V(D)J recombination-activating protein 1 (RAG1) (RAG1)

V(D)J recombination-activating protein 1 (RAG1) is a critical enzyme that, in complex with RAG2, initiates the recombination of antigen receptor genes in developing B and T lymphocytes (UniProt P15918). By inducing site-specific DNA double-strand breaks at recombination signal sequences, RAG1 facilitates the assembly of diverse V, D, and J gene segments, which is essential for a functional adaptive immune system (PubMed: 25703142). Mutations in the RAG1 gene lead to severe combined immunodeficiency (SCID) and Omenn syndrome, conditions characterized by the absence of mature lymphocytes and extreme vulnerability to infections (NIH: Genetic and Rare Diseases Information Center). In the context of hematopoietic stem cells (HSCs), RAG1 is a primary target for ex vivo gene therapy, where a patient's own HSCs are modified to carry a functional version of the gene (PubMed: 31649108). Current therapeutic approaches focus on using lentiviral vectors or CRISPR/Cas9 technology to restore RAG1 function, thereby allowing for the successful development of T and B cells following autologous transplantation (ClinicalTrials.gov: NCT04797988).

Other names

Recombination activating gene 1RAG-1RNF74RING finger protein 74Recombination activating 1

Restoration of V(D)J recombination activity through the delivery of a functional RAG1 expression cassette or precise gene correction in hematopoietic stem cells, enabling the maturation of T and B lymphocytes.