The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border

Microcytic anemia (mk) mice and Belgrade (b) rats are severely iron deficie nt because of impaired intestinal iron absorption and defective iron metabo lism in peripheral tissues. Both animals carry a glycine to arginine substi tution at position 185 in the iron transporter known as Nramp2/DMT1 (divale nt metal transporter 1). DMT1 messenger RNA (mRNA) and protein expression h as been examined in the gastrointestinal tract of mk mice. Northern blot an alysis indicates that, by comparison to mk/+ heterozygotes, mk/mk homozygot es show a dramatic increase in the level of DMT1 mRNA in the duodenum, This increase in RNA expression is paralleled by a concomitant increase of the 100-kd DMT1 isoform I protein expression in the duodenum, Immunohistochemic al analyses show that, as for normal mice on a low iron diet, DMT1 expressi on in enterocytes of mk/mk mice is restricted to the duodenum, However, and in contrast to normal enterocytes, little if any expression of DMT1 is see n at the apical membrane in mk/mk mice. These results suggest that the G185 R mutation, which was shown to impair the transport properties of DMT1, als o affects the membrane targeting of the protein in mk/mk enterocytes, This loss of function of DMT1 is paralleled by a dramatic increase in expression of the defective protein in mk/mk mice. This is consistent with a feedback regulation of DMT1 expression by iron stores. (C) 2000 by The American Soc iety of Hematology.