LAUSR

The RAG1 and RAG2 proteins initiate the process of V(D)J recombination and therefore play an essential role in adaptive immunity. While null mutations in the RAG genes cause severe combined immune deficiency with lack of T and B cells (T−B− SCID) and susceptibility to life‐threatening, early‐onset infections, studies in humans and mice have demonstrated that hypomorphic RAG mutations are associated with defects of central and peripheral tolerance resulting in immune dysregulation. In this review, we provide an overview of the extended spectrum of RAG deficiencies and their associated clinical and immunological phenotypes in humans. We discuss recent advances in the mechanisms that control RAG expression and function, the effects of perturbed RAG activity on lymphoid development and immune homeostasis, and propose novel approaches to correct this group of disorders.