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Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene


Although disorders of iron metabolism are prevalent, iron transport remains poorly understood. To address this problem, we undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anaemia (mk). Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization1–4. We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function. Nramp2 is homologous to Nrampl, a gene active in host defense. If Nramp2 is mk, as the cumulative evidence suggests, our findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.

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  1. 1

    Russell, E.S. et al. Characterization and genetic studies of microcytic anemia in house mouse. Blood 35, 838–850 (1970).

  2. 2

    Edwards, J.A. & Hoke, J.E. Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proc. Soc. Exp. Biol. Med. 141, 81–84 (1972).

  3. 3

    Harrison, D.E. Marrow transplantation and iron therapy in mouse hereditary microcytic anemia. Blood 40, 893–901 (1972).

  4. 4

    Edwards, J.A. & Hoke, J.E. Red cell iron uptake in hereditary microcytic anemia. Blood 46, 381–388 (1975).

  5. 5

    Grunheid, S., Cellier, M., Vidal, S. & Gros, P. Identification and characterization of a second mouse Nramp gene. Genomics 25, 514–525 (1995).

  6. 6

    Handa, S., Ferguson, J.M., Wallace, M.E. & Bulfield, G. Characterization and mapping of a viable anaemic mutant in the mouse: a new allele, mkvan, at the microcytic anaemia locus. Genet. Res. 51, 42–47 (1987).

  7. 7

    McFarland, E.C. & Russell, E.S. Microcytic anemia (mk) has been located close to Ca on chromosome 15. Mouse News Letter 53, 35 (1975).

  8. 8

    Lander, E.S. & Botstein, D. Homozygosity mapping: a new way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).

  9. 9

    Bird, A.P. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res. 8, 1499–1504 (1980).

  10. 10

    Hogan, B., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1986).

  11. 11

    Supek, F., Supekova, L., Nelson, H. & Nelson, N. A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc. Natl. Acad. Sci. USA 93, 5105–5110 (1996).

  12. 12

    Cellier, M., Belouchi, A. & Gros, P. Resistance to intracellular infections: comparative genomic analysis of Nramp. Trends Genet. 12, 201–204 (1996).

  13. 13

    Cellier, M. et al. Nramp defines a family of membrane proteins. Proc. Natl. Acad. Sci. USA 92, 10089–10093 (1995).

  14. 14

    Vidal, S.M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Beg. Cell 73, 469–485 (1993).

  15. 15

    Vidal, S. et al. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp 7 gene. J. Exp. Med. 182, 655–666 (1995).

  16. 16

    Grunheid, S., Pinner, E., Desjardins, M. & Gros, P. Natural resistance to infection with intracellular pathogens: the Nrampl protein is recruited to the membrane of the phagosome. J. Exp. Med. 185, 717–730 (1997).

  17. 17

    Rodrigues, V., Cheah, P.Y, Ray, K. & Chia, W. malvolio, the Drosophila homologue of mouse NRAMP-1 (Beg), is expressed in macrophages and in the nervous system and is required for normal taste behavior. EMBO J. 14, 3007–3020 (1995).

  18. 18

    West, A.H. et al. Two related genes encoding extremely hydrophobic proteins suppress a lethal mutation in the yeast mitochondrial processing enhancing protein. J. Biol. Chem. 267, 24625–24633 (1992).

  19. 19

    Thomson, A.B.R., Olatunbosun, D. & Valberg, L.S. Interrelation of intestinal transport system for manganese and iron. J. Lab. Clin. Med. 78, 642–655 (1971).

  20. 20

    Dancis, A. et al. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell 76, 393–402 (1994).

  21. 21

    Askwith, C. et al. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell 76, 403–410 (1994).

  22. 22

    Russell, E.S., McFarland, E.C. & Kent, E.L. Low viability, skin lesions, and reduced fertility associated with microcytic anemia in the mouse. Transplant. Proc. 2, 144–151 (1970).

  23. 23

    Weinberg, E.D. The iron-withholding defense system. ASM News 59, 559–562 (1993).

  24. 24

    Manly, K.F. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm. Genome 4, 303–313 (1993).

  25. 25

    Lennon, G.G., Auffray, C., Polymeropoulos, M. & Scares, M.B., The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics 33, 151–152 (1996).

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Correspondence to Nancy C. Andrews.

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