Nramp2 is mutated in the anemic Belgrade (b) rat:: Evidence of a role for Nramp2 in endosomal iron transport
Nramp2 is mutated in the anemic Belgrade (b) rat:: Evidence of a role for Nramp2 in endosomal iron transport
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DOI：
10.1073/pnas.95.3.1148
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发表时间：
1998-02-03
影响因子：
11.1
通讯作者：
Andrews, NC
中科院分区：
文献类型：
--
作者：
Fleming, MD;Romano, MA;Andrews, NC
贝尔格莱德(B)大鼠有一种常染色体隐性遗传，小细胞性，低色素性贫血伴随着网织红细胞铁摄取和胃肠道铁吸收异常，网织红细胞缺陷似乎是转铁蛋白循环内内体铁转运失败，这种表型的方面类似于小细胞性贫血(MK)突变的小鼠，最近，墨水被归因于编码推定的铁转运蛋白Nramp2基因的错义突变。为了研究大鼠Nramp2也发生突变的可能性，我们建立了大鼠7号染色体着丝粒部分与Nramp2表型的连锁，该区域与小鼠的染色体位置一致，大鼠Nramp2基因内的A多态与b表型共分离，在b Nramp2基因中存在甘氨酸到精氨酸的错义突变(G185R)，但在正常等位基因中不存在。引人注目的是，这种氨基酸变化与在MK小鼠中看到的相同。对大鼠Nramp2等位基因编码的蛋白质的功能研究表明，该突变扰乱了铁的运输，这些结果证实了NrampZ是贝尔格莱德大鼠缺陷蛋白的假设，并提出了MK和b动物所共有的表型是G185R突变所特有的可能性，此外，这些动物的表型特征表明，NrampZ对于正常的肠道铁吸收和转铁蛋白循环内体外的铁运输都是必不可少的。
The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption, The b reticulocyte defect appears to be failure of iron transport out of endosomes within the transferrin cycle, Aspects of this phenotype are similar to those reported for the microcytic anemia (mk) mutation in the mouse, Recently, ink has been attributed to a missense mutation in the gene encoding the putative iron transporter protein Nramp2. To investigate the possibility that Nramp2 was also mutated in the b rat, we established linkage of the phenotype to the centromeric portion of rat chromosome 7, This region exhibits synteny to the chromosomal location of Nramp2 in the mouse, A polymorphism within the rat Nramp2 gene cosegregated with the b phenotype, A glycine-to-arginine missense mutation (G185R) was present in the b Nramp2 gene, but not in the normal allele, Strikingly, this amino acid alteration is the same as that seen in the mk mouse, Functional studies of the protein encoded by the b allele of rat Nramp2 demonstrated that the mutation disrupted iron transport, These results confirm the hypothesis that NrampZ is the protein defective in the Belgrade rat and raise the possibility that the phenotype shared by mk and b animals is unique to the G185R mutation, Furthermore, the phenotypic characteristics of these animals indicate that NrampZ is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome.