N-terminal truncated human RAG1 proteins can direct T-cell receptor but not immunoglobulin gene rearrangements

The proteins encoded by RAG1 and RAG2 can initiate gene recombination by si te-specific cleavage of DNA in immunoglobulin and T-cell receptor (TCR) loc i. We identified a new homozygous RAG1 gene mutation (631delT) that leads t o a premature stop codon in the 5' part of the RAG1 gene. The patient carry ing this 631delT RAG1 gene mutation died at the age of 5 weeks from an Omen n syndrome-like T+/B- severe combined immunodeficiency disease. The high nu mber of blood T-lymphocytes (55 x 10(6)/ml) showed an almost polyclonal TCR gene rearrangement repertoire not of maternal origin. In contrast, B-lymph ocytes and immunoglobulin gene rearrangements were hardly detectable. We sh owed that the 631delT RAG1 gene can give rise to an N-terminal truncated RA G1 protein, using an internal AUG codon as the translation start site. Cons istent with the V(D)J recombination in T cells, this N-terminal truncated R AG1 protein was active in a plasmid V(D)J recombination assay. Apparently, the N-terminal truncated RAG1 protein can recombine TCR genes but not immun oglobulin genes. We conclude that the N-terminus of the RAG1 protein is spe cifically involved in immunoglobulin gene rearrangements. (Blood. 2000;96:2 03-209) (C) 2000 by The American Society of Hematology.