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PRKDC mutations associated with immunodeficiency, granuloma and aire-dependent autoimmunity


PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-PK) crucial for DNA double-strand break (DSB) repair and V(D)J recombination. In mice, DNA-PK also interacts with the transcription factor AIRE (autoimmune regulator) to promote central T cell tolerance.


We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity, associated to decreasing T and B cell counts over time diagnosed in two unrelated patients.


Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency.


We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA DSB repair and V(D)J recombination. Circulating T cells had a skewed cytokine response typical of Th1 and Th2 profiles. Moreover, mutated DNA-PKcs failed to promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo, with the production of anti-Calcium Sensing Receptor (anti-CaSR) autoantibodies, which are usually found in AIRE-deficient patients.


Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoantibodies and these findings highlight the essential role of DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Belot, A., Mathieu, AL., Veronese, E. et al. PRKDC mutations associated with immunodeficiency, granuloma and aire-dependent autoimmunity. Pediatr Rheumatol 12 (Suppl 1), P42 (2014).

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