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Phenotypes Associated with This Genotype
Genotype
MGI:2429787
Allelic
Composition
Hmox1tm1Poss/Hmox1tm1Poss
Genetic
Background
involves: 129S2/SvPas * C57BL/6
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Hmox1tm1Poss mutation (1 available); any Hmox1 mutation (10 available)
phenotype observed in females
phenotype observed in males
N normal phenotype

Iron-loading of Hmox1tm1Poss/Hmox1tm1Poss tissues.

mortality/aging
• post-weaning survivors commonly die after 25 weeks of age; one homozygote lived up to 22 months
• homozygotes exhibit low postnatal survival, with only 20% of the expected number of homozygotes obtained at 3 weeks; a similar survival % is observed in matings between homozygous and heterozygous mutant mice
• percentage of surviving homozygotes can be increased to 48% of those expected by in vitro fertilization techniques using gametes from homozygous and heterozygous animals

hematopoietic system
• adult homozygotes exhibit extramedullary hematopoiesis
• at 20-24 weeks of age, homozygotes display normochromic and microcytic anemia which becomes severe by 40-55 weeks of age
• at 10 (but not at 6) weeks of age, homozygotes start displaying significantly lower red blood cell counts relative to wild-type mice
• at 10 weeks of age, homozygotes start displaying significantly reduced hematocrits relative to wild-type mice
• at 10 (but not at 6) weeks of age, homozygotes start displaying significantly reduced blood hemoglobin concentrations relative to wild-type mice
• at 10 weeks of age, homozygotes start displaying extremely reduced mean corpuscular volumes relative to wild-type mice
• by 20 weeks of age, homozygotes exhibit variable erythrocyte size on blood smears
• adult homozygotes exhibit high peripheral white blood cell counts
• adult homozygotes exhibit enlarged spleens due to both extramedullary hematopoiesis and follicular hyperplasia
• adult homozygotes display spleen follicular hyperplasia
• adult homozygotes display high splenic CD4+:CD8+ T-cell ratios with numerous activated CD4+ T cells

homeostasis/metabolism
• at day 3 after cisplatin administration, homozygotes exhibit significantly increased BUN values, indicating exacerbated renal dysfunction relative to similarly treated wild-type mice; no significant differences in body weight reduction are observed
• despite iron deficiency, homozygotes exhibit progressively increasing serum ferritin levels up to ~50 weeks of age
• by 20 weeks of age, homozygotes exhibit an increased total iron-binding capacity (high serum transferrin levels), resulting in a reduced iron saturation percentage and increased iron deposition relative to wild-type mice
• by ~50 weeks of age, all homozygotes exhibit pathological iron-loading (nonheme iron deposits) in renal proximal cortical tubules, liver Kupffer cells, hepatocytes, and hepatic vascular tissue (with variable severity) while the spleen remains unaffected
• by 20 weeks of age, homozygotes display significantly reduced serum iron levels relative to wild-type mice

immune system
• adult homozygotes exhibit high peripheral white blood cell counts
• adult homozygotes exhibit enlarged spleens due to both extramedullary hematopoiesis and follicular hyperplasia
• adult homozygotes display spleen follicular hyperplasia
• adult homozygotes display high splenic CD4+:CD8+ T-cell ratios with numerous activated CD4+ T cells
• adult homozygotes display high lymph node CD4+:CD8+ T-cell ratios with numerous activated CD4+ T cells
• homozygotes develop a progressive chronic inflammatory disease
• at ~50 weeks of age, homozygotes show hepatic inflammatory cell infiltrates, consisting of lymphocytes, plasma cells, neutrophils, and macrophages
• many infiltrates are periportal while others show a predilection for the portal venous tissue which often contains iron deposits
• hepatic vascular lesions invlove the proliferation of smooth muscle, the infiltration of neutrophils and lymphocytes into the vessel wall, and adherence of monocytes to the inner vessel wall
• at ~50 weeks, homozygotes display glomerulonephritis, caused either by iron toxicity or by deposition of immune complexes
• at ~50 weeks of age, homozygotes occasionally exhibit vascular and perivascular infiltrates in their lungs

renal/urinary system
• at day 3 after cisplatin administration, homozygotes display a 6.6-fold increase in renal tubular apoptosis whereas wild-type mice show a 3-fold increase over saline-treated mice, respectively
• at day 3, cisplatin-treated homozygotes exhibit severe changes in acute renal injury, including tubular necrosis, degeneration, loss of brush border, red cell extravasation, tubular casts, and apoptotic bodies in the proximal and distal tubules; in contrast, wild-type mice display only mild changes with loss of brush border and red cell extravasation
• at ~50 weeks, homozygotes display glomerulonephritis, caused either by iron toxicity or by deposition of immune complexes
• by ~75 weeks, homozygotes display severely damaged glomeruli with membranous proliferation, lobularity, crescent formation, and sclerosis
• by ~75 weeks, homozygotes display glomerular crescent formation
• at day 3 after cisplatin-induced renal injury, homozygotes display more severe loss of brush border than wild-type mice
• at day 3 after cisplatin-induced renal injury, homozygotes display tubular casts
• at day 3 after cisplatin-induced renal injury, homozygotes develop more severe renal failure than wild-type mice

liver/biliary system
• at ~50 weeks of age, homozygotes show hepatic inflammatory cell infiltrates, consisting of lymphocytes, plasma cells, neutrophils, and macrophages
• many infiltrates are periportal while others show a predilection for the portal venous tissue which often contains iron deposits
• hepatic vascular lesions invlove the proliferation of smooth muscle, the infiltration of neutrophils and lymphocytes into the vessel wall, and adherence of monocytes to the inner vessel wall
• at ~50 weeks of age, homozygotes display fibrosis within hepatic inflammatory cell infiltrates
• regenerative nodules indicative of hepatic injury are occasionally observed

behavior/neurological
• as early as 25 weeks of age, most post-weaning survivors exhibit poor grooming
• as early as 25 weeks of age, most post-weaning survivors appear less active than wild-type mice

growth/size/body
• homozygotes are slightly smaller than wild-type or heterozygous littermates from birth to early adulthood
• between 20 and 40 weeks of age, most surviving homozygotes exhibit significant weight loss indicative of wasting

cellular
• at day 3 after cisplatin administration, homozygotes display a 6.6-fold increase in renal tubular apoptosis whereas wild-type mice show a 3-fold increase over saline-treated mice, respectively
• at day 3, cisplatin-treated homozygotes exhibit severe changes in acute renal injury, including tubular necrosis, degeneration, loss of brush border, red cell extravasation, tubular casts, and apoptotic bodies in the proximal and distal tubules; in contrast, wild-type mice display only mild changes with loss of brush border and red cell extravasation
• as a result of iron deposition, livers from 20-24-wk-old homozygotes display increased oxidized proteins and lipid peroxidation values of 51% and 95% while kidneys show increases of 69% and 74% relative to heterozygous values, respectively
• notably, mutant brains, which have no iron deposition, show no evidence of enhanced oxidative damage

reproductive system
• mature male homozygotes show a ~25% reduction in testicular size relative to similarly sized heterozygotes
• as early as 25 weeks of age, most post-weaning survivors breed poorly
• mating pairs of homozygous mutant mice fail to yield viable litters

endocrine/exocrine glands
• mature male homozygotes show a ~25% reduction in testicular size relative to similarly sized heterozygotes

respiratory system
• at ~50 weeks of age, homozygotes occasionally exhibit vascular and perivascular infiltrates in their lungs

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
hemochromatosis DOID:2352 OMIM:231100
OMIM:PS235200
J:79254


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
07/09/2019
MGI 6.14
The Jackson Laboratory