RGD Reference Report - Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia. - Rat Genome Database

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Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia.

Authors: Kenawi, Moussa  Rouger, Emmanuel  Island, Marie-Laure  Leroyer, Patricia  Robin, François  Rémy, Séverine  Tesson, Laurent  Anegon, Ignacio  Nay, Kévin  Derbré, Frédéric  Brissot, Pierre  Ropert, Martine  Cavey, Thibault  Loréal, Olivier 
Citation: Kenawi M, etal., FASEB J. 2019 Dec;33(12):13492-13502. doi: 10.1096/fj.201901106R. Epub 2019 Sep 27.
RGD ID: 38549582
Pubmed: PMID:31560858   (View Abstract at PubMed)
DOI: DOI:10.1096/fj.201901106R   (Journal Full-text)

Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague-Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp-/- rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp-/- rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non-transferrin-bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.-Kenawi, M., Rouger, E., Island, M.-L., Leroyer, P., Robin, F., Remy, S., Tesson, L., Anegon, I., Nay, K., Derbré, F., Brissot, P., Ropert, M., Cavey, T., Loréal, O. Ceruloplasmin deficiency does not induce macrophagic iron overload: lessons from a new rat model of hereditary aceruloplasminemia.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CpRatdecreased circulating ceruloplasmin level  IMP  RGD 
Cpem1AngRatdecreased circulating ceruloplasmin level  IMP  RGD 
SD-Cpem1Ang+/-Ratdecreased circulating ceruloplasmin level  IMP  RGD 
SD-Cpem1Ang-/-Ratdecreased circulating ceruloplasmin level  IMP compared to SD-Cpem1Ang+/- and wild-typeRGD 
CpRatdecreased circulating copper level  IMP  RGD 
Cpem1AngRatdecreased circulating copper level  IMP  RGD 
SD-Cpem1Ang+/-Ratdecreased circulating copper level  IMP  RGD 
SD-Cpem1Ang-/-Ratdecreased circulating copper level  IMP compared to SD-Cpem1Ang+/- and wild-typeRGD 
CpRatdecreased circulating iron level  IMP  RGD 
Cpem1AngRatdecreased circulating iron level  IMP  RGD 
SD-Cpem1Ang-/-Ratdecreased circulating iron level  IMP  RGD 
CpRatdecreased spleen iron level  IMP  RGD 
Cpem1AngRatdecreased spleen iron level  IMP  RGD 
SD-Cpem1Ang-/-Ratdecreased spleen iron level  IMP  RGD 
CpRatincreased circulating manganese level  IMP  RGD 
Cpem1AngRatincreased circulating manganese level  IMP  RGD 
SD-Cpem1Ang-/-Ratincreased circulating manganese level  IMP  RGD 
CpRatincreased circulating unsaturated transferrin level  IMP  RGD 
Cpem1AngRatincreased circulating unsaturated transferrin level  IMP  RGD 
SD-Cpem1Ang-/-Ratincreased circulating unsaturated transferrin level  IMP  RGD 
CpRatincreased liver iron level  IMP  RGD 
Cpem1AngRatincreased liver iron level  IMP  RGD 
SD-Cpem1Ang-/-Ratincreased liver iron level  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cp  (ceruloplasmin)
Cpem1Ang  (ceruloplasmin; CRISPR/Cas9 induced mutant1, Ang)

SD-Cpem1Ang+/-  (NA)
SD-Cpem1Ang-/-  (NA)

Objects referenced in this article
Strain SD-Cpem1Ang+/+ null Rattus norvegicus

Additional Information