Recombination activating gene 1 also known as RAG-1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''RAG1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
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
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
and
T-cell receptor V(D)J recombination
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell rece ...
. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires
RAG-2
The recombination-activating genes (RAGs) encode parts of a protein complex that plays important roles in the rearrangement and recombination of the genes encoding immunoglobulin and T cell receptor molecules. There are two recombination-activ ...
. The
RAG-1/2 complex recognizes
recombination signal sequences (RSSs) 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
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
and
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
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
Omenn syndrome is an autosomal recessive severe combined immunodeficiency. It is associated with hypomorphic mutation, hypomorphic missense mutations in immunologically relevant genes of T-cells (and B-cells) such as recombination activating genes ...
. RAG deficiency is considered an
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disease. The disorder is generally identified in infants. Complete loss-of-function in RAG1/2, the main components responsible for V(D)J 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 (CID-G/A), as well as other milder forms, such as antibody deficiency, Idiopathic CD4
+ T lymphopenia or vasculitis. RAG deficiency can be measured by in vitro quantification of recombination activity.
71 RAG1 and 39 RAG2 variants have been functionally assayed to date (2019) (less than 10% of the potential point mutations that may cause disease). However, top candidate variants have been ranked by their predicted clinical relevance.
References
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