RAG1


Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene.
The RAG1 and RAG2 genes are largely conserved in humans. 55.99% and 55.98% of the encoded amino acids contain no reported variants, respectively.

Function

The protein encoded by this gene is involved in antibody and T-cell receptor VJ recombination. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG-2. The RAG-1/2 complex recognizes recombination signal sequences that flank the V, D and J regions in the genes that encode the heavy and light chains of antibodies and components of T-cell receptors. The complex binds to the RSSs and nicks the DNA. This leads to the removal of the intervening DNA and the eventual ligation of the V, D and J sequences. Defects in this gene can cause several different diseases.

Clinical significance

Because of these effects, Rag1 deletion is used in mouse models of disease to impair T cell and B cell development, and functionally deletes mature T and B cells from the immune system.
In humans, RAG deficiency was first recognised as a form of immune dysregulation known as Omenn syndrome. RAG deficiency is considered an autosomal recessive disease. The disorder is generally identified in infants. Complete loss-of-function in RAG1/2, the main components responsible for VJ recombination activity, produces severe immunodeficiency in humans. Hypomorphic RAG variants can retain partial recombination activity and result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity. RAG deficiency can be measured by in vitro quantification of recombination activity. 71 RAG1 and 39 RAG2 variants have been functionally assayed to date . However, top candidate variants have been ranked by their predicted clinical relevance.