Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Krüppel-like factor

Miroslawa Siatecka, Kenneth E. Sahr, Sabra G. Andersen, Mihaly Mezei, James J. Bieker, Luanne L. Peters

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Studies of mouse models of anemia have long provided fundamental insights into red blood cell formation and function. Here we show that the semidominant mouse mutation Nan ("neonatal anemia") carries a single amino acid change (E339D) within the second zinc finger of the erythroid Krüppel-like factor (EKLF), a critical erythroid regulatory transcription factor. The mutation alters the DNA-binding specificity of EKLF so that it no longer binds promoters of a subset of its DNA targets. Remarkably, even when mutant Nan and wild-type EKLF alleles are expressed at equivalent levels, the mutant form selectively interferes with expression of EKLF target genes whose promoter elements it no longer binds. This interference yields a distorted genetic output and selective protein deficiencies that differ from those seen in EKLF-heterozygous and EKLF-null red blood cells and presents a unique and unexpected mechanism of inherited disease.

Original languageEnglish
Pages (from-to)15151-15156
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number34
DOIs
StatePublished - 24 Aug 2010

Keywords

  • Mouse model
  • Neonatal anemia
  • Red blood cells
  • Zinc finger mutation

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