NRAMP2 IS MUTATED IN THE ANEMIC BELGRADE (B) RAT - EVIDENCE OF A ROLEFOR NRAMP2 IN ENDOSOMAL IRON TRANSPORT

The Belgrade (b) rat has an autosomal recessively inherited, microcyti c, hypochromic anemia associated with abnormal reticulocyte iron uptak e and gastrointestinal iron absorption, The b reticulocyte defect appe ars to be failure of iron transport out of endosomes within the transf errin cycle, Aspects of this phenotype are similar to those reported f or the microcytic anemia (mk) mutation in the mouse, Recently, ink has been attributed to a missense mutation in the gene encoding the putat ive iron transporter protein Nramp2. To investigate the possibility th at 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 phen otype, A glycine-to-arginine missense mutation (G185R) was present in the b Nramp2 gene, but not in the normal allele, Strikingly, this amin o 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 demonstr ated that the mutation disrupted iron transport, These results confirm the hypothesis that NrampZ is the protein defective in the Belgrade r at and raise the possibility that the phenotype shared by mk and b ani mals is unique to the G185R mutation, Furthermore, the phenotypic char acteristics of these animals indicate that NrampZ is essential both fo r normal intestinal iron absorption and for transport of iron out of t he transferrin cycle endosome.