The proteins encoded by RAG1 and RAG2 can initiate gene recombination by site-specific cleavage of DNA in immunoglobulin and T-cell receptor (TCR) loci. We identified a new homozygous RAG1 gene mutation (631delT) that leads to a premature stop codon in the 5' part of the RAG1 gene. The patient carrying this 631delT RAG1 gene mutation died at the age of 5 weeks from an Omenn syndrome-like T(+)/B(- )severe combined immunodeficiency disease. The high number of blood T-lymphocytes (55 x 10(6)/mL) showed an almost polyclonal TCR gene rearrangement repertoire not of maternal origin. In contrast, B-lymphocytes and immunoglobulin gene rearrangements were hardly detectable. We showed that the 631delT RAG1 gene can give rise to an N-terminal truncated RAG1 protein, using an internal AUG codon as the translation start site. Consistent with the V(D)J recombination in T cells, this N-terminal truncated RAG1 protein was active in a plasmid V(D)J recombination assay. Apparently, the N-terminal truncated RAG1 protein can recombine TCR genes but not immunoglobulin genes. We conclude that the N-terminus of the RAG1 protein is specifically involved in immunoglobulin gene rearrangements.

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Keywords *Gene Rearrangement, *Gene Rearrangement, T-Lymphocyte, *Genes, Immunoglobulin, *Genes, RAG-1, B-Lymphocytes/immunology, Codon, Terminator, Consanguinity, Fatal Outcome, Female, Homeodomain Proteins/*genetics/*immunology, Homozygote, Humans, Immunologic Deficiency Syndromes/*genetics/immunology, Immunophenotyping, Infant, Newborn, Male, Sequence Deletion, T-Lymphocytes/*immunology
Persistent URL
Journal Blood
Noordzij, J.G, Verkaik, N.S, Hartwig, N.G, de Groot, R, van Gent, D.C, & van Dongen, J.J.M. (2000). N-terminal truncated human RAG1 proteins can direct T-cell receptor but not immunoglobulin gene rearrangements. Blood. Retrieved from