The scid MutationThe 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 Prkdcscid allele is an T-to-A transversion point mutation at codon 4095, which creates a premature stop codon2,3. 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 Prkdcscid 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 Prkdcscid 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.
Development of some functional T and B cellsScid mice can become "leaky", meaning that some functional T and B cells can develop. This appears to arise from a low frequency of V(D)J coding joint formation, with recombination often occurring at sections of short homology5. This leakiness varies by the strain/stock background, with age and by housing conditions, with the original C.B-17 scid actually being the leakiest strain.
IgG+M antibody levels in the sera from aged NOG (7-10 months old) and NOD-scid (6-7 months old) mice were measured by ELISA. In C.B-17- scid (6-9 months old) mice, serum IgG+M+A antibody levels measured in 1989 were used in this figure.
While the C.B-17 scid may be fine for short term experiments, longer term experiments may be challenging. The ICR scid is a less leaky alternative on an outbred background. As an outbred, ICR scid mice are larger, hardier and less expensive. However, the outbred background can introduce more experimental variation. Note that larger animals also require additional compound for dosing. In general, the ICR scid is an excellent value. The NOD scid is special in that the NOD inbred strain background imparts some additional immunodeficiency. NOD mice lack complement C5, and they have defects in macrophage and dendritic cell function. They are also on the less leaky end of the spectrum. This makes it the most immunocompromised of the basic scid models. The major drawback to the NOD scid is that it develops thymic lymphomas at a high rate, so the effective lifespan is somewhere between 7-9 months. Longer term studies are not advisable in the NOD scid strain.
The scid mutation introduces a few other special considerations. As this mutation affects DNA repair, mice carrying Prkdcscid are more sensitive to radiation. They are thus not ideal choices for experiments involving clinically relevant radiation doses. Scid mice may also be more sensitive to drugs which damage DNA. When using drugs with this type of mechanism, a tolerance study is recommended to help choose appropriate doses for follow on efficacy studies.
Knockout of the Rag2 gene
The basic mechanism of V(D)J recombination.
Adapted from Nature Reviews Genetics.
So why isn't the Rag2 used as widely as the scid? Much of this can be traced to historical accident and the weight of the publication record. The scid got a head start! But researchers are starting to realize the advantages of the Rag2 knockout and choose it for experiments where a scid might have drawbacks. Use of Rag2 knockouts has increased significantly, and that trend is likely to continue. For your next experiment, consider carefully the unique characteristics of these two models and determine which best meets your needs.
Take advantage of our Smart Select Program. Smart Select is a complimentary animal model trial program allowing you to trial up to 20 animals in your facility at no cost to your organization. Learn more today.