Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency

• Main Authors: Ashlee J. Conway, Fiona C. Brown, Elinor J. Hortle, Gaetan Burgio, Simon J. Foote, Craig J. Morton, Stephen M. Jane, David J. Curtis
• Format: Article
• Language: English
• Published: The Company of Biologists 2018-05-01
• Series: Disease Models & Mechanisms
• Subjects: Erythropoiesis; N-ethyl-N-nitrosourea; Anaemia; TPI deficiency; Transplantation
• Online Access: http://dmm.biologists.org/content/11/5/dmm034678

In this study, we performed a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued.