What is the role of RAG1 and RAG2 proteins in the pathophysiology of severe combined immunodeficiency (SCID)?

Updated: Aug 11, 2020
  • Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement, which is followed by light-chain gene rearrangement. Once the rearrangement process is finished, recombination signal sequences that served to approximate the different genes from each other are removed with the help of the RAG1 and RAG2 proteins. RAG1/RAG2 deficiency is responsible for the B- and T-cell maturation defects in some persons with SCID.

Omenn syndrome is a rare, inherited disorder with a pooly understood pathogenesis. In this condition, mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) cause a defect in the VDJ rearrangement that is needed for mature B-cells and T-cells to develop, resulting in a paradoxical combination of immunodeficiency and immune dysregulation.

In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1. [4] Mice bred from this animal exhibited major manifestations of Omenn syndrome, including high numbers of memory-phenotype T cells, hepatosplenomegaly and eosinophilia, oligoclonal T cells, and elevated levels of IgE. When the CD4+ T cells in the mice were depleted, a reduction in their IgE levels resulted. Thus, Khiong et al concluded that these "memory mutant" mice may be a model for human Omenn syndrome, and that many manifestations of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells. [4]

Artemis deficiency (with mutations in the Artemis protein that result in defective VDJ recombination) decreases both B and T cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in defective circulating T- and B-cells and serum immunoglobulins.

Bloom syndrome, or congenital telangiectatic erythema, results from a mutation in the helicase enzyme called BLM RecQ. This mutation leads to defects in DNA repair and is characterized by an increased risk of malignancy and radiation sensitivity.

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