Microcytic anemia (mk) mice and Belgrade (b) rats are severely iron deficient 
because of impaired intestinal iron absorption and defective iron metabolism in 
peripheral tissues. Both animals carry a glycine to arginine substitution at 
position 185 in the iron transporter known as Nramp2/DMT1 (divalent metal 
transporter 1). DMT1 messenger RNA (mRNA) and protein expression has been 
examined in the gastrointestinal tract of mk mice. Northern blot analysis 
indicates that, by comparison to mk/+ heterozygotes, mk/mk homozygotes 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. Immunohistochemical analyses show 
that, as for normal mice on a low-iron diet, DMT1 expression 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 seen at the apical membrane in 
mk/mk mice. These results suggest that the G185R mutation, which was shown to 
impair the transport properties of DMT1, also 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. 
(Blood. 2000;96:3964-3970)