These knock-in mice carry a H67D mutation in the mouse Hfe (hemochromotosis) gene that is homologous to a human H63D mutation found at higher frequencies in neurodegenerative diseases. Brain concentrations of iron aren't significantly modified in these mice, but proteins that manage the iron are.
James R Connor, The Pennsylvania State University
The Hfe (hemochromotosis) gene expresses a protein commonly associated with iron homeostasis. Increasing evidence suggests a potential role in neurodegenerative diseases.
These knock-in mice carry a H67D mutation in the mouse Hfe gene that is homologous to a human H63D mutation found at higher frequencies in neurodegenerative diseases. At 6 and 12 months of age, mutant mice have higher body weight than wildtype mice. Homozygotes have altered brain and hepatic iron homeostasis, and increased oxidative stress and gliosis in the brain.
Brain concentrations of iron aren't significantly modified in these mice, but proteins that manage the iron are. Six-month-old H67D mice have increased levels of HFE and H-ferritin (FTH1) expression. At 12 months, H67D mice have increased H- and L-ferritin (FTL1) but decreased transferrin (TRF) expression, suggesting increased iron storage and decreased iron mobilization.
When combined with a G93A mutant SOD1 (superoxide dismutase 1, soluble) mouse model for amyotrophic lateral sclerosis (ALS) (see Stock No. 002726), mice show a shorter survival time and an accelerated disease progression.
An H67D point mutation (199C to G) that disrupted a BspHI restriction site was introduced into exon 2 of the mouse gene upstream of a loxP-flanked neomycin resistance cassette. The targeting vector was introduced to 129X1/SvJ-derived RW-4 embryonic stem (ES) cells. Chimeric males were bred to C57BL/6J females for germ-line transmission. This strain was maintained on a mixed C57BL/6-129 genetic background by the donating laboratory.
|Allele Name||hemochromatosis; targeted mutation 1, James Connor|
|Allele Type||Targeted (Not Specified)|
|Gene Symbol and Name||Hfe, hemochromatosis|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Exon 2 was replaced with a modified exon 2 in which a C to G point mutation results in the amino acid substitution of aspartic acid for histidine at position 67 (p.H67D). The mutation recapitulates the human mutation, p.H63D, observed in many patients with hereditary hemochromatosis (HH). A loxP site flanked neomycin resistance gene cassette was inserted into intron 2.|
Heterozygotes and homozygotes are viable and fertile.
When using the B6;129X1-Hfetm1Jrco/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #023025 in your Materials and Methods section.