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In disease-associated genes, understanding the functional significance of deep intronic nucleotide variants represents a difficult challenge. We previ-ously reported that an NF1 intron 30 exonization event is triggered from a single correct nomenclature is ‘c.293-279 AG’ mutation [Raponi M, Upadhyaya M & Baralle D (2006)Hum Mutat27, 294–295]. | ỊFEBS Journal Polypyrimidine tract binding protein regulates alternative splicing of an aberrant pseudoexon in NF1 1 .-2r -- 3 -2 3 Michela Raponi Emanuele Buratti Miriam Llorian Cristiana Stuani Christopher W. J. Smith and Diana Baralle1 1 Human Genetics Division University of Southampton UK 2 Department of Molecular Pathology InternationalCentre for Genetic Engineering and Biotechnology Trieste Italy 3 Department of Biochemistry University of Cambridge UK Keywords intron NF1 pseudoexon PTB nPTB splicing Correspondence D. Baralle Human Genetics Division University of Southampton Duthie Building Mailpoint 808 Southampton General Hospital Tremona Road Southampton SO16 6YD UK Fax 44 2380794346 Tel 44 2380796162 E-mail D.Baralle@soton.ac.uk Received 30 July 2008 revised 23 September 2008 accepted 9 October 2008 In disease-associated genes understanding the functional significance of deep intronic nucleotide variants represents a difficult challenge. We previously reported that an NF1 intron 30 exonization event is triggered from a single correct nomenclature is c.293-279 A G mutation Raponi M Upadhyaya M Baralle D 2006 Hum Mutat 27 294-295 . In this paper we investigate which characteristics play a role in regulating inclusion of the aberrant pseudoexon. Our investigation shows that pseudoexon inclusion levels are strongly downregulated by polypyrimidine tract binding protein and its homologue neuronal polypyrimidine tract binding protein. In particular we provide evidence that the functional effect of polypyrimidine tract binding protein is proportional to its concentration and map the cisacting elements that are principally responsible for this negative regulation. These results highlight the importance of evaluating local sequence context for diagnostic purposes and the utility of developing therapies to turn off activated pseudoexons. doi 10.1111 j.1742-4658.2008.06734.x Pseudoexons are intronic sequences that are approximately the same length as exons 200 bp with
