title: DNA-PKcs deficiency in human: long predicted, finally found.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Immunology, Erasmus MC,, Rotterdam, The Netherlands. m.vanderburg@erasmusmc.nl
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011836:Radiation Tolerance; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human