Human Molecular Genetics Advance Access originally published online on January 13, 2006
Human Molecular Genetics 2006 15(5):679-689; doi:10.1093/hmg/ddi482
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Mild Nijmegen breakage syndrome phenotype due to alternative splicing
1Institute of Human Genetics, Charité Berlin, Germany, 2Department of Biology, University ‘Roma Tre’, Rome, Italy, 3Institute of Medical Genetics and 4IRCCS San Matteo, Pavia, Italy
* To whom correspondence should be addressed at: Institute of Human Genetics, Charité, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49 30450566328; Fax: +49 30450566904; Email: raymonda.varon-mateeva{at}charite.de
Received November 21, 2005; Accepted January 11, 2006
Hypomorphic mutations of the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), characterized by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and high cancer predisposition. Over 90% of NBS patients are homozygous for the 657
5 mutation and are of Slavic origin; however, 10 further truncating mutations have been identified in patients of other ethnical origin. Partially functional proteins produced by alternative initiation of translation, and possibly diminishing the severity of the NBS phenotype, have been described for several NBS1 mutations. Here, we report a 53-year-old NBS patient, homozygous for the NBS1 mutation, 742insGG, in exon 7 and who presents with a particularly mild phenotype. In an attempt to find a potential molecular explanation for the mild phenotype observed, we carried out a conventional semi-quantitative and quantitative RT–PCR analyses which revealed two transcripts of almost equal amounts in the patient and her parents—the expected full-length transcript carrying the 742insGG mutation and a second transcript with deleted exons 6 and 7. The transcript was also observed in controls and other NBS patients, however, at quantities more than 100-fold lower than that in the patient described here. Because the skipping of exons 6 and 7 results in an internal in-frame deletion, which eliminates the truncating GG-insertion, we propose that this transcript may code for a partially functional protein of 
70 kDa that could be responsible for the unusually mild NBS phenotype observed in this patient. Indeed, complementation analysis of null-mutant mouse cells indicates that the alternatively spliced mRNA codes for a protein with significant functional capacity.
These two authors contributed equally to this study.