title: Loss of juxtaposition of RAG-induced immunoglobulin DNA ends is implicated in the precursor B-cell differentiation defect in NBS patients.
abstract: 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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pac
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Berkowska
authors.forename: Bozenna
authors.initials: B
authors.lastname: Goryluk-Kozakiewicz
authors.forename: Anna
authors.initials: A
authors.lastname: Wakulinska
authors.forename: Bozenna
authors.initials: B
authors.lastname: Dembowska-Baginska
authors.forename: Hanna
authors.initials: H
authors.lastname: Gregorek
authors.forename: Barbara H
authors.initials: BH
authors.lastname: Barendregt
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007223:Infant; D008297:Male; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011995:Recombination, Genetic / Q000235:genetics / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D007136:Immunoglobulins; D046912:Multiprotein Complexes; C112156:NBN protein, human; D009687:Nuclear Proteins