title: N-terminal truncated human RAG1 proteins can direct T-cell receptor but not immunoglobulin gene rearrangements.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus University Rotterdam, University Hospital Rotterdam-Dijkzigt, Rotterdam, The Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: Noordzij
authors.forename: N S
authors.initials: NS
authors.lastname: Verkaik
authors.forename: N G
authors.initials: NG
authors.lastname: Hartwig
authors.forename: R
authors.initials: R
authors.lastname: de Groot
authors.forename: D C
authors.initials: DC
authors.lastname: van Gent
authors.forename: J J
authors.initials: JJ
authors.lastname: van Dongen
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D018388:Codon, Terminator; D003241:Consanguinity; D017809:Fatal Outcome; D005260:Female; D015321:Gene Rearrangement; D015329:Gene Rearrangement, T-Lymphocyte; D005803:Genes, Immunoglobulin; D016654:Genes, RAG-1; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology*; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology; D016130:Immunophenotyping; D007231:Infant, Newborn; D008297:Male; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018388:Codon, Terminator; D018398:Homeodomain Proteins; C064658:RAG-1 protein