Human Molecular Genetics Advance Access published online on January 13, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi482
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1 Institute of Human genetics, Charité, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany
* To whom correspondence should be addressed. Hypomorphic mutations of the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), characterised by microcephaly, chromosomal instability, radiosensitivity, immunodeficiency and high cancer predisposition. Over 90% of NBS patients are homozygous for the 657
Received November 21, 2005
Revised January 11, 2006
Accepted January 11, 2006
Article
Mild Nijmegen Breakage Syndrome (NBS) Phenotype Due to Alternative Splicing
Raymonda Varon 1 *,
Véronique Dutrannoy 2,
Georg Weikert 2,
Caterina Tanzarella 3,
Antonio Antoccia 3,
Lars Stöckl 2,
Emanuela Spadoni 4,
Lars-Arne Krüger 2,
Alessandra di Masi 3,
Karl Sperling 2,
Martin Digweed 2,
and
Paola Maraschio 5
2 Institute of Human Genetics , Charitè Berlin, Germany
3 Department of Biology, University "Roma Tre", Rome, Italy
4 Institute of Medical Genetics, Pavia, Italy
5 Institute of Medical Genetics, Pavia, Italy; IRCCS San Matteo. Pavia, Italy
Raymonda Varon, E-mail: raymonda.varon-mateeva{at}charite.de
Abstract 
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 analysis which revealed two transcripts in 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 in the patient described here. Since 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 
70kDa 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.
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