title: G runs in cystathionine beta-synthase c.833C/c.844_845ins68 mRNA are splicing silencers of pathogenic 3' splice sites.
abstract: The c.844_845ins68 is an evolutionary conserved polymorphism of the cystathionine beta-synthase gene that segregates with the pathogenic c.833C mutation and consists of a 68nt insertion duplicating the 3' splice site between intron 7 and exon 8. The gene rearrangement brought two GGGG runs close to each other and generated a splicing control element that allows the constitutive selection of the more distal 3' splice site in the c.844_854ins68 carriers. In this study, we have characterized functionally the two G4 runs within the duplication and have found that they work as silencers of the upstream potentially pathogenic 3' splice sites has been functionally characterized. This selection allows skipping of both the 68nt-insertion and the c.833C mutation, and is essential to preserve the wild-type ORF. Knocking down hnRNP H and F expression modulated the rescue of the proximal 3' splice site more than hnRNP H alone. These observations suggest that hnRNP H/F contribute jointly to prevention of CBS deficiency in c.844_854ins68 carriers by silencing the potentially pathogenic upstream acceptor site.
authors.affiliation: Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 Trieste, Italy. mromano@icgeb.org
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation; D006367:HeLa Cells; D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
chemical_list: D034541:Heterogeneous-Nuclear Ribonucleoprotein Group F-H; D012333:RNA, Messenger; D003541:Cystathionine beta-Synthase