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Polypyrimidine tract binding protein regulates alternative splicing of an aberrant pseudoexon in NF1
Author(s) -
Raponi Michela,
Buratti Emanuele,
Llorian Miriam,
Stuani Cristiana,
Smith Christopher W. J.,
Baralle Diana
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2008.06734.x
Subject(s) - polypyrimidine tract , polypyrimidine tract binding protein , rna splicing , intron , genetics , context (archaeology) , biology , exon , alternative splicing , gene , mutation , computational biology , rna , paleontology
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.