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

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.
Authors	Miroslawa Siatecka, Kenneth E Sahr, Sabra G Andersen, Mihaly Mezei, James J Bieker, Luanne L Peters
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 34 Pg. 15151-6 (Aug 24 2010) ISSN: 1091-6490 [Electronic] United States
PMID	20696915 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Hemoglobins Kruppel-Like Transcription Factors Mutant Proteins erythroid Kruppel-like factor DNA
Topics	Amino Acid Substitution Anemia (genetics, metabolism) Animals Base Sequence Binding Sites (genetics) Chromosome Mapping DNA (genetics, metabolism) Disease Models, Animal Erythrocytes (metabolism) Female Gene Expression Genes, Reporter Hemoglobins (genetics) Heterozygote Humans K562 Cells Kruppel-Like Transcription Factors (chemistry, genetics, metabolism) Male Mice Mice, Inbred C3H Mice, Mutant Strains Models, Molecular Mutant Proteins (chemistry, genetics, metabolism) Mutation, Missense Phenotype Pregnancy Promoter Regions, Genetic Transcriptional Activation Zinc Fingers (genetics)

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