Alt. symbols: RNF74 | MGC43321

Approved name: recombination activating 1
Alt. names: recombination activating gene 1 | recombination activating protein 1, RING finger protein 74, V(D)J recombination-activating protein 1

Location: 11p12: 36510372 - 36593156 (+)
Gene type: protein_coding, 6 transcripts.

Scores: LoFtool: 0.156000 | pLI: 0.00189800 | LOEUF: 0.736

HGNC: 9831

NCBI: 5896, RefSeq: NG_007528.1

Ensembl: ENSG00000166349.11

LRG_98 | Status: public

OMIM: 179615

Expression | ProteinAtlas

The RAG1 gene encodes the catalytic subunits of the RAG complex. This complex is a tetramer formed by a dimer of RAG1 subunits and two RAG2 subunits. The RAG complex is crucial for the maturation of lymphocytes (B cells and T cells) as it is involved in the rearrangement and recombination of the genes that encode the immunoglobulins and the T cell receptors (V(D)J recombination). This process is important because it generates the diversity of antibodies and receptors that is needed to recognise a wide variety of antigens. These proteins are encoded by genes made of fragments known as variable (V), diversity (D), and joining (J) segments. Specifically, RAG1 binds to conserved recombination signal sequences (RSS) of the DNA and catalyses a double-strand DNA break between the RSS and the adjacent coding segment, during the V(D)J recombination phase. In addition to its endonuclease activity, RAG1 also acts as an E3 ubiquitin-protein ligase that mediates mono-ubiquitination of histone H3, which is required for the joining step of V(D)J recombination. Although RAG2 is not a catalytic component, it is required for all known catalytic activities of the complex. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and mono-specific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. The RAG1 protein is composed of 1040 amino acids, which are encoded by a single exon, and it is almost twice the size of RAG2. RAG1 has an N-terminal domain that interacts with importin alpha-1, a DNA-binding domain, 2 Zinc-finger domains and several Zinc-binding sites.

There are more than 70 loss-of-function variants described in RAG1 that cause severe combined immunodeficiency or Omenn syndrome, when both alleles of the gene are affected. Therefore, this condition is inherited in an autosomal recessive manner and is characterized by almost absent protection against bacterial, viral, or fungal infections, and by symptoms of autoimmunity that can be fatal in childhood. Few isolated cases of patients with a phenotype suggestive of common variable immunodeficienc y caused by mutations in RAG1 has also been described (Abraham et al. 2013, Abolhassani et al. 2014). Mutations in the RAG2 gene (which forms the RAG complex with RAG1) cause the same type of severe immunodeficiency as that caused by mutations in RAG1. Additionally, the mouse model of the hypomorphic variant p.Ser723Cys in RAG1 showed that mice homozygous for the mutation had an early lymphopoiesis defect and a reduction in V(D)J recombination, due to a low recombinase activity of Rag1. On the other hand, heterozygotes for the p.Ser723Cys variant exhibited accelerated senescence of the immune system in older age. This accelerated immune dysfunction was also due to a failure of B and T lymphocyte maturation, and to lower levels of V(D)J recombination in thymocytes and bone marrow cells (Giblin et al., 2009). All kinds of pathogenic variants have been described for the gene (point mutations, deletions, insertions) that lead to a loss of function of the protein, either because they affect an important amino acid residue (missense variants) or because a functional protein cannot be synthesized (nonsense or frameshift mutations). Missense mutations affect evolutionarily conserved residues belonging to virtually all known functional domains of the protein. The variants described that affect residues of the N-terminal domain that interact alpha-1 importin (aa. 1-288) are scarce and therefore their pathogenicity is more questionable. [Load More]