These mice carry a targeted mutation of Hfe, hemochromatosis, exhibit iron loading, and have applications in studies of hereditary hemochromatosis, iron homeostasis and innate immune response.
Nancy C. Andrews, Duke University School of Medicine
Hfe, hemochromatosis, is involved in regulation of intestinal iron absorption. Mice that are homozygous for this targeted mutation are viable, fertile, normal in size and recapitulate human hereditary hemochromatosis. Hereditary hemochromatosis is a genetic disorder of iron hyperabsorption that results in hyperferremia and iron loading in tissues. By 4 weeks of age, homozygotes on the 129S6/SvEvTac background display elevated blood iron levels and up to 2.2-fold higher hepatic nonheme iron than controls. At 10 weeks of age, homozygotes on the 129S6/SvEvTac background have up to 3.3-fold higher hepatic nonheme iron than controls. Iron loading is less severe in homozygotes on the C57BL/6J background. Heterozygotes exhibit some iron loading. Macrophages isolated from homozygotes have impaired TLR4/TRAM/TRIF pathway signalling, with reduced production of TNF-alpha and IL-6. When challenged with Salmonella typhimurium induced enterocolitis, homozygotes exhibit a less severe inflammatory response. Expression of Hamp (hepcidin antimicrobial peptide) is reduced in homozygotes. 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.
A targeting vector containing a floxed NEO/cytosine deaminase cassette was used to replace part of exon 3 and all of exon 4. The construct was electroporated into 129S6/SvEvTac derived TC-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice, and then backcrossed to C57BL/6J for more than 10 generations.
|Allele Name||targeted mutation 2, Nancy C Andrews|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Hfe, hemochromatosis|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||A LoxP site flanked neomycin resistance gene cassette replaced a segment of genomic sequence starting in exon 3 and ending in intron 4.|
|Mutations Made By|| |
Nancy Andrews, Duke University School of Medicine
When maintaining a live colony, these mice can be bred as homozygotes.
When using the Hfe- mouse strain in a publication, please cite the originating article(s) and include JAX stock #017784 in your Materials and Methods section.