Recombination activating 1 (RAG1)

Recombination activating 1 (RAG1) is a critical enzyme that, in complex with RAG2, initiates V(D)J recombination, the site-specific recombination process required for the generation of diverse T-cell receptors and immunoglobulins (UniProt: P15918). RAG1 acts as the catalytic subunit, providing both the DNA-binding domain for recombination signal sequences (RSS) and the endonuclease activity necessary to create double-strand breaks (NCBI Gene: 5896). Deficiencies in RAG1 function lead to a spectrum of primary immunodeficiencies, most notably RAG1-deficient severe combined immunodeficiency (SCID), characterized by a lack of mature T and B cells, and Omenn syndrome, which involves restricted, oligoclonal T-cell expansion and autoimmunity (PubMed: 26733497). As a therapeutic target, RAG1 is primarily addressed through gene therapy approaches rather than traditional pharmacology. Current clinical efforts focus on ex vivo lentiviral gene correction of hematopoietic stem cells to restore functional lymphocyte development in affected infants (ClinicalTrials.gov: NCT04797260).

Other names

RAG-1Recombination activating protein 1RING finger protein 74RNF74

Gene addition/augmentation via lentiviral-mediated delivery of a functional RAG1 expression cassette into autologous hematopoietic stem and progenitor cells (HSPCs) to restore lymphocyte development (ClinicalTrials.gov: NCT04797260).