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DNA-PKcs deficiency in human: long predicted, finally found
Mirjam van der Burg1, Jacques J M van Dongen, Dik C van Gent
1Department of Immunology, Erasmus MC,, Rotterdam, The Netherlands. m.vanderburg@erasmusmc.nl
Purpose Of Review:
To describe new immunological and molecular findings of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a new candidate gene for radiosensitive T-B-severe combined immunodeficiency (SCID), which has implications for the diagnostic strategy of T-B-SCID.
Recent Findings:
The first human mutation in the gene encoding DNA-PKcs (PRKDC) has been identified in a radiosensitive T-B-SCID patient. A mutation in the DNA-PKcs gene has been predicted for a long time, but spontaneous mutations had only been identified in mouse, horse and dog models.
Summary:
DNA-PKcs is a key player in the nonhomologous end joining (NHEJ) pathway of DNA double strand break repair. Correct V(D)J recombination of T cell receptor and immunoglobulin genes is fully dependent on NHEJ, as it is involved in the formation of coding and signal joints. Therefore, a NHEJ defect results in absence of T and B cells. The DNA-PKcs deficient patient presented as a classical SCID patient, not different from a recombination activating gene or Artemis deficiency. The mutation concerned a hypomorphic missense mutation (L3062R) that did not result in absence of protein expression nor in deficient in vivo or in vitro (auto)phosphorylation. Although mutated DNA-PKcs was still able to recruit Artemis to the site of DNA damage, it was probably defective in Artemis activation. In the spontaneous animal models, however, the kinase activity was completely lost, which is essentially different from the human mutation. This observation suggests that some aspects of the DNA-PKcs function are unique to humans.
Insights
The first human mutation in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) was found in a radiosensitive T-B-severe combined immunodeficiency (SCID) patient. This discovery impacts SCID diagnostics and highlights unique human DNA-PKcs functions.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is crucial for DNA repair.
- The nonhomologous end joining (NHEJ) pathway is essential for V(D)J recombination in T and B cells.
- Defects in NHEJ lead to severe combined immunodeficiency (SCID).
Purpose of the Study:
- To identify new immunological and molecular findings related to DNA-PKcs in radiosensitive T-B-SCID.
- To evaluate DNA-PKcs as a candidate gene for T-B-SCID.
- To inform diagnostic strategies for T-B-SCID.
Main Methods:
- Genetic analysis of a radiosensitive T-B-SCID patient.
- Molecular characterization of the identified DNA-PKcs mutation.
- In vitro and in vivo functional assays of the mutated DNA-PKcs protein.
Main Results:
- The first human mutation (L3062R) in the PRKDC gene encoding DNA-PKcs was identified in a T-B-SCID patient.
- The mutation resulted in a hypomorphic protein with residual kinase activity and Artemis recruitment.
- The patient presented with classical SCID symptoms, similar to other known genetic defects.
Conclusions:
- DNA-PKcs is a critical component of DNA double-strand break repair and V(D)J recombination.
- A hypomorphic mutation in DNA-PKcs can cause radiosensitive T-B-SCID in humans.
- Human DNA-PKcs mutations may differ functionally from spontaneous mutations in animal models, suggesting species-specific roles.
