Divalent metal transporter-1 (DMT1/DCT1/Nramp2) is the major Fe(2+) transporter 
mediating cellular iron uptake in mammals. Phenotypic analyses of animals with 
spontaneous mutations in DMT1 indicate that it functions at two distinct sites, 
transporting dietary iron across the apical membrane of intestinal absorptive 
cells, and transporting endosomal iron released from transferrin into the 
cytoplasm of erythroid precursors. DMT1 also acts as a proton-dependent 
transporter for other heavy metal ions including Mn(2+), Co(2+), and Cu(2), but 
not for Mg(2+) or Ca(2+). A unique mutation in DMT1, G185R, has occurred 
spontaneously on two occasions in microcytic (mk) mice and once in Belgrade (b) 
rats. This mutation severely impairs the iron transport capability of DMT1, 
leading to systemic iron deficiency and anemia. The repeated occurrence of the 
G185R mutation cannot readily be explained by hypermutability of the gene. Here 
we show that G185R mutant DMT1 exhibits a new, constitutive Ca(2+) permeability, 
suggesting a gain of function that contributes to remutation and the mk and b 
phenotypes.