RAG2 gene

RAG2 (Recombination Activating 2) is a protein-coding gene located on chromosome 11p12. The RAG2 gene encodes a protein of the same name (RAG2) that is involved in the activation of immunoglobulin V-D-J recombination. 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. In this complex, RAG2 is not the catalytic component. However, RAG2 is required for all known catalytic activities mediated by RAG1.

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).

The RAG complex also plays a role in allelic exclusion of pre-B cells, a process that results in the expression of a single allele of the immunoglobulin heavy chain to enhance clonality and monospecific recognition by the B cell antigen receptor (BCR) expressed on individual B lymphocytes. Introduction of DNA breaks by the RAG complex on one immunoglobulin allele results in ATM-dependent repositioning of the other allele in pericentromeric heterochromatin, preventing access to the RAG complex and recombination of the second allele.

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.

Complete loss of function in RAG1/2 leads to 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 (CID-G/A).

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

1. Schatz DG et al (2011) Recombination centres and the orchestration of V(D)J recombination. Nat Rev Immunol 11:251-263
2. Matthews AG et al (2009) Regulation of RAG transposition. Adv Exp Med Biol 650:16-31.
3. Villa A et al. (2019) RAG gene defects at the verge of immunodeficiency and immune dysregulation. Immunol Rev 287:73-90.