Journal Article

Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein

Lars Krüger, Ilja Demuth, Heidemarie Neitzel, Raymonda Varon, Karl Sperling, Krystyna H. Chrzanowska, Eva Seemanova and Martin Digweed

in Carcinogenesis

Volume 28, issue 1, pages 107-111
Published in print June 2006 | ISSN: 0143-3334
Published online January 2007 | e-ISSN: 1460-2180 | DOI:
Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein

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The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of ∼70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.

Journal Article.  3417 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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