Peters L L, Andrews N C, Eicher E M, Davidson M B, Orkin S H, Lux S E
Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts.
Nature. 1993 Apr 22;362(6422):768-70. doi: 10.1038/362768a0.
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.
核DNA结合蛋白NF-E2被认为可介导α-和β-珠蛋白基因座控制区强大的红系增强子活性，并参与调控编码血红素生物合成的两种酶（胆色素原脱氨酶和亚铁螯合酶）的基因。NF-E2的主要成分是一种45K多肽（称为p45 NF-E2），它属于转录因子的碱性区域-亮氨酸拉链家族。NF-E2的这个亚基在造血祖细胞以及红系、巨核细胞和肥大细胞系的分化细胞中特异性表达。编码p45 NF-E2的基因（小鼠基因Nfe2）已被定位到小鼠15号染色体上靠近微细胞症（mk）突变的位置。纯合mk小鼠由于珠蛋白合成减少以及肠道和红系铁吸收缺陷而患有严重的低色素小细胞贫血。在这里，我们通过对p45 NF-E2基因进行特征分析并确定其在野生型和mk等位基因中的DNA序列，来研究mk突变是否位于Nfe2内。mk等位基因携带一个错义突变，该突变导致p45 NF-E2蛋白第173位氨基酸处的缬氨酸被丙氨酸取代。在正常小鼠的红系组织以及正常和重度贫血的β地中海贫血（Hbbd-th3/Hbbd-th3）小鼠的十二指肠中检测到了p45 NF-E2信使RNA的表达。我们提出，mk突变导致NF-E2形式受损，无法正常调节珠蛋白生成和铁代谢。
