title: Imbalanced globin chain synthesis determines erythroid cell pathology in thalassemic mice.
abstract: BACKGROUND
  beta-thalassemia occurs from the imbalanced globin chain synthesis due to the absence or inadequate beta-globin chain production. The excessive unbound alpha-globin chains precipitate in erythroid precursors and mature red blood cells leading to ineffective erythropoiesis and hemolysis.
  
  
  METHODS
  In 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.
  
  
  RESULTS
  The alpha/beta-globin chain ratio in beta(IVSII-654)-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 beta(E)-globin transgene, with a more balanced globin chain synthesis, 0.92+/-0.05. Moreover, transgenic mice harboring 8 extra copies of the human beta(E)-globin transgene showed inversely imbalanced alpha/beta-globin synthesis ratio, 0.83+/-0.01, that resulted in a mild beta-thalassemia phenotype due to the excessive beta-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 beta(IVSII-654)-thalassemic mice showed increased phosphatidylserine exposure in basophilic and polychromatophilic stages, which was restored to the normal level in doubly heterozygous mice.
  
  
  CONCLUSIONS
  Imbalanced alpha/beta-globin chain as a consequence of either reduction or enhancement of beta-globin chain synthesis can cause abnormal red blood cell properties in mouse models.
authors.affiliation: Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Salaya, Phuttamonthon 4 Rd., Phuttamonthon, Nakornpathom, Thailand. stpfc@mahidol.ac.th
authors.forename: Kanitta
authors.initials: K
authors.lastname: Srinoun
authors.forename: Saovaros
authors.initials: S
authors.lastname: Svasti
authors.forename: Worrakavee
authors.initials: W
authors.lastname: Chumworathayee
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
authors.forename: Phantip
authors.initials: P
authors.lastname: Vattanaviboon
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.forename: Pranee
authors.initials: P
authors.lastname: Winichagoon
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004913:Erythrocytes, Abnormal / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D055542:alpha-Globins / Q000096:biosynthesis* / Q000235:genetics; D055544:beta-Globins / Q000096:biosynthesis* / Q000235:genetics; D017086:beta-Thalassemia / Q000378:metabolism* / Q000473:pathology*
chemical_list: D017382:Reactive Oxygen Species; D055542:alpha-Globins; D055544:beta-Globins