title: Co-inheritance of alpha- and beta-thalassaemia in mice ameliorates thalassaemic phenotype.
abstract: Beta-thalassaemia is an inherited disease caused by defective synthesis of the beta-globin chain of haemoglobin, leading to an imbalance in globin chains. Excess alpha-globin chains precipitate in erythroid progenitor cells resulting in cell death, ineffective erythropoiesis and severe anaemia. Decreased alpha-globin synthesis leads to milder symptoms, exemplified by individuals who co-inherit alpha-thalassaemia and beta-thalassaemia. In this study, we set out to investigate whether co-inheritance of alpha- and beta-thalassaemia in mice leads to reduced anaemia. Heterozygous murine beta-globin knockout (KO) mice (beta+/-) which display severe anaemia were mated with heterozygous alpha-globin KO mice (alpha++/--). The resulting progeny were genotyped and classed as wild-type WT (alpha++/++;beta+/+), heterozygous alpha-KO (alpha++/--;beta+/+), heterozygous beta-KO (alpha++/++;beta+/-) or double heterozygous (DH) alpha-KO/beta-KO (alpha++/--;beta+/-). Mice were bled and full blood examinations (FBE) performed. FBE results for heterozygous beta-KO mice (beta+/-) 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 alpha-KO/beta-KO mice showed near normal red blood cell indices. These results indicate that reduction of alpha-globin expression leads to correction of the globin chain imbalance in beta-thalassaemic mice and therefore an improved phenotype. The analysis of DH alpha-KO/beta-KO mice leads to the following conclusions: (1) co-inheritance of alpha- and beta-thalassaemia in mice improves the thalassaemic phenotype, identical to the situation in humans; (2) the heterozygous murine beta-globin KO mouse model is a suitable in vivo model to test for therapeutic knockdown of alpha-globin.
authors.affiliation: Cell and Gene Therapy Research Group, The Murdoch Childrens Research Institute, The University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville 3052, Melbourne, Australia. joanna.voon@mcri.edu.au
authors.forename: Hsiao Phin Joanna
authors.initials: HP
authors.lastname: Voon
authors.forename: Hady
authors.initials: H
authors.lastname: Wardan
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
mesh_terms: D000818:Animals; D005434:Flow Cytometry; D006403:Hematologic Tests; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D013154:Spleen; D017085:alpha-Thalassemia / Q000150:complications*; D017086:beta-Thalassemia / Q000150:complications*