Description

Strain Information

Type Coisogenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Homozygote x Homozygote         (Female x Male)   21-MAR-13 Species laboratory mouse Generation F?pN1F1 (11-DEC-12) Generation Definitions   Donating Investigator Nancy C. Andrews,   Children's Hospital/HHMI

Description
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.

Development
A targeting vector containing a NEO cassette replaced exon 3 and the coding portion of exon 4. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to 129S6/SvEvTac mice, and then backcrossed to 129S6/SvEvTac for more than 10 generations.

Control Information

	Control
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls

Additional Web Information

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Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Hemochromatosis, Type 2A; HFE2A

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Hfe2^tm1Nca/Hfe2⁺

        involves: 129S4/SvJae * 129S6/SvEvTac

• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • normal hepcidin expression   (MGI Ref ID J:100178)

Hfe2^tm1Nca/Hfe2^tm1Nca

        involves: 129S4/SvJae * 129S6/SvEvTac

• mortality/aging
• *normal* mortality/aging
  • no pre-natal lethality detected   (MGI Ref ID J:100178)
• homeostasis/metabolism phenotype
• abnormal iron homeostasis
  • greatly increased expression of ferroportin at the basolateral membrane of intestinal villi detected by immunohistochemistry   (MGI Ref ID J:100178)
  • decreased expression of hepatic hepcidin detected by northern blot analysis   (MGI Ref ID J:100178)
• • abnormal iron level
    • at 6 to 7 weeks of age non-heme iron is increased in the pancreas and testis   (MGI Ref ID J:100178)
    • histology shows increased iron in the exocrine and endocrine pancreas, a subset of anterior pituitary, and arteriolar endothelial cells of the testis, but no iron accumulation in splenic macrophages   (MGI Ref ID J:100178)
  • • decreased spleen iron level
      • decrease in splenic non-heme iron   (MGI Ref ID J:100178)
    • hemochromatosis
      • phenotypically similar to juvenile hemochromatosis in human, but without the hepatic fibrosis, cardiomyopathy, diabetes, or infertility.   (MGI Ref ID J:100178)
    • increased circulating iron level
      • at 6 to 7 weeks of age serum transferrin saturation is close to 100%   (MGI Ref ID J:100178)
    • increased kidney iron level
      • at 6 to 7 weeks of age non-heme iron is increased in the kidney   (MGI Ref ID J:100178)
      • histology shows increased iron in distal tubules of the kidney   (MGI Ref ID J:100178)
    • increased liver iron level
      • at 6 to 7 weeks of age there is a 20 fold increase in non-heme iron in the liver   (MGI Ref ID J:100178)
      • histology shows pericanicular accumulation of iron in liver parenchymal cells   (MGI Ref ID J:100178)
• hematopoietic system phenotype
• *normal* hematopoietic system phenotype
  • normal hemoglobin levels   (MGI Ref ID J:100178)
• • decreased spleen iron level
    • decrease in splenic non-heme iron   (MGI Ref ID J:100178)
• reproductive system phenotype
• *normal* reproductive system phenotype
  • normal fertility in both females and males   (MGI Ref ID J:100178)
• immune system phenotype
• decreased spleen iron level
  • decrease in splenic non-heme iron   (MGI Ref ID J:100178)
• liver/biliary system phenotype
• increased liver iron level
  • at 6 to 7 weeks of age there is a 20 fold increase in non-heme iron in the liver   (MGI Ref ID J:100178)
  • histology shows pericanicular accumulation of iron in liver parenchymal cells   (MGI Ref ID J:100178)
• renal/urinary system phenotype
• increased kidney iron level
  • at 6 to 7 weeks of age non-heme iron is increased in the kidney   (MGI Ref ID J:100178)
  • histology shows increased iron in distal tubules of the kidney   (MGI Ref ID J:100178)

Hfe2^tm1Nca/Hfe2^tm1Nca

        involves: 129P2/OlaHsd * 129S4/SvJae * 129S6/SvEvTac * C57BL/6

• homeostasis/metabolism phenotype
• abnormal iron level
  • at 8 weeks, mice exhibit increased liver, heart, pancreas, and muscle iron levels compared with wild-type mice   (MGI Ref ID J:160248)
• • decreased spleen iron level
    • spleen iron levels are decreased compared to in wild-type mice   (MGI Ref ID J:160248)
    • splenic macrophages exhibit decreased iron levels compared with wild-type cells   (MGI Ref ID J:160248)
  • increased liver iron level
    • at 8 weeks, specifically in hepatocytes   (MGI Ref ID J:160248)
• hematopoietic system phenotype
• abnormal macrophage morphology
  • splenic macrophages exhibit decreased iron levels compared with wild-type cells   (MGI Ref ID J:160248)
• decreased spleen iron level
  • spleen iron levels are decreased compared to in wild-type mice   (MGI Ref ID J:160248)
  • splenic macrophages exhibit decreased iron levels compared with wild-type cells   (MGI Ref ID J:160248)
• liver/biliary system phenotype
• abnormal hepatocyte morphology
  • hepatocytes exhibit increased iron accumulation compared with wild-type cells   (MGI Ref ID J:160248)
• increased liver iron level
  • at 8 weeks, specifically in hepatocytes   (MGI Ref ID J:160248)
• immune system phenotype
• abnormal macrophage morphology
  • splenic macrophages exhibit decreased iron levels compared with wild-type cells   (MGI Ref ID J:160248)
• decreased spleen iron level
  • spleen iron levels are decreased compared to in wild-type mice   (MGI Ref ID J:160248)
  • splenic macrophages exhibit decreased iron levels compared with wild-type cells   (MGI Ref ID J:160248)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Hematological Research
Anemia, Iron Deficiency and Transport Defects
      hemochromatosis

Internal/Organ Research
Liver Defects
      hemochromatosis

Metabolism Research
Hemochromatosis
      iron metabolism defects
Iron Metabolism

Mouse/Human Gene Homologs
hemochromatosis

Sensorineural Research
Eye Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Hfe2tm1Nca
Allele Name		targeted mutation 1, Nancy C Andrews
Allele Type		Targeted (knock-out)
Common Name(s)		Hfe2-; Hjv-;
Mutation Made By		Nancy Andrews,   Children's Hospital/HHMI
Strain of Origin		129S4/SvJae
Gene Symbol and Name		Hfe2, hemochromatosis type 2 (juvenile) (human homolog)
Chromosome		3
Gene Common Name(s)		2310035L15Rik; 5230400G09Rik; AI414844; AI789733; DL-M; HFE2A; HJV; JH; RGM domain family, member C; RGMC; RIKEN cDNA 2310035L15 gene; RIKEN cDNA 5230400G09 gene; Rgmc; expressed sequence AI414844; expressed sequence AI789733; hemojuvelin;
Molecular Note		Exon 3 and the coding sequence in exon 4 were replaced upon the insertion of a floxed neo cassette, therefore deleting most of the coding sequence for the protein. [MGI Ref ID J:100178]

Genotyping

Genotyping Information

Genotyping Protocols

Hfe2^tm1NcaMCA,

Separated MCA

Hfe2^tm1Nca, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Huang FW; Pinkus JL; Pinkus GS; Fleming MD; Andrews NC. 2005. A mouse model of juvenile hemochromatosis. J Clin Invest 115(8):2187-2191. [PubMed: 16075059]  [MGI Ref ID J:100178]

Additional References

Hfe2^tm1Nca related

Babitt JL; Huang FW; Wrighting DM; Xia Y; Sidis Y; Samad TA; Campagna JA; Chung RT; Schneyer AL; Woolf CJ; Andrews NC; Lin HY. 2006. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38(5):531-9. [PubMed: 16604073]  [MGI Ref ID J:109016]

Finberg KE; Whittlesey RL; Fleming MD; Andrews NC. 2010. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 115(18):3817-26. [PubMed: 20200349]  [MGI Ref ID J:160248]

Gnana-Prakasam JP; Reddy SK; Veeranan-Karmegam R; Smith SB; Martin PM; Ganapathy V. 2011. Polarized distribution of heme transporters in retinal pigment epithelium and their regulation in the iron-overload disease hemochromatosis. Invest Ophthalmol Vis Sci 52(12):9279-86. [PubMed: 22058337]  [MGI Ref ID J:191392]

Gnana-Prakasam JP; Tawfik A; Romej M; Ananth S; Martin PM; Smith SB; Ganapathy V. 2012. Iron-mediated retinal degeneration in haemojuvelin-knockout mice. Biochem J 441(2):599-608. [PubMed: 21943374]  [MGI Ref ID J:179221]

Schmidt PJ; Andrews NC; Fleming MD. 2010. Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin. Blood 116(25):5679-87. [PubMed: 20837779]  [MGI Ref ID J:167407]

Sebastiani G; Gkouvatsos K; Maffettone C; Busatto G; Guido M; Pantopoulos K. 2011. Accelerated CCl4-induced liver fibrosis in Hjv-/- mice, associated with an oxidative burst and precocious profibrogenic gene expression. PLoS One 6(9):e25138. [PubMed: 21966437]  [MGI Ref ID J:177657]

Truksa J; Gelbart T; Peng H; Beutler E; Beutler B; Lee P. 2009. Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6. Br J Haematol 147(4):571-81. [PubMed: 19751239]  [MGI Ref ID J:182123]

Zhang AS; Gao J; Koeberl DD; Enns CA. 2010. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. J Biol Chem 285(22):16416-23. [PubMed: 20363739]  [MGI Ref ID J:163885]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX18

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as heterozygotes or homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   21-MAR-13
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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