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Human Dna-Dependent Protein Kinase Catalytic Subunit Deficiency: A Comprehensive Review and Update Publisher Pubmed



Adelon J1, 2 ; Abolhassani H3, 4 ; Esenboga S5 ; Fouyssac F6 ; Cagdas D5 ; Tezcan I5 ; Kuskonmaz B7 ; Cetinkaya D7 ; Suarez F8, 9, 10, 11, 12 ; Mahdaviani SA13 ; Plassart S14 ; Mathieu AL14, 15 ; Fabien N16 ; Malcus C17 Show All Authors
Authors
  1. Adelon J1, 2
  2. Abolhassani H3, 4
  3. Esenboga S5
  4. Fouyssac F6
  5. Cagdas D5
  6. Tezcan I5
  7. Kuskonmaz B7
  8. Cetinkaya D7
  9. Suarez F8, 9, 10, 11, 12
  10. Mahdaviani SA13
  11. Plassart S14
  12. Mathieu AL14, 15
  13. Fabien N16
  14. Malcus C17
  15. Morfinsherpa F18, 19
  16. Billaud G18
  17. Tusseau M2, 15, 20
  18. Benezech S1, 2, 15
  19. Walzer T15
  20. De Villartay JP21
  21. Bertrand Y1, 2
  22. Belot A2, 14, 15, 22

Source: Journal of Allergy and Clinical Immunology Published:2024


Abstract

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non–homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in Prkdc define the Scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far. Objectives: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human. Methods: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material. Results: We report on 7 patients; 6 patients displayed the autosomal recessive p.L3062R mutation in PRKDC-encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n = 5 of 7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naive CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values, naive CD4+CD45RA+ T cells decreased over time (n = 5 of 6). Hematopoietic stem cell transplantation was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was observed, respectively, for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 years). Conclusions: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections. © 2024
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