RAG1 gene

RAG1 (RAG1 is the acronym for Recombination Activating 1) is a protein-coding gene located on chromosome 11p12. The encoded protein is involved in antibody and T cell receptor V(D)J recombination. RAG1 and RAG2 together form the RAG1/2 complex, a V(D)J recombinase. However, the RAG 1/2 complex can also act as a transposase, inserting the DNA fragments produced during V(D)J recombination into an unrelated piece of DNA. This process is referred to as RAG transposition. It can potentially cause insertional mutagenesis, chromosomal translocations and genomic instability (Matthews AG et al. 2009).

Related pathways include the interleukin-7 pathway and the RET pathway.

Mutations of RAG can induce a broad spectrum of clinical and immunological diseases in humans, characterized by varying degrees of impairment of T and B cell development and alterations in immunity. The phenotypic heterogeneity of these diseases, correlates in many cases with different degrees of recombination activity of the mutant RAG proteins.

In humans, RAG deficiency was first recognized as a form of immune dysregulation known as Omenn syndrome. RAG deficiency is considered an autosomal recessive disorder. The disorder is usually detected in infants.

PFOA (substance belonging to per- and polyfluoroalkyl substances -PFAS-) decreases the expression of RAG1 and RAG2, genes involved in immunoglobulin and T cell receptor V(D)J recombination (Janssen AWF et al. 2022).

Complete loss of function in RAG1/2 leads to severe immunodeficiency in humans.

Hypomorphic RAG variants can retain partial recombination activity and lead to a distinct phenotype of combined immunodeficiencies with granuloma and/or autoimmunity (CID-G/A) (see Primary Immunodeficiencies below).

Initial attempts are being made to treat RAG deficiency with gene therapy (Villa A et al. 2019).

1. Janssen AWF et al (2022) Perfluoroalkyl substances (PFASs) decrease the expression of recombination-activating genes (RAG1 and RAG2) in human B lymphoma Namalwa cells. Arch Toxicol 97:457-468.

2. Matthews AG et al (2009) Regulation of RAG transposition. Adv Exp Med Biol 650:16-31.

3. Schatz DG et al (2011) Recombination centers and the orchestration of V(D)J recombination. Nat Rev Immunol 11:251-263.
4. Villa A et al (2019) RAG gene defects at the verge of immunodeficiency and immune dysregulation. Immunol Rev 287:73-90.