title: 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.affiliation: Department of Developmental and Regenerative Biology, Black Family Stem Cell Institute, and Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Miroslawa
authors.initials: M
authors.lastname: Siatecka
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sahr
authors.forename: Sabra G
authors.initials: SG
authors.lastname: Andersen
authors.forename: Mihaly
authors.initials: M
authors.lastname: Mezei
authors.forename: James J
authors.initials: JJ
authors.lastname: Bieker
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
mesh_terms: D019943:Amino Acid Substitution; D000740:Anemia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D006454:Hemoglobins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D006454:Hemoglobins; D051741:Kruppel-Like Transcription Factors; D050505:Mutant Proteins; C080774:erythroid Kruppel-like factor; D004247:DNA