Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency

The V(D)J recombination, which leads to the somatic rearrangement of variab le, diversity, and joining segments, is the mechanism accountable for the d iversity of T cell receptor- and Ig-encoding genes. The products of the RAG 1 and RAG2 genes are the lymphoid-specific factors responsible for the init iation of the V(D)J recombination through the generation of a DNA double st rand break. RAGI or RAG2 gene inactivation in the mouse leads to abortion o f the V(D)J rearrangement process, early block in both T and B cell maturat ion, and, ultimately, to severe combined immune deficiency (SCID). A human SCID condition is also characterized by an absence of mature T and B lympho cytes and is associated with mutations in either RAG1- or RAG2-encoding gen es. Based on the predicted beta-propeller three-dimensional structure model for RAGS, we found that six out of the seven mutations described to date i n T-B-SCID patients are clustered on one side of the propeller, in regions exposed to solvent. This finding reinforces the biological significance of this predicted model and suggests that RAG1 interacts with RAGS on one of t he side of the scaffold formed by the beta-propeller.