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

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Anemia, Animals, Base-Sequence, Binding-Sites, Chromosome-Mapping, DNA, Disease-Models-Animal, Erythrocytes, Gene-Expression, Genes-Reporter, Hemoglobins, Heterozygote, Humans, K562-Cells, Kruppel-Like-Transcription-Factors, Mice-Inbred-C3H, Mice-Mutant-Strains, Models-Molecular, Mutant-Proteins, Mutation-Missense, Phenotype, Pregnancy, Promoter-Regions-Genetic, Transcriptional-Activation, Zinc-Fingers

JAX Source

Proc Natl Acad Sci U S A 2010 Aug; 107(34):15151-6.


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 Kruppel-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.