Severe combined immunodeficiency disease (SCID) can be immunologically classified by the absence or presence of T, B, and natural killer (NK) cells. About 30% of T-B-NK+ SCID patients carry mutations in the recombination activating genes (RAG). Some T-B-NK+ SCID patients without RAG gene mutations are sensitive to ionizing radiation, and several of these radiosensitive (RS) SCID patients were recently shown to have large deletions or truncation mutations in the Artemis gene, implying a role for Artemis in DNA double-strand break (dsb) repair. We identified 5 RS-SCID patients without RAG gene mutations, 4 of them with Artemis gene mutations. One patient had a large genomic deletion, but the other 3 patients carried simple missense mutations in conserved amino acid residues in the SNM1 homology domain of the Artemis protein. Extrachromosomal V(D)J recombination assays showed normal and precise signal joint formation, but inefficient coding joint formation in fibroblasts of these patients, which could be complemented by the wild-type Artemis gene. The cells containing the missense mutations in the SNM1 homology domain had the same recombination phenotype as the cells with the large deletion, indicating that these amino acid residues are indispensable for Artemis function. Immunogenotyping and immunophenotyping of bone marrow samples of 2 RS-SCID patients showed the absence of complete VH-JH gene rearrangements and consequently a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint - that is, at the transition from Cylglμ- pre-B-I cells to Cylgμ+ pre-B-I cells. The completeness of this arrest illustrates the importance of Artemis at this stage of lymphoid differentiation.

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Persistent URL dx.doi.org/10.1182/blood-2002-01-0187, hdl.handle.net/1765/55078
Journal Blood
Citation
Noordzij, P.G, Verkaik, N.S, van der Burg, M, van Veelen, L.R, de Bruin-Versteeg, S, Wiegant, W.W, … van Dongen, J.J.M. (2003). Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow. Blood, 101(4), 1446–1452. doi:10.1182/blood-2002-01-0187