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

Daniel P. Heruth, Troy Hawkins, Derek P. Logsdon, Margaret I. Gibson, Inna V. Sokolovsky, Ndona N. Nsumu, Stephanie L. Major, Barbara Fegley, Gerald M. Woods, Karen B. Lewing, Kathleen A. Neville, Kenneth Cornetta, Kenneth R. Peterson, Robert A. White

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)303-307
Number of pages5
JournalGenomics
Volume96
Issue number5
DOIs
StatePublished - Nov 1 2010

Keywords

  • Anemia
  • EKLF
  • Hereditary Spherocytosis
  • KLF1
  • Mouse mutant

ASJC Scopus subject areas

  • Genetics

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    Heruth, D. P., Hawkins, T., Logsdon, D. P., Gibson, M. I., Sokolovsky, I. V., Nsumu, N. N., Major, S. L., Fegley, B., Woods, G. M., Lewing, K. B., Neville, K. A., Cornetta, K., Peterson, K. R., & White, R. A. (2010). Mutation in erythroid specific transcription factor KLF1 causes Hereditary Spherocytosis in the Nan hemolytic anemia mouse model. Genomics, 96(5), 303-307. https://doi.org/10.1016/j.ygeno.2010.07.009