{Reference Type}: Journal Article
{Title}: Human DNA-dependent protein kinase catalytic subunit deficiency: a comprehensive review and update.
{Author}: Adelon J;Abolhassani H;Esenboga S;Fouyssac F;Cagdas D;Tezcan I;Kuskonmaz B;Cetinkaya D;Suarez F;Mahdaviani SA;Plassart S;Mathieu AL;Fabien N;Malcus C;Morfin-Sherpa F;Billaud G;Tusseau M;Benezech S;Walzer T;De Villartay JP;Bertrand Y;Belot A;
{Journal}: J Allergy Clin Immunol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 6
{Factor}: 14.29
{DOI}: 10.1016/j.jaci.2024.06.018
{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.
OBJECTIVE: 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; 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).
CONCLUSIONS: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections.