Molecular Pathology of Severe Combined Immunodeficiency in Mice, Horses, and Dogs

Abstract

Severe combined immunodeficiency (SCID) is an inherited disorder of humans, mice, horses, and dogs, in which affected individuals are incapable of generating antigen-specific immune responses. It occurs when lymphocyte precursors fail to differentiate into mature lymphocytes because of mutations within recombinase-activating genes 1 and 2 or within the genes encoding deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PK). It also occurs when differentiated lymphocytes are incapable of completing signal transduction pathways because of defects in cell surface receptors for interleukins (IL). A spontaneous mutation in DNA-PKcs of BALB/c mice results in SCID, as do experimentally induced mutations in RAG1 and RAG2. SCID in horses results from a spontaneous mutation in DNA-PKcs. Two molecular mechanisms account for SCID in dogs. Jack Russell Terriers have a mutation within the DNA-PKcs gene, whereas Cardigan Welsh Corgi and Basset Hound have different defects in the gene encoding the γ chain that is common to the receptors for IL-2, −4, −7, −9, −15, and −21. The location of the mutation within target genes influences the spectrum of diseases observed in affected animals.