Co-inheritance of α- and β-thalassaemia in mice ameliorates thalassaemic phenotype

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Abstract

β-Thalassaemia is an inherited disease caused by defective synthesis of the β-globin chain of haemoglobin, leading to an imbalance in globin chains. Excess α-globin chains precipitate in erythroid progenitor cells resulting in cell death, ineffective erythropoiesis and severe anaemia. Decreased α-globin synthesis leads to milder symptoms, exemplified by individuals who co-inherit α-thalassaemia and β-thalassaemia. In this study, we set out to investigate whether co-inheritance of α- and β-thalassaemia in mice leads to reduced anaemia. Heterozygous murine β-globin knockout (KO) mice (β+/-) which display severe anaemia were mated with heterozygous α-globin KO mice (α++/--). The resulting progeny were genotyped and classed as wild-type WT (α++/+++/+), heterozygous α-KO (α++/--+/+), heterozygous β-KO (α++/+++/-) or double heterozygous (DH) α-KO/β-KO (α++/--+/-). Mice were bled and full blood examinations (FBE) performed. FBE results for heterozygous β-KO mice (β+/-) showed marked reductions in haemoglobin and haematocrit levels and significant increases in red cell distribution widths and reticulocyte counts compared to WT mice. In contrast, FBE results for DH α-KO/β-KO mice showed near normal red blood cell indices. These results indicate that reduction of α-globin expression leads to correction of the globin chain imbalance in β-thalassaemic mice and therefore an improved phenotype. The analysis of DH α-KO/β-KO mice leads to the following conclusions: (1) co-inheritance of α- and β-thalassaemia in mice improves the thalassaemic phenotype, identical to the situation in humans; (2) the heterozygous murine β-globin KO mouse model is a suitable in vivo model to test for therapeutic knockdown of α-globin.

Original languageEnglish
Pages (from-to)184-188
Number of pages5
JournalBlood Cells, Molecules, and Diseases
Volume39
Issue number2
DOIs
Publication statusPublished - 1 Sep 2007
Externally publishedYes

Keywords

  • α- and β-thalassaemia
  • Blood
  • Co-inheritance
  • Mouse model

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