title: Polypyrimidine tract binding protein regulates alternative splicing of an aberrant pseudoexon in NF1.
abstract: 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 cis-acting 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.
authors.affiliation: Human Genetics Division, University of Southampton, UK.
authors.forename: Michela
authors.initials: M
authors.lastname: Raponi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.forename: Miriam
authors.initials: M
authors.lastname: Llorian
authors.forename: Cristiana
authors.initials: C
authors.lastname: Stuani
authors.forename: Christopher W J
authors.initials: CW
authors.lastname: Smith
authors.forename: Diana
authors.initials: D
authors.lastname: Baralle
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D004742:Enhancer Elements, Genetic; D005091:Exons / Q000235:genetics*; D005786:Gene Expression Regulation; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D007438:Introns / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics; D017384:Sequence Deletion
chemical_list: C412481:DAZAP1 protein, human; D025542:Neurofibromin 1; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein