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. 1998 Feb 3;95(3):1148-53.
doi: 10.1073/pnas.95.3.1148.

Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport

M D Fleming  1 , M A Romano, M A Su, L M Garrick, M D Garrick, N C Andrews
Affiliations

Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport

M D Fleming et al. Proc Natl Acad Sci U S A. .

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The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption VSports手机版. 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, mk 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 Nramp2 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 Nramp2 is essential both for normal intestinal iron absorption and for transport of iron out of the transferrin cycle endosome. .

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Figures

Figure 1
Figure 1
Nramp2 and the b phenotype map to proximal rat chromosome 7. Ninety-two [Belgrade × Fischer 344] F1 × Belgrade backcross animals were genotyped with microsatellite markers mapping to the centromeric portion of rat chromosome 7, and with a marker of rat Nramp2. The b phenotype was recombinationally inseparable from D7Mit1 and Nramp2 (lod = 25.6). Genetic distances and standard deviations, expressed in centiMorgans, are indicated on the left side of the figure, and markers are identified on the right.
Figure 2
Figure 2
Amino acid alignment of alternative Nramp2 C-terminal exons. Predicted amino acid sequences of alternatively spliced Nramp2 C-terminal exons from mouse and rat are indicated by boxes. Two forms, 568 aa and 561 aa, have been isolated from rat (M.D.F., GenBank accession no. AF029757 and ref. 17) and mouse (M.D.F., GenBank accession no. AF029758 and ref. 28). The human C terminus determined from a cDNA clone lacking N-terminal sequences (GenBank accession no. L37347) resembles the 561-aa form from rat and mouse.
Figure 3
Figure 3
Belgrade rats have a glycine-to-arginine missense mutation in Nramp2. Multiple overlapping RT-PCR clones spanning the wild-type and b allele of Nramp2 were isolated and sequenced. A single polymorphism resulting in a glycine-to-arginine substitution at codon 185 was identified. The presence of the mutation, indicated by the arrow, was verified by sequencing genomic PCR clones of the region.
Figure 4
Figure 4
The G185R mutation disrupts Nramp2-mediated iron uptake activity. HEK293T cells were transfected with expression plasmids containing wild-type or G185R mutant Nramp2 cDNA, and iron uptake activity was measured. Iron uptake is expressed as fold stimulation compared with cells transfected with plasmids containing the wild-type cDNA in an antisense orientation. Error bars indicate the standard deviation based on four independent experiments.
Figure 5
Figure 5
Proposed model of iron metabolism that incorporates Nramp proteins. Aspects of mammalian iron metabolism including absorption by intestinal epithelial cells, uptake by erythrocytes, and recycling by macrophages are depicted. Possible roles for Nramp2 and Nramp1 are based on phenotypes of mutant animals and functional studies, and are discussed in the text.
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