title: prp8 mutations that cause human retinitis pigmentosa lead to a U5 snRNP maturation defect in yeast.
abstract: Prp8 protein (Prp8p) is a highly conserved pre-mRNA splicing factor and a component of spliceosomal U5 small nuclear ribonucleoproteins (snRNPs). Although it is ubiquitously expressed, mutations in the C terminus of human Prp8p cause the retina-specific disease retinitis pigmentosa (RP). The biogenesis of U5 snRNPs is poorly characterized. We present evidence for a cytoplasmic precursor U5 snRNP in yeast that lacks the mature U5 snRNP component Brr2p and depends on a nuclear localization signal in Prp8p for its efficient nuclear import. The association of Brr2p with the U5 snRNP occurs within the nucleus. RP mutations in Prp8p in yeast result in nuclear accumulation of the precursor U5 snRNP, apparently as a consequence of disrupting the interaction of Prp8p with Brr2p. We therefore propose a novel assembly pathway for U5 snRNP complexes that is disrupted by mutations that cause human RP.
authors.affiliation: Wellcome Trust Centre for Cell Biology, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
authors.forename: Kum-Loong
authors.initials: KL
authors.lastname: Boon
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Grainger
authors.forename: Parastoo
authors.initials: P
authors.lastname: Ehsani
authors.forename: J David
authors.initials: JD
authors.lastname: Barrass
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Auchynnikava
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.forename: Jean D
authors.initials: JD
authors.lastname: Beggs
mesh_terms: D006801:Humans; D017403:In Situ Hybridization; D046911:Macromolecular Substances / Q000378:metabolism; D009154:Mutation; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020365:RNA Helicases; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C440573:Aar2p protein, S cerevisiae; D046911:Macromolecular Substances; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; C077018:PRP8 protein, S cerevisiae; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; D017415:Ribonucleoprotein, U5 Small Nuclear; D029701:Saccharomyces cerevisiae Proteins; C104158:BRR2 protein, S cerevisiae; D020365:RNA Helicases