Faculty Research 1990 - 1999


Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2.

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Amino-Acid-Sequence, Anemia: ge, Animal, Base-Sequence, Chromosome-Mapping, Duodenum: me, DNA, DNA-Binding-Proteins: ge, me, Enhancer-Elements-(Genetics), Globin: ge, Iron: me, Mice, Mice-Inbred-C3H, Mice-Inbred-C57BL, Mice-Inbred-DBA, Molecular-Sequence-Data, Mutation, Organ-Specificity, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Transcription-Factors: ge, me

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Nature 1993 Apr 22;362(6422):768-70


The nuclear DNA-binding protein NF-E2 is thought to mediate the powerful erythroid enhancer activity of the alpha- and beta-globin locus control regions and participates in the control of genes encoding two enzymes of haem biosynthesis (porphobilinogen deaminase and ferrochelatase). The major component of NF-E2 is a 45K polypeptide (designated p45 NF-E2) that belongs to the basic region-leucine zipper family of transcription factors. This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakaryocyte and mast cell lineages. The gene encoding p45 NF-E2 (murine gene Nfe2) has been mapped to mouse chromosome 15 near the mutation microcytosis (mk). Homozygous mk mice have severe hypochromic microcytic anaemia as a result of decreased globin synthesis and defects in intestinal and erythroid iron absorption. Here we investigate whether the mk mutation lies within Nfe2 by characterizing the p45 NF-E2 gene and determining its DNA sequence in wild-type and mk alleles. The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein. Expression of p45 NF-E2 messenger RNA was detected in erythroid tissues of normal mice and in the duodenum of normal and severely anaemic beta-thalassaemic (Hbbd-th3/Hbbd-th3) mice. We propose that the mk mutation results in an impaired form of NF-E2 which fails to regulate both globin production and iron metabolism properly.

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