda

Gibbons

Higgs

2015

Blood

122

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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“…Genetic factors involved in an improvement of imbalanced globin chain synthesis, i.e., b ? -thalassemia mutations, athalassemia interactions and modifiers to fetal hemoglobin levels are the strongest factors determining the disease severity (Quek and Thein 2007;Sripichai et al 2008b;Winichagoon et al 2000). In addition, multiple modifying factors in several pathways involved in the pathophysiology of the disease have been identified (Thein 2005).…”

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confidence: 99%

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

et al. 2009

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b-Thalassemia/HbE disease is clinically variable. In searching for genetic factors modifying the disease severity, patients were selected based on their disease severities, and a genome-wide association study (GWAS) was performed. Genotyping was conducted with the Illumina Human 610-Quad BeadChips array using DNAs from 618 Thai b0-thalassemia/HbE patients who were classified as 383 severe and 235 mild phenotypes by a validated scoring system. Twenty-three SNPs in three independent genes/regions were identified as being significantly associated with the disease severity. The highest association was observed with SNPs in the b-globin gene cluster (chr.11p15), and rs2071348 of the HBBP1 gene revealed the most significant association [P = 2.96 9 10(-13), odds ratio (OR) = 4.33 (95% confidence interval (CI), 2.74-6.84)]. The second was identified in the intergenic region between the HBS1L and MYB genes (chr.6q23), among which rs9376092 was the most significant [P = 2.36 9 10(-10), OR = 3.07 (95% CI, 2.16-4.38)]. The third region was located in the BCL11A gene (chr.2p16.1), and rs766432 showed the most significant association [P = 5.87 9 10-10, OR = 3.06 (95% CI, 2.15-4.37)]. All three loci were replicated in an independent cohort of 174 Indonesian patients. The associations to fetal hemoglobin levels were also observed with SNPs on these three regions. Our data indicate that several genetic loci act in concert to influence HbF levels of beta(0)-thalassemia/HbE patients. This study revealed that all the three reported loci and the alpha-globin gene locus are the best and common predictors of the disease severity in beta-thalassemia.

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Coinheritance of the different copy numbers of α-globin gene modifies severity of β-thalassemia/Hb E disease

Cited by 49 publications

References 18 publications

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice

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

A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E

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