RESUMO
The nuclease ARTEMIS is an essential factor of V(D)J recombination during lymphocyte development and in the repair of DNA double-strand breaks (DSB) by the nonhomologous end joining (NHEJ) pathway. Patients with mutations in the DCLRE1C gene, which encodes ARTEMIS, suffer from radiosensitive B(-/low) T(-/low) severe combined immunodeficiency (SCID) or radiosensitive Omenn syndrome. To date, causative DCLRE1C mutations inherited as a recessive trait have been reported in 49 patients. In this study, molecular diagnoses of 29 novel patients presenting with the phenotype of B(-/low) SCID revealed mutations in the DCLRE1C gene. In total, 13 different mutated DCLRE1C alleles were detected, nine of which have not been described before. By far the most frequent mutations (59%) were gross deletions of exons 1-3 or exons 1-4 due to a homologous recombination of the wild-type DCLRE1C gene with a pseudo-DCLRE1C gene located 61.2 kb 5' to the DCLRE1C start codon. Fine mapping of the recombination intervals revealed private mutations in most cases. MEIG1, a gene encoding a protein that is essential for spermatogenesis in mice, is lost by the gross deletions. Functional analyses on patients' fibroblasts demonstrated that the corresponding alleles carry null mutations of the DCLRE1C gene.