PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Anne Laure Mathieu, Estelle Verronese, Gillian I. Rice, Fanny Fouyssac, Yves Bertrand, Capucine Picard, Marie Chansel, Jolan E. Walter, Luigi D. Notarangelo, Manish J. Butte, Kari Christine Nadeau, Krisztian Csomos, David J. Chen, Karin Chen, Ana Delgado, Chantal Rigal, Christine Bardin, Catharina Schuetz, Despina Moshous, Héloïse ReumauxFrançois Plenat, Alice Phan, Marie Thérèse Zabot, Brigitte Balme, Sébastien Viel, Jacques Bienvenu, Pierre Cochat, Mirjam Van Der Burg, Christophe Caux, E. Helen Kemp, Isabelle Rouvet, Christophe Malcus, Jean Francois Méritet, Annick Lim, Yanick J. Crow, Nicole Fabien, Christine Ménétrier-Caux, Jean Pierre De Villartay, Thierry Walzer, Alexandre Belot

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

Original languageEnglish (US)
Pages (from-to)1578-1588.e5
JournalJournal of Allergy and Clinical Immunology
Issue number6
StatePublished - Jun 1 2015


  • Autoimmune regulator
  • DNA-dependent protein kinase catalytic subunit
  • VDJ recombination
  • autoimmunity
  • recombination-activating gene
  • severe combined immunodeficiency
  • tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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