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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
Show Affiliations
Authors Affiliations
  1. 1. Department of Pediatric Immunology and Hematology, Institut d'Hematologie et d'Oncologie Pediatrique, Lyon, France
  2. 2. Hospices Civils de Lyon, Lyon, France
  3. 3. Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  4. 4. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
  5. 5. Department of Pediatric Immunology, Ihsan Dogramaci Children's Hospital, Hacettepe University, Ankara, Turkey
  6. 6. Department of Pediatric Oncology, Children's Hospital, Nancy, France
  7. 7. Department of Pediatric Hematology, Ihsan Dogramaci Children's Hospital, Hacettepe University, Ankara, Turkey
  8. 8. Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM UMR1163/CNRS URL 8254, Paris, France
  9. 9. French National Center for Primary Immunodeficiencies, Necker University Hospital, AP-HP, Paris, France
  10. 10. INSERM UMR1163, Imagine Institut, Sorbonne Paris Cite, Paris, France
  11. 11. Department of Hematology, Hopital Universitaire Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, Paris, France
  12. 12. Universite Paris Cite, Paris, France
  13. 13. Pediatric Respiratory Diseases Research Centre, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  14. 14. Centre de References Maladies Rares, Rhumatismes inflammatoires et les maladies Auto-Immunes Systemiques rares de l'Enfant (RAISE), Lyon, France
  15. 15. Centre International de Recherche en Infectiologie (CIRI), Institut National de la Sante et de la Recherche Medicale (INSERM) U1111, Centre National de la Recherche Scientifique Unite Mixte de Recherche (UMR) 5308, Ecole Normale Superieure de Lyon, Universite Claude Bernard Lyon, Lyon, France
  16. 16. Department of Immunology, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Benite, France
  17. 17. Department of Immunology, Hopital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
  18. 18. Laboratoire de Virologie, Institut des Agents Infectieux, Hospices Civils de Lyon, Groupement Hospitalier Nord, Lyon, France
  19. 19. Laboratoire Virologie et Pathologies humaines (VirPath), Centre International de Recherche en Infectiologie (CIRI), Institut National de la Sante et de la Recherche Medicale (INSERM) U1111, Centre National de la Recherche Scientifique Unite Mixte de Recherche (UMR) 5308, Ecole Normale Superieure de Lyon, Universite Claude Bernard Lyon, Lyon, France
  20. 20. Service de Genetique, Groupe Hospitalier Est, Hospices Civils de Lyon, Bron, France
  21. 21. Laboratory “Genome Dynamics in the Immune System” INSERM UMR 1163, Imagine Institute, Universite de Paris Cite, Paris, France
  22. 22. Department of Pediatrics Nephrology, Rheumatology, and Dermatology, Hopital Femme-Mere-Enfant, Bron, France

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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