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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2157-2163
The G185R Mutation Disrupts Function of the Iron Transporter Nramp2
Maureen A. Su,
Cameron C. Trenor III,
Judith C. Fleming,
Mark D. Fleming, and
Nancy C. Andrews
From the Division of Hematology/Oncology, Children's Hospital,
Boston; the Department of Pathology, Brigham and Women's Hospital,
Boston; the Department of Pediatrics, Harvard Medical School, Boston;
and the Howard Hughes Medical Institute, Boston, MA.
Microcytic anemia (mk) mice and Belgrade (b) rats
have severe iron deficiency anemia due to defects in intestinal iron
transport and erythroid iron utilization. Both animal mutants carry the same missense mutation in Nramp2, the first mammalian iron
transporter to be identified. This mutation, in which glycine 185 is
changed to arginine (G185R), occurs within predicted transmembrane
domain 4 of the protein. We have performed site-directed mutagenesis of
murine Nramp2, focusing on amino acids of transmembrane domain 4 that are highly conserved among Nramp-like proteins. We have expressed each mutant form in transfected cells and examined iron transport function, subcellular localization, and protein amounts. All
tested forms of Nramp2 localize to the plasma membrane and to
transferrin-containing endosomes. Most transmembrane domain 4 mutations
affect the amount of protein detected and consequently show diminished
iron transport. The G185R mutation, however, causes near total loss of
Nramp2 function that cannot be fully explained by a decreased amount of
protein, indicating that G185R disrupts iron transport through an
alteration in the function of Nramp2, rather than degradation of the
protein.
© 1998 by The American Society of Hematology.
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