B. Corneo et al., Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency, J BIOL CHEM, 275(17), 2000, pp. 12672-12675
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.