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

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

Submit Data | Help | Video Tutorials | News | Publications | Download | REST API | Citing RGD | Contact

General

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

Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
decreased circulating ceruloplasmin level		IMP		38549582; 38549582; 38549582		RGD
decreased circulating ceruloplasmin level		IMP		38549582	compared to SD-Cpem1Ang+/- and wild-type	RGD
decreased circulating copper level		IMP		38549582; 38549582; 38549582		RGD
decreased circulating copper level		IMP		38549582	compared to SD-Cpem1Ang+/- and wild-type	RGD
decreased circulating iron level		IMP		38549582; 38549582; 38549582		RGD
decreased spleen iron level		IMP		38549582; 38549582; 38549582		RGD
increased circulating manganese level		IMP		38549582; 38549582; 38549582		RGD
increased circulating unsaturated transferrin level		IMP		38549582; 38549582; 38549582		RGD
increased liver iron level		IMP		38549582; 38549582; 38549582		RGD

Objects Annotated

Genes (Rattus norvegicus)

Cp (ceruloplasmin)

Cp^em1Ang (ceruloplasmin; CRISPR/Cas9 induced mutant1, Ang)

Strains

SD-Cp^em1Ang+/- (NA)

SD-Cp^em1Ang-/- (NA)

Objects referenced in this article

Strain	SD-Cp^em1Ang+/+	null	Rattus norvegicus

Additional Information