title: An apparent pseudo-exon acts both as an alternative exon that leads to nonsense-mediated decay and as a zero-length exon.
abstract: Pseudo-exons are intronic sequences that are flanked by apparent consensus splice sites but that are not observed in spliced mRNAs. Pseudo-exons are often difficult to activate by mutation and have typically been viewed as a conceptual challenge to our understanding of how the spliceosome discriminates between authentic and cryptic splice sites. We have analyzed an apparent pseudo-exon located downstream of mutually exclusive exons 2 and 3 of the rat alpha-tropomyosin (TM) gene. The TM pseudo-exon is conserved among mammals and has a conserved profile of predicted splicing enhancers and silencers that is more typical of a genuine exon than a pseudo-exon. Splicing of the pseudo-exon is fully activated for splicing to exon 3 by a number of simple mutations. Splicing of the pseudo-exon to exon 3 is predicted to lead to nonsense-mediated decay (NMD). In contrast, when "prespliced" to exon 2 it follows a "zero length exon" splicing pathway in which a newly generated 5' splice site at the junction with exon 2 is spliced to exon 4. We propose that a subset of apparent pseudo-exons, as exemplified here, are actually authentic alternative exons whose inclusion leads to NMD.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, United Kingdom.
authors.forename: Sushma-Nagaraja
authors.initials: SN
authors.lastname: Grellscheid
authors.forename: Christopher W J
authors.initials: CW
authors.lastname: Smith
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018389:Codon, Nonsense; D017124:Conserved Sequence; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D011544:Pseudogenes; D020871:RNA Stability; D051381:Rats; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D014335:Tropomyosin