Artemis is required for V(D)J recombination and the repair of a subset of radiation-induced DNA double strand breaks (DSBs). Artemis-null patients display radiosensitivity (RS) and severe combined immunodeficiency (SCID), classified as RS-SCID. Strongly impacting hypomorphic Artemis mutations confer marked infant immunodeficiency and a predisposition for EBV-associated lymphomas. Here, we provide evidence that a polymorphic Artemis variant (c.512C >G: p.171P >R), which has a world-wide prevalence of 15%, is functionally impacting. The c.512C >G mutation causes an ∼3-fold decrease in Artemis endonuclease activity in vitro. Cells derived from a patient who expressed a single Artemis allele with the polymorphic mutational change, showed radiosensitivity and a DSB repair defect in G2 phase, with Artemis cDNA expression rescuing both phenotypes. The c.512C >G change has an additive impact on Artemis function when combined with a novel C-terminal truncating mutation (p.436C >X), which also partially inactivates Artemis activity. Collectively, our findings provide strong evidence that monoallelic expression of the c.512C >G variant impairs Artemis function causing significant radiosensitivity and a G2 phase DSB repair defect. The patient exhibiting monoallelic c.512C >G-Artemis expression showed immunodeficiency only in adulthood, developed bilateral carcinoma of the nipple and myelodysplasia raising the possibility that modestly decreased Artemis function can impact clinically.

DNA double strand break repair, Immunodeficiency, Radiosensitivity, V(D)J recombination,
D N A Repair
Erasmus MC: University Medical Center Rotterdam

Woodbine, L, Grigoriadou, S, Goodarzi, A.A, Riballo, E, Tape, C, Oliver, A.W, … Jeggo, P.A. (2010). An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity. D N A Repair, 9(9), 1003–1010. doi:10.1016/j.dnarep.2010.07.001