The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS patients.

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Keywords NBN protein, human, Nijmegen breakage syndrome, T lymphocyte, adolescent, adult, article, cell cycle protein, cell differentiation, cell proliferation, child, double stranded DNA break, female, genetic recombination, genetics, human, immunoglobulin, immunology, infant, male, metabolism, multiprotein complex, nuclear protein, pathology, pre B lymphocyte, preschool child, somatic hypermutation
Persistent URL dx.doi.org/10.1182/blood-2009-10-250514, hdl.handle.net/1765/20693
Journal Blood
Citation
van der Burg, M, Pac, M, Berkowska, M.A, Goryluk-Kozakiewicz, B, Wakunlinska, A, Dembowska-Baginska, B, … Langerak, A.W. (2010). Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients. Blood, 115(23), 4770–4777. doi:10.1182/blood-2009-10-250514