Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor.
Document Type
Article
Publication Date
2010
Keywords
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
First Page
15151
Last Page
15156
JAX Source
Proc Natl Acad Sci U S A 2010 Aug; 107(34):15151-6.
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 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.
Recommended Citation
Siatecka M,
Sahr KE,
Andersen SG,
Mezei M,
Bieker JJ,
Peters LL.
Severe anemia in the Nan mutant mouse caused by sequence-selective disruption of erythroid Kruppel-like factor. Proc Natl Acad Sci U S A 2010 Aug; 107(34):15151-6.