Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model

abstract Article history:Received 3 February 2010Accepted 28 July 2010Available online 5 August 2010Keywords:Hereditary SpherocytosisAnemiaKLF1EKLFMouse mutant KLF1 regulates definitive erythropoiesis of red blood cells by facilitating transcription through high affinitybinding to CACCC elements within its erythroid specific target genes including those encoding erythrocytemembrane skeleton (EMS) proteins. Deficiencies of EMS proteins in humans lead to the hemolytic anemiaHereditary Spherocytosis (HS) which includes a subpopulation with no known genetic defect. Here wereport that a mutation, E339D, in the second zinc finger domain of KLF1 is responsible for HS in the mousemodel Nan. The causative nature of this mutation was verified with an allelic test cross between Nan/+ andheterozygous Klf1 +/− knockout mice. Homology modeling predicted Nan KLF1 binds CACCC elements moretightly, suggesting that Nan KLF1 is a competitive inhibitor of wild-type KLF1. This is the first association of aKLF1 mutation with a disease state in adult mammals and also presents the possibility of being anothercausative gene for HS in humans.© 2010 Elsevier Inc. All rights reserved.