RAG

RAG1 and RAG2 are lymphocyte-specific enzymes that initiate V(D)J recombination, the process by which immunoglobulin and T-cell receptor gene segments (Variable, Diversity, Joining) are rearranged to generate the vast diversity of antigen receptors needed for adaptive immunity. RAG proteins recognize recombination signal sequences (RSS) flanking the V, D, and J gene segments and introduce double-strand DNA breaks, which are then repaired by non-homologous end joining (NHEJ) machinery, including proteins like Artemis, DNA-PKcs, XRCC4, and DNA ligase IV. Complete loss-of-function mutations in RAG1 or RAG2 result in a failure of both B and T lymphocyte maturation, leading to T-B-NK+ SCID, a life-threatening immunodeficiency presenting in infancy with recurrent severe infections, failure to thrive, and absence of thymic shadow on chest X-ray. Partial (hypomorphic) RAG mutations can cause Omenn syndrome, characterized by erythroderma, lymphadenopathy, eosinophilia, and elevated IgE, due to residual but dysregulated T-cell function with oligoclonal, autoreactive T cells. Diagnosis involves flow cytometry showing absent B and T cells with normal or elevated NK cells, and genetic testing confirms RAG1/RAG2 mutations. Treatment requires hematopoietic stem cell transplantation, and Artemis deficiency (a downstream NHEJ defect) presents similarly but with additional radiosensitivity. This topic is high-yield for USMLE Step 1 in immunology, particularly for distinguishing types of SCID and understanding V(D)J recombination mechanisms.