Human DNA-dependent protein kinase catalytic subunit deficiency: A comprehensive review and update

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.