Sequence-selective disruption of EKLF zinc finger-DNA interactions: a unique mechanism of severe anemia in the Nan mutant mouse Abstract: Studies of mouse models of anemia have long provided fundamental insights into red blood cell formation and function. Here we show that the semi-dominant 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 such 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 yields a distorted genetic output and selective protein deficiencies that differ from those seen in EKLF-heterozygous and EKLF-null red cells, and presents a unique and unexpected mechanism of inherited disease.