NONSENSE MUTATION AT TYR-4046 IN THE DNA-DEPENDENT PROTEIN-KINASE CATALYTIC SUBUNIT OF SEVERE COMBINED IMMUNE-DEFICIENCY MICE

The severe combined immune deficiency (SCID) mouse was reported as an animal model for human immune deficiency. Through the course of severa l studies, the DNA-dependent protein kinase catalytic subunit (DNA-PKc s) gene came to be considered a candidate for the SCID-responsible gen e, We isolated an ORF of the murine DNA-PKcs gene from SCID mice and t heir parent strain C.B-17 mice and determined the DNA sequences. The O RF of the murine DNA-PKcs gene contained 4125-aa residues and bad 78.9 % homology with the human DNA-PKcs gene. A particularly important find ing is that a T to A transversion results in the substitution of termi nation codon in SCID mice for the Tyr-4046 in C.B-17 mice. No other mu tation was detected in the ORF of the gene, The generality of this tra nsversion was confirmed using four individual SCID and wild-type mice, The substitution took place in the phosphatidylinositol 3-kinase doma in, and the mutated gene encodes the truncated products missing 83 res idues of wild-type DNA-PKcs products. Furthermore, the quantity of DNA -PKcs transcript in wild-type and SCID cells was almost equal, These o bservations indicate that the DNA-PKcs gene is the SCID-responsible ge ne itself and that the detected mutation leads to the SCID aberration.