Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis

Hereditary hemochromatosis (HH) is a common disorder of iron metabolism cau sed by mutation in HFE, a gene encoding an MHC class I-like protein. Clinic al studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genet ic factors other than Hfe genotype influence the severity of iron loading i n the murine model of HH, we bred the disrupted murine Hfe allele onto thre e different genetically defined mouse strains (AKR, C57BL/6, and C3H), whic h differ in basal iron status and sensitivity to dietary iron loading. Seru m transferrin saturations (percent saturation of serum transferrin with iro n), hepatic and splenic iron concentrations, and hepatocellular iron distri bution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/ -), and knockout (Hfe -/-) mice from each strain. Although the Hfe -/- mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hf e gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectivel y. The Hfe -/- mice also demonstrated strain-dependent differences in trans ferrin saturation, with the highest values in AKR mice and the lowest Value s in C3H mice. These observations demonstrate that heritable factors marked ly influence iron homeostasis in response to Hfe disruption. Analysis of mi ce from crosses between C57BL/6 and AKR mice should allow the mapping and s ubsequent identification of genes modifying the severity of iron loading in this murine model of HH.