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DCLRE1C
DNA cross-link repair 1C
DCLRE1C is located on the short (p) arm of chromosome 10, at band 10p13. Arm ratio per GRCh38 - banding schematic.
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Overview
DCLRE1C (DNA cross-link repair 1C) encodes a nuclease protein commonly known as Artemis, which is fundamental to a DNA repair pathway called non-homologous end joining. This pathway is particularly important during V(D)J recombination, the process by which developing lymphocytes assemble functional antibody and T-cell receptor genes. Without properly functioning Artemis, the immune system cannot generate the diverse repertoire of B cells and T cells needed to recognise and respond to pathogens. Pathogenic variants in DCLRE1C follow an autosomal recessive inheritance pattern, meaning two altered copies-one inherited from each parent-are required to cause disease.
What the gene does
The Artemis protein functions as an endonuclease with specialised activity on DNA hairpin structures. During V(D)J recombination in developing lymphocytes, the RAG recombinase creates hairpin-sealed coding ends at gene segments that must be joined together. Artemis, when activated by interaction with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), cleaves these hairpin structures to open the DNA ends for subsequent processing and ligation. This opening step is essential for joining variable (V), diversity (D), and joining (J) gene segments into functional antigen receptor genes. Beyond its role in immune development, Artemis also participates in general DNA double-strand break repair, helping cells maintain genomic stability after exposure to ionising radiation or other DNA-damaging agents. The protein's nuclease activity is tightly regulated to ensure DNA is cleaved only at appropriate sites and times during the repair process.
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Chromosome location
DCLRE1C is located on the short arm of chromosome 10 at position 10p13. The gene spans approximately 16 kilobases of genomic DNA and contains 15 exons that are transcribed and spliced to produce the messenger RNA template for Artemis protein synthesis.
Protein structure
The Artemis protein comprises 692 amino acids and contains a metallo-beta-lactamase fold that provides its nuclease catalytic activity. The protein includes two disordered regions: one spanning amino acids 504-555 and another from amino acids 640-664. These intrinsically disordered segments may facilitate protein-protein interactions or regulatory modifications. The C-terminal region of Artemis interacts with DNA-PKcs, an association required for both activation of the nuclease domain and recruitment to sites of DNA damage.
Key variants
Pathogenic variants in DCLRE1C are distributed throughout the gene and include missense substitutions, nonsense mutations, small insertions or deletions causing frameshifts, and splice-site alterations. Many disease-causing variants disrupt the nuclease catalytic domain or interfere with the protein's ability to interact with DNA-PKcs. The severity of immune deficiency can vary depending on whether the variant completely abolishes protein function or permits some residual activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.109+1G>T | - | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.1147C>T | p.Arg383Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.161+2T>G | - | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.352G>T | p.Gly118Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.356C>G | p.Ser119Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.571C>T | p.Arg191Ter | Pathogenic | ★★★☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.1103del | p.Lys368fs | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.1156+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
c.184_191del | p.Ser62fs | Pathogenic/Likely pathogenic | ★★☆☆ | Histiocytic medullary reticulosis |
c.353G>T | p.Gly118Val | Pathogenic/Likely pathogenic | ★★☆☆ | Severe combined immunodeficiency due to DCLRE1C deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in DCLRE1C cause a form of severe combined immunodeficiency (SCID) characterised by absent or severely reduced T cells and B cells, though natural killer cells may be present (T-B-NK+ SCID phenotype). Affected infants typically present in the first months of life with recurrent severe infections, failure to thrive, and heightened sensitivity to ionising radiation. This radiosensitivity distinguishes Artemis-deficient SCID from other SCID subtypes and has important implications for conditioning regimens before haematopoietic stem cell transplantation. Some individuals with hypomorphic variants that retain partial protein function may present later in childhood with a milder combined immunodeficiency phenotype rather than classic SCID.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DCLRE1C variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
DCLRE1C is included on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical relevance in the UK healthcare system. The gene appears on the Primary immunodeficiency or monogenic inflammatory bowel disease panel (version R15), the Infantile enterocolitis & monogenic inflammatory bowel disease panel, and the Gastrointestinal epithelial barrier disorders panel, all with a green classification indicating strong evidence for clinical validity. DCLRE1C is also listed on the COVID-19 research panel, highlighting interest in immune-related genes during pandemic research efforts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is DCLRE1C-related immunodeficiency inherited?
DCLRE1C-related severe combined immunodeficiency follows an autosomal recessive pattern. This means an affected individual must inherit one pathogenic variant from each parent. Parents who each carry one altered copy are typically healthy but have a 25% chance with each pregnancy of having an affected child.
Why are individuals with DCLRE1C variants particularly sensitive to radiation?
The Artemis protein repairs DNA double-strand breaks caused by ionising radiation as well as those created during normal V(D)J recombination. When Artemis function is impaired, cells cannot efficiently repair radiation-induced DNA damage, making affected individuals unusually vulnerable to harm from X-rays or other radiation sources.
Can DCLRE1C-related SCID be treated?
Haematopoietic stem cell transplantation can reconstitute immune function in individuals with Artemis-deficient SCID, though careful attention to conditioning regimens is required given the radiosensitivity. Early diagnosis through newborn screening programmes improves outcomes by enabling transplantation before serious infections occur.