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

Nature volume 362, pages 768770 (22 April 1993) | Download Citation

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Abstract

THE nuclear DNA-binding protein NF-E2 is thought to mediate the powerful erythroid enhancer activity of the α- and β-globin locus control regions1–4 and participates in the control of genes encoding two enzymes of haem biosynthesis (porphobilinogen deaminase and ferrochelatase) 1,5. 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 factors6. This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakary-ocyte and mast cell lineages6. 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 β-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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Author information

Affiliations

  1. Division of Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Luanne L. Peters
    • , Nancy C. Andrews
    • , Mark B. Davidson
    • , Stuart H. Orkin
    •  & Samuel E. Lux
  2. The Jackson Laboratory, Bar Harbor, Maine 04609, USA

    • Eva M. Eicher
  3. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Stuart H. Orkin
  4. To whom correspondence should be addressed.

    • Samuel E. Lux

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https://doi.org/10.1038/362768a0

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