Hfe2, hemochromatosis type 2 (juvenile) (human homolog), is involved in regulation of intestinal iron absorption. Mice that are homozygous for this targeted mutation are viable, fertile, normal in size and recapitulate some of the symptoms of human Type 2A hemochromatosis or hereditary juvenile hemochromatosis. Type 2A hemochromatosis is a genetic disorder of iron hyperabsorption that results in severe early onset iron loading in tissues, as well as low hepcidin levels, hypogonadotropic hypogonadism, and cardiomyopathy. At 4 weeks of age, the livers of homozygotes are grossly brown. At 6 to 7 weeks of age, homozygotes exhibit up to 20-fold more non-heme iron in the liver, increased non-heme iron levels in the pancreas, heart, kidney and testis, and decreased non-heme iron levels in the spleen. Histological analysis reveals iron accumulation in hepatocytes (pericanicular), exocrine and endocrine pancreas, renal distal tubules, cells of the anterior pituitary, and in arteriolar endothelial cells of the testis. A diminished amount of iron is found in proximal duodenal enterocytes. Homozygotes have a decreased level of hepatic hepcidin mRNA, and increased ferroportin protein levels in intestinal basolateral membrane, hepatic and splenic macrophages when compared to controls. Serum levels of iron are also elevated. Homozygotes over the age of 18 months exhibit iron loading in the retina, with retinal pigment epithelium hyperplasia and loss of ganglion cells, compared to age-matched controls. Although levels of Bmp6 mRNA is elevated in liver of homozygous mice, bone morphogenetic protein (BMP) signaling is impaired in hepatocytes. 5 week old homozygous males on an iron depleted diet for 25 days exhibit approximately 7-fold greater hepatic non-heme iron level when compared to controls. Carbon tetrachloride (CCl4) induced liver damage and fibrosis occurs earlier and is more severe in homozygotes compared to wildtype controls. The Donating Investigator notes that the level of iron loading in mutant animals varies based on the iron content of the diet, breeding strategy, and other factors.

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These Hfe2 knockout mice exhibit iron loading and have applications in studies of juvenile or Type2A hemochromatosis, iron homeostasis and iron-induced oxidative damage.

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