Scid mutants or Rag2 Knockouts - Which Immunodeficient Model is Best for Your Study?

Mice with compromised immune systems are invaluable research tools. Starting with the discovery of athymic nude mice in the 1960's, the portfolio of immunodeficient rodents has grown significantly. Although these models are used quite widely, not all researchers understand their intrinsic characteristics and how those characteristics impact experimental outcomes. Learn more about two key immunodeficient models, scid mutants and Rag2 knockouts, and how to choose the most appropriate model for your study.

The scid mutation

The scid mutation was first discovered in 1983 by Mel Bosma at the Fox Chase Cancer Center¹. Scid stands for severe combined immunodeficiency. This mutation arose spontaneously in a colony of C.B-17 mice that Bosma was using for studies of immunoglobulin isotypes. The scid mutation is a mutation in the Prkdc gene, protein kinase, DNA activated, catalytic polypeptide. The specific genetic alteration in the Prkdc^scid allele is an T-to-A transversion point mutation at codon 4095, which creates a premature stop codon^2,3. Prkdc is involved in DNA repair via non-homologous end joining (NHEJ). V(D)J recombination, which rearranges the genetic components of antibodies and T cell receptors during B and T cell development, requires NHEJ for proper function.

Due to the NHEJ defect in Prkdc^scid mutants, scid mice lack both mature T and B cells. As one of the first immunodeficient models available, that original scid, the C.B-17 scid, was disseminated worldwide and has been used in thousands of studies. The Prkdc^scid allele was also backcrossed onto other strain and stock backgrounds to make models such as the outbred ICR scid and the NOD scid. Among the scids that Taconic Biosciences offers, the C.B-17 scid is the most requested, primarily due to the wealth of historical data and publications using the strain. But it may not always be the best experimental choice.

References:

1. Bosma GC, Custer RP, Bosma MJ. (1983) A severe combined immunodeficiency mutation in the mouse. Nature. 301(5900):527-30.
2. Blunt T, Gell D, Fox M, Taccioli GE, Lehmann AR, Jackson SP, Jeggo PA. (1996) Identification of a nonsense mutation in the carboxyl-terminal region of DNA-dependent protein kinase catalytic subunit in the scid mouse. Proc Natl Acad Sci U S A. 93(19):10285-90.
3. Araki R, Fujimori A, Hamatani K, Mita K, Saito T, Mori M, Fukumura R, Morimyo M, Muto M, Itoh M, Tatsumi K, Abe M. (1997) Nonsense mutation at Tyr-4046 in the DNA-dependent protein kinase catalytic subunit of severe combined immune deficiency mice. Proc Natl Acad Sci U S A. 94(6):2438-43.
4. Lieber MR. (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 79:181-211.
5. Kotloff DB, Bosma MJ, Ruetsch NR. (1993) V(D)J recombination in peritoneal B cells of leaky scid mice. J Exp Med. 178(6):1981-94.
6. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, et al. (1992) RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 68(5):855-67.