Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation F4N1p Generation Definitions   Donating Investigator Zena Harris,   Johns Hopkins Univ School of Medicine

Description
Mice that are homozygous null for the Cp gene demonstrate a progressive accumulation of iron in hepatocytes and reticuloendothelial cells. By one year of age, iron content of the liver and spleen reaches three to six-fold that observed in wild-type litter mates. The Cp gene product appears to be necessary for proper iron efflux from these cell types. This strain represents a viable murine model for aceruloplasminemia. At one year of age there is no evidence of anemia, diabetes, or neurological symptoms despite iron accumulation at the corresponding tissue sites.

Development
The majority of exon 17 and exon 18 has been replaced with a neomycin cassette resulting in the generation of an unstable mRNA.

Control Information

	Control
	None Available
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Aceruloplasminemia - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Cp^tm1Hrs/Cp^tm1Hrs

        involves: 129X1/SvJ * Black Swiss

• homeostasis/metabolism phenotype
• abnormal iron homeostasis
  • ferrokinetic studies showed normal rates of iron absorption, initial tissue iron distribution, and plasma iron turnover   (MGI Ref ID J:57730)
  • no differences were detected in cellular iron uptake; however, homozygotes displayed a significant impairment in hepatocyte iron efflux   (MGI Ref ID J:57730)
  • homozygotes showed elevated serum ferritin   (MGI Ref ID J:57730)
• • abnormal iron level
    • at 1 year of age, there was no evidence of diabetes, anemia, or neurological deficits despite iron accumulation in these sites   (MGI Ref ID J:57730)
  • • increased liver iron level
      • hepatic iron displayed a 3.5-fold increase in aceruloplasminemic mice due to loss of ferroxidase function   (MGI Ref ID J:71807)
      • progressive accumulation of parenchymal iron, reaching a 3- to 6-fold increase in the iron content of the liver by 1 year of age   (MGI Ref ID J:57730)
      • the liver displayed normal cellular architecture with abundant iron in reticuloendothelial cells   (MGI Ref ID J:57730)
    • increased spleen iron level
      • progressive accumulation of parenchymal iron, reaching a 3- to 6-fold increase in the iron content of the spleen by 1 year of age   (MGI Ref ID J:57730)
      • the spleen displayed normal cellular architecture with abundant iron in reticuloendothelial cells   (MGI Ref ID J:57730)
• abnormal liver copper level
  • aceruloplasminemic mice showed normal copper gastrointestinal absorption, hepatic uptake, and biliary copper excretion   (MGI Ref ID J:71807)
  • the copper content of brain, heart, spleen, and kidney was normal, and homozygotes exhibited normal copper-zinc superoxide dismutase activity in these tissues   (MGI Ref ID J:71807)
  • notably, hepatic copper content was significantly elevated in aceruloplasminemic mice   (MGI Ref ID J:71807)
• hematopoietic system phenotype
• *normal* hematopoietic system phenotype
  • the hemoglobin concentration remained normal relative to wild-type   (MGI Ref ID J:57730)
• • increased spleen iron level
    • progressive accumulation of parenchymal iron, reaching a 3- to 6-fold increase in the iron content of the spleen by 1 year of age   (MGI Ref ID J:57730)
    • the spleen displayed normal cellular architecture with abundant iron in reticuloendothelial cells   (MGI Ref ID J:57730)
• liver/biliary system phenotype
• abnormal liver copper level
  • aceruloplasminemic mice showed normal copper gastrointestinal absorption, hepatic uptake, and biliary copper excretion   (MGI Ref ID J:71807)
  • the copper content of brain, heart, spleen, and kidney was normal, and homozygotes exhibited normal copper-zinc superoxide dismutase activity in these tissues   (MGI Ref ID J:71807)
  • notably, hepatic copper content was significantly elevated in aceruloplasminemic mice   (MGI Ref ID J:71807)
• increased liver iron level
  • hepatic iron displayed a 3.5-fold increase in aceruloplasminemic mice due to loss of ferroxidase function   (MGI Ref ID J:71807)
  • progressive accumulation of parenchymal iron, reaching a 3- to 6-fold increase in the iron content of the liver by 1 year of age   (MGI Ref ID J:57730)
  • the liver displayed normal cellular architecture with abundant iron in reticuloendothelial cells   (MGI Ref ID J:57730)
• immune system phenotype
• increased spleen iron level
  • progressive accumulation of parenchymal iron, reaching a 3- to 6-fold increase in the iron content of the spleen by 1 year of age   (MGI Ref ID J:57730)
  • the spleen displayed normal cellular architecture with abundant iron in reticuloendothelial cells   (MGI Ref ID J:57730)

View Research Applications

Research Applications

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

Cp^tm1Hrs related

Hematological Research
Anemia, Iron Homeostasis Defects

Metabolism Research
Iron Metabolism

Mouse/Human Gene Homologs
aceruloplasminemia

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Cptm1Hrs
Allele Name		targeted mutation 1, Z Leah Harris
Allele Type		Targeted (knock-out)
Common Name(s)		Cp-; CpKO;
Mutation Made By		Zena Harris,   Johns Hopkins Univ School of Medicine
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Cp, ceruloplasmin
Chromosome		3
Gene Common Name(s)		CERP; CP-2; D3Ertd555e; DNA segment, Chr 3, ERATO Doi 555, expressed; RATCERP;
Molecular Note		A neomycin resistance cassette replaced a genomic fragment containing part of exon 17, intron 17 and part of exon 18, which include sequences encoding the residues essential for the formation of the trinuclear copper cluster of the encoded protein. Western blot analysis on serum derived from homozygous mice demonstrated that no detectable encoded protein was present, and activity assays on serum of homozygous mice confirmed that no functional protein is made from this allele. [MGI Ref ID J:57730]

Genotyping

Genotyping Information

Genotyping Protocols

Cp^tm1Hrs, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Additional References

Cp^tm1Hrs related

Cherukuri S; Potla R; Sarkar J; Nurko S; Harris ZL; Fox PL. 2005. Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2(5):309-19. [PubMed: 16271531]  [MGI Ref ID J:129671]

Cherukuri S; Tripoulas NA; Nurko S; Fox PL. 2004. Anemia and impaired stress-induced erythropoiesis in aceruloplasminemic mice. Blood Cells Mol Dis 33(3):346-55. [PubMed: 15528156]  [MGI Ref ID J:95008]

Dunaief JL. 2006. Iron induced oxidative damage as a potential factor in age-related macular degeneration: the Cogan Lecture. Invest Ophthalmol Vis Sci 47(11):4660-4. [PubMed: 17065470]  [MGI Ref ID J:123093]

Gray LW; Kidane TZ; Nguyen A; Akagi S; Petrasek K; Chu YL; Cabrera A; Kantardjieff K; Mason AZ; Linder MC. 2009. Copper proteins and ferroxidases in human plasma and that of wild-type and ceruloplasmin knockout mice. Biochem J 419(1):237-45. [PubMed: 19076073]  [MGI Ref ID J:149076]

Hadziahmetovic M; Dentchev T; Song Y; Haddad N; He X; Hahn P; Pratico D; Wen R; Harris ZL; Lambris JD; Beard J; Dunaief JL. 2008. Ceruloplasmin/hephaestin knockout mice model morphologic and molecular features of AMD. Invest Ophthalmol Vis Sci 49(6):2728-36. [PubMed: 18326691]  [MGI Ref ID J:136925]

Hadziahmetovic M; Song Y; Ponnuru P; Iacovelli J; Hunter A; Haddad N; Beard J; Connor JR; Vaulont S; Dunaief JL. 2011. Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice. Invest Ophthalmol Vis Sci 52(1):109-18. [PubMed: 20811044]  [MGI Ref ID J:171564]

Hadziahmetovic M; Song Y; Wolkow N; Iacovelli J; Grieco S; Lee J; Lyubarsky A; Pratico D; Connelly J; Spino M; Harris ZL; Dunaief JL. 2011. The oral iron chelator deferiprone protects against iron overload-induced retinal degeneration. Invest Ophthalmol Vis Sci 52(2):959-68. [PubMed: 21051716]  [MGI Ref ID J:171550]

Hahn P; Dentchev T; Qian Y; Rouault T; Harris ZL; Dunaief JL. 2004. Immunolocalization and regulation of iron handling proteins ferritin and ferroportin in the retina. Mol Vis 10:598-607. [PubMed: 15354085]  [MGI Ref ID J:93208]

Hahn P; Qian Y; Dentchev T; Chen L; Beard J; Harris ZL; Dunaief JL. 2004. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A 101(38):13850-5. [PubMed: 15365174]  [MGI Ref ID J:92620]

Harris ZL; Durley AP; Man TK; Gitlin JD. 1999. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci U S A 96(19):10812-7. [PubMed: 10485908]  [MGI Ref ID J:57730]

Kaneko H; Dridi S; Tarallo V; Gelfand BD; Fowler BJ; Cho WG; Kleinman ME; Ponicsan SL; Hauswirth WW; Chiodo VA; Kariko K; Yoo JW; Lee DK; Hadziahmetovic M; Song Y; Misra S; Chaudhuri G; Buaas FW; Braun RE; Hinton DR; Zhang Q; Grossniklaus HE; Provis JM; Madigan MC; Milam AH; Justice NL; Albuquerque RJ; Blandford AD; Bogdanovich S; Hirano Y; Witta J; Fuchs E; Littman DR; Ambati BK; Rudin CM; Chong MM; Provost P; Kugel JF; Goodrich JA; Dunaief JL; Baffi JZ; Ambati J. 2011. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471(7338):325-30. [PubMed: 21297615]  [MGI Ref ID J:170350]

Meyer LA; Durley AP; Prohaska JR; Harris ZL. 2001. Copper transport and metabolism are normal in aceruloplasminemic mice. J Biol Chem 276(39):36857-61. [PubMed: 11461924]  [MGI Ref ID J:71807]

Texel SJ; Camandola S; Ladenheim B; Rothman SM; Mughal MR; Unger EL; Cadet JL; Mattson MP. 2012. Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem 120(1):125-34. [PubMed: 22035068]  [MGI Ref ID J:179065]

Texel SJ; Zhang J; Camandola S; Unger EL; Taub DD; Koehler RC; Harris ZL; Mattson MP. 2011. Ceruloplasmin deficiency reduces levels of iron and BDNF in the cortex and striatum of young mice and increases their vulnerability to stroke. PLoS One 6(9):e25077. [PubMed: 21949858]  [MGI Ref ID J:177872]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

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	Control
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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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