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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 withoutRAGgene 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 theArtemisgene, implying a role for Artemis in DNA double-strand break (dsb) repair. We identified 5 RS-SCID patients without RAGgene mutations, 4 of them withArtemisgene 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 Artemisgene. 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-JHgene rearrangements and consequently a complete B-cell differentiation arrest at the pre–B-cell receptor checkpoint—that is, at the transition from CyIgμ−pre-B-I cells to CyIgμ+pre-B-II cells. The completeness of this arrest illustrates the importance of Artemis at this stage of lymphoid differentiation.

X-linked agammaglobulinemia is caused by mutations in the BTKgene, which result in a precursor B-cell differentiation arrest in the bone marrow and the absence of or strongly reduced B lymphocytes in blood. We identified a patient with a mild clinical phenotype, low numbers of B lymphocytes, and a splice-site mutation in the BTKgene. The precursor B-cell compartment in the bone marrow of this patient was almost identical to that in healthy children. Using real-time quantitative polymerase chain reaction, we were able to detect low levels of wild-type BTKtranscripts in his granulocytes. Therefore, we speculated that wild-type BTKtranscripts might be responsible for a milder clinical and immunological phenotype, as has been shown in several other diseases. Consequently, we quantified the expression of wild-type BTKtranscripts in granulocytes of eight additional patients with splice-site mutations and compared their phenotypes with 17 patients with other types of BTKmutations. In these eight patients, the presence of low levels of wild-type BTKtranscripts did not show a clear correlation with the percentage, absolute number, or immunophenotype of B lymphocytes nor with age or serum immunoglobulin levels at diagnosis. Nevertheless, we postulate that the presence of wild-type BTKtranscripts can be one of the many factors that influence the clinical and immunological phenotype in X-linked agammaglobulinemia.