SCID in Jack Russell terriers: A new animal model of DNA-PKcs deficiency

We recently described the incidence of a SCID disease in a litter of Jack R ussell terriers. In this study, we show that the molecular defect in these animals is faulty V(D)J recombination. Furthermore, we document a complete deficit in DNA-dependent protein kinase activity that can be explained by a marked diminution in the expression of the catalytic subunit DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We conclude that as is the ca se in C.B-17 SCID mice and in Arabian SCID foals, the defective factor in t hese SCID puppies is DNA-PKcs. In mice, it has been clearly established tha t DNA-PKcs deficiency produces an incomplete block in V(D)J recombination, resulting in "leaky" coding joint formation and only a modest defect in sig nal end ligation. In contrast, DNA-PKcs deficiency in horses profoundly blo cks both coding and signal end joining. Here, we show that although DNA-PKc s deficiency in canine lymphocytes results in a block in both coding and si gnal end joining, the deficit in both is intermediate between that seen in SCID mice and SCID foals. These data demonstrate significant species variat ion in the absolute necessity for DNA-PKcs during V(D)J recombination. Furt hermore, the severity of the V(D)J recombination deficits in these three ex amples of genetic DNA-PKcs deficiency inversely correlates with the relativ e DNA-PK enzymatic activity expressed in normal fibroblasts derived from th ese three species.