title: Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model.
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.
authors.affiliation: Department of Pediatrics, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Heruth
authors.forename: Troy
authors.initials: T
authors.lastname: Hawkins
authors.forename: Derek P
authors.initials: DP
authors.lastname: Logsdon
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Gibson
authors.forename: Inna V
authors.initials: IV
authors.lastname: Sokolovsky
authors.forename: Ndona N
authors.initials: NN
authors.lastname: Nsumu
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Major
authors.forename: Barbara
authors.initials: B
authors.lastname: Fegley
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Woods
authors.forename: Karen B
authors.initials: KB
authors.lastname: Lewing
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Neville
authors.forename: Kenneth
authors.initials: K
authors.lastname: Cornetta
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Peterson
authors.forename: Robert A
authors.initials: RA
authors.lastname: White
mesh_terms: D000743:Anemia, Hemolytic / Q000235:genetics / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D013103:Spherocytosis, Hereditary / Q000235:genetics*; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D051741:Kruppel-Like Transcription Factors; C080774:erythroid Kruppel-like factor