Characterization of Urinary Iron Loss in the fsn (flaky skin) Anemia Mouse Mutant

Abstract

Iron overloading is a serious medical problem for blood transfusion-dependent diseases such as sickle cell disease, β–Thalassemia Major, and Myelodysplastic syndromes which require chronic blood transfusions to treat their related sequelae. Alternative treatment options to iron chelation therapy are currently lacking. The goal of this study was to identify a mechanism in a mouse model with the unique ability to excrete excess iron through urine and can uncover a novel pharmaceutical target to treat iron overload. The flaky–skin anemia (fsn) mouse possesses a mutation in the Ttc7 gene (tetratricopeptide repeat domain 7) and had been observed to excrete elevated iron levels in its urine. We hypothesized that the mutation in fsn results in decreased transferrin–bound iron reabsorption in the kidney, resulting in elevated iron excretion in the urine. While the mechanism of high iron excretion in fsn mice remains unknown, we have ruled out the possibility of transferrin–bound iron leak from the kidney. fsn kidney cells not only expressed TfR1 (transferrin receptor 1) on the surface, but were capable of endocytosing transferrin–bound iron. Additionally, Cubilin and Megalin, known transferrin receptors, mRNA levels were not significantly different between fsn and WT littermate kidneys. However, we have detected lower levels of Dmt1 mRNA in the fsn kidney. Further work should focus on DMT1 protein expression in the nephron and investigate whether DMT1 (divalent metal transporter 1) protein levels impact the pathogenesis observed in the fsn anemia mouse mutant.