Document Type
Article
Publication Title
Genomics
Abstract
KLF1 regulates definitive erythropoiesis of red blood cells by facilitating transcription through high affinity binding to CACCC elements within its erythroid specific target genes including those encoding erythrocyte membrane skeleton (EMS) proteins. Deficiencies of EMS proteins in humans lead to the hemolytic anemia Hereditary Spherocytosis (HS) which includes a subpopulation with no known genetic defect. Here we report that a mutation, E339D, in the second zinc finger domain of KLF1 is responsible for HS in the mouse model Nan. The causative nature of this mutation was verified with an allelic test cross between Nan/+ and heterozygous Klf1+/− knockout mice. Homology modeling predicted Nan KLF1 binds CACCC elements more tightly, suggesting that Nan KLF1 is a competitive inhibitor of wild-type KLF1. This is the first association of a KLF1 mutation with a disease state in adult mammals and also presents the possibility of being another causative gene for HS in humans.
DOI
10.1016/j.ygeno.2010.07.009
Publication Date
11-2010
Keywords
Hereditary Spherocytosis, Anemia, KLF1, EKLF, Mouse mutant
ISSN
1089-8646
Recommended Citation
Heruth DP, Hawkins T, Logsdon DP, Gibson MI, Sokolovsky IV, Nsumu NN, Major SL, Fegley B, Woods GM, Lewing KB, Neville KA, Cornetta K, Peterson KR, White RA. Mutation in Erythroid Specific Transcription Factor KLF1 Causes Hereditary Spherocytosis in the Nan Hemolytic Anemia Mouse Model. Genomics. 2010; 96(5). doi: 10.1016/j.ygeno.2010.07.009.
