%0 Journal Article
%T Human DNA-dependent protein kinase catalytic subunit deficiency: a comprehensive review and update.
%A Adelon J
%A Abolhassani H
%A Esenboga S
%A Fouyssac F
%A Cagdas D
%A Tezcan I
%A Kuskonmaz B
%A Cetinkaya D
%A Suarez F
%A Mahdaviani SA
%A Plassart S
%A Mathieu AL
%A Fabien N
%A Malcus C
%A Morfin-Sherpa F
%A Billaud G
%A Tusseau M
%A Benezech S
%A Walzer T
%A De Villartay JP
%A Bertrand Y
%A Belot A
%J J Allergy Clin Immunol
%V 0
%N 0
%D 2024 Jul 6
%M 38977084
%F 14.29
%R 10.1016/j.jaci.2024.06.018
%X <B>BACKGROUND: </B>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.<BR><B>OBJECTIVE: </B>To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4+CD45RA+ T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4+CD45RA+ T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y).<BR><B>CONCLUSIONS: </B>DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.