title: Mild Nijmegen breakage syndrome phenotype due to alternative splicing.
abstract: 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 657Delta5 mutation and are of Slavic origin; however, 10 further truncating mutations have been identified in patients of other ethnic 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 approximately 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.
authors.affiliation: Institute of Human Genetics, Charité, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. raymonda.varon-mateeva@charite.de
authors.forename: Raymonda
authors.initials: R
authors.lastname: Varon
authors.forename: Véronique
authors.initials: V
authors.lastname: Dutrannoy
authors.forename: Georg
authors.initials: G
authors.lastname: Weikert
authors.forename: Caterina
authors.initials: C
authors.lastname: Tanzarella
authors.forename: Antonio
authors.initials: A
authors.lastname: Antoccia
authors.forename: Lars
authors.initials: L
authors.lastname: Stöckl
authors.forename: Emanuela
authors.initials: E
authors.lastname: Spadoni
authors.forename: Lars-Arne
authors.initials: LA
authors.lastname: Krüger
authors.forename: Alessandra
authors.initials: A
authors.lastname: di Masi
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Martin
authors.initials: M
authors.lastname: Digweed
authors.forename: Paola
authors.initials: P
authors.lastname: Maraschio
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D005091:Exons / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005808:Genes, Recessive; D005816:Genetic Complementation Test; D006720:Homozygote; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics; D010641:Phenotype; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D011839:Radiation, Ionizing; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins