DCLRE1C

DCLRE1C, also known as Artemis, is a protein that in humans is encoded by the DCLRE1C gene. This protein is involved in DNA repair and V(D)J recombination, a process essential for the generation of immune system diversity. Mutations in DCLRE1C can lead to severe immunodeficiency disorders, including Omenn syndrome and Severe Combined Immunodeficiency (SCID), particularly the type known as Artemis-deficient SCID.

Function

DCLRE1C plays a critical role in the repair of DNA double-strand breaks (DSBs) through the non-homologous end joining (NHEJ) pathway. This pathway is crucial for the repair of DSBs that occur during DNA replication, meiosis, and as a result of exposure to ionizing radiation. DCLRE1C's role in V(D)J recombination, a process specific to lymphocyte development, involves the precise joining of variable (V), diversity (D), and joining (J) gene segments to generate the diverse repertoire of antibodies and T cell receptors necessary for the adaptive immune response.

Clinical Significance

Mutations in the DCLRE1C gene result in a failure to repair DNA DSBs and an inability to successfully undergo V(D)J recombination. This leads to a spectrum of immunodeficiency disorders, the most severe being SCID. Patients with Artemis-deficient SCID present with profound lymphopenia (reduced number of lymphocytes), absent or reduced T cells, B cells, and natural killer (NK) cells, making them highly susceptible to infections. Omenn syndrome is another condition associated with mutations in DCLRE1C, characterized by the presence of oligoclonal T cells, severe autoimmunity, and failure to thrive.

Genetic and Molecular Aspects

The DCLRE1C gene is located on chromosome 10 in humans. The Artemis protein has endonuclease and exonuclease activities, which are vital for its role in DNA repair and V(D)J recombination. The precise molecular mechanisms by which Artemis functions and is regulated are subjects of ongoing research, with implications for understanding the pathogenesis of related immunodeficiencies and potential therapeutic interventions.

Treatment and Management

Management of conditions resulting from DCLRE1C mutations, particularly Artemis-deficient SCID, involves preventing and treating infections, and may include bone marrow transplantation (BMT) or gene therapy. BMT from a matched sibling donor has been the standard treatment, offering the possibility of a cure by reconstituting a functional immune system. Gene therapy, aiming to correct the genetic defect in the patient's own cells, represents a promising alternative, with several clinical trials underway.