Prkcdg510s/g510s mice – preclinical model of lupus

We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of SLE in the mouse genome, by means of CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulate the human phenotype, presenting with glomerulonephritis, splenomegaly, and various serum autoantibodies, including anti-nuclear, and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell autonomous role of PRKCD in immune regulation. The penetrance of the lupus phenotype is 100% in this mouse model.

Interest / Relevance: Systemic lupus erythematosus (SLE) is a devastating autoimmune disease whose symptoms may include joint pain, fever, skin rash and organ damage. SLE is currently incurable and the therapeutic arsenal to treat SLE remains very limited, without specific treatment for the different clinical forms of the disease. Autosomal recessive PRKCD deficiency has previously been associated with the development of severe forms of systemic lupus erythematosus (SLE) in human patients. PrkcdG510S/G510S mice recapitulate the human phenotype, presenting with glomerulonephritis, splenomegaly, and various serum autoantibodies, including anti-nuclear, and had reduced lifespan. Treatment of mice with rapamycin, a specific mTORC1 inhibitor, significantly improves autoimmune symptoms. This demonstrates the role of the mTOR pathway in the lupus phenotype in PrkcdG510S/G510S mice and shows that this mouse model can be used to test the efficacy of novel lupus therapies.
Keywords: Lupus mouse model, autoimmunity mouse model, preclinical model of lupus
Publications:
1. Moreews M Mathieu AL Pouxvielh K Reuschlé Q Drouillard A Dessay P Meignien M Zhang J Fallone L Rousseaux N Ainouze M Rey A Omarjee O Decembre E Lenief V Djebali S Thaunat O Dreux M Genestier L Defrance T Soulas-Sprauel P Marçais A Walzer T* Belot A*. mTOR activation underlies enhanced B cell proliferation and autoimmunity in PrkcdG510S/G510S mice. Submitted 2. Belot A Kasher PR Trotter EW Foray AP Debaud AL Rice GI Szynkiewicz M Zabot MT Rouvet I Bhaskar SS Daly SB Dickerson JE Mayer J O'Sullivan J Juillard L Urquhart JE Fawdar S Marusiak AA Stephenson N Waszkowycz B W Beresford M Biesecker LG C M Black G René C Eliaou JF Fabien N Ranchin B Cochat P Gaffney PM Rozenberg F Lebon P Malcus C Crow YJ Brognard J Bonnefoy N. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation.Arthritis Rheum. 2013 Aug65(8):2161-71. doi: 10.1002/art.38008.

Reference:

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Thierry WALZER
Inserm Transfert
Research Tools
Species: Mouse
Genotype: PrkcdG510S/G510S mice
Strain: PrkcdG510S/G510S
Genetic Background: C57BL/6
Applications: Preclinical model of lupus
Rare disease:
Last update: 04/01/2023

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