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

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 regions^1–4 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 (Hbb^d-th3/Hbb^d-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.