title: Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing.
abstract: The PQBP1 (polyglutamine tract-binding protein 1) gene encodes a nuclear protein that regulates pre-mRNA splicing and transcription. Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation disorders including Golabi-Ito-Hall syndrome. The missense mutation that causes this syndrome is unique among other PQBP1 mutations reported to date because it maps within a functional domain of PQBP1, known as the WW domain. The mutation substitutes tyrosine 65 with cysteine and is located within the conserved core of aromatic amino acids of the domain. We show here that the binding property of the Y65C-mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. Furthermore, in Golabi-Ito-Hall-derived lymphoblasts we showed that the complex between PQBP1-Y65C and WBP11 (WW domain-binding protein 11) splicing factor was compromised. In these cells a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides an insight into the molecular mechanism that underlies the X chromosome-linked mental retardation entities classified globally as Renpenning syndrome.
authors.affiliation: Institut für Medizinische Immunologie, Charité-Universitätsmedizin Berlin, Berlin 10115, Germany.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Tapia
authors.forename: Emilia
authors.initials: E
authors.lastname: Nicolaescu
authors.forename: Caleb B
authors.initials: CB
authors.lastname: McDonald
authors.forename: Valeria
authors.initials: V
authors.lastname: Musi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Oka
authors.forename: Yujin
authors.initials: Y
authors.lastname: Inayoshi
authors.forename: Adam C
authors.initials: AC
authors.lastname: Satteson
authors.forename: Virginia
authors.initials: V
authors.lastname: Mazack
authors.forename: Jasper
authors.initials: J
authors.lastname: Humbert
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Gaffney
authors.forename: Monique
authors.initials: M
authors.lastname: Beullens
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Christiane
authors.initials: C
authors.lastname: Landgraf
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
mesh_terms: D017398:Alternative Splicing; D002151:Calorimetry / Q000379:methods; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D002942:Circular Dichroism; D004268:DNA-Binding Proteins; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics*; D011392:Proline / Q000737:chemistry; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D011392:Proline
references.citation: FEBS Lett. 2006 Apr 17;580(9):2335-40
references.pmid: 16597440
references.citation: J Biol Chem. 1999 Dec 17;274(51):36513-9
references.pmid: 10593949
references.citation: FEBS Lett. 2002 Feb 20;513(1):30-7
references.pmid: 11911877
references.citation: J Med Genet. 2006 Jun;43(6):e30
references.pmid: 16740914
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7819-23
references.pmid: 7644498
references.citation: Cell. 2000 Dec 22;103(7):1001-4
references.pmid: 11163176
references.citation: Hum Mutat. 2010 Jan;31(1):90-8
references.pmid: 19847789
references.citation: J Mol Biol. 2006 Jul 21;360(4):865-81
references.pmid: 16784750
references.citation: Hum Mol Genet. 1999 Jun;8(6):977-87
references.pmid: 10332029
references.citation: CRC Crit Rev Biochem. 1974 Jan;2(1):113-75
references.pmid: 4591332
references.citation: Biochem Biophys Res Commun. 2002 Jun 7;294(2):268-71
references.pmid: 12051705
references.citation: Cell. 1992 Jul 24;70(2):351-64
references.pmid: 1638635
references.citation: Nucleic Acids Res. 2002 Oct 15;30(20):e109
references.pmid: 12384611
references.citation: Anal Biochem. 1989 May 15;179(1):131-7
references.pmid: 2757186
references.citation: J Biol Chem. 2000 Jul 7;275(27):20562-71
references.pmid: 10781604
references.citation: Annu Rev Biophys Biomol Struct. 2000;29:291-325
references.pmid: 10940251
references.citation: J Mol Biol. 2000 Mar 17;297(1):119-33
references.pmid: 10704311
references.citation: J Biol Chem. 2004 Jul 23;279(30):31833-41
references.pmid: 15133021
references.citation: Trends Biochem Sci. 1994 Dec;19(12):531-3
references.pmid: 7846762
references.citation: Biopolymers. 2000;55(3):188-206
references.pmid: 11074414
references.citation: Eur J Hum Genet. 2007 Jan;15(1):29-34
references.pmid: 17033686
references.citation: Eur J Cell Biol. 2008 Oct;87(10):817-29
references.pmid: 18599155
references.citation: Clin Genet. 2004 Oct;66(4):318-26
references.pmid: 15355434
references.citation: Proteomics. 2004 Mar;4(3):643-55
references.pmid: 14997488
references.citation: Mol Biotechnol. 2007 May;36(1):38-43
references.pmid: 17827536
references.citation: Trends Biochem Sci. 2009 Oct;34(10):471-82
references.pmid: 19744855
references.citation: Nat Struct Biol. 2000 May;7(5):375-9
references.pmid: 10802733
references.citation: Biochem Biophys Res Commun. 2000 Jul 5;273(2):592-5
references.pmid: 10873650
references.citation: J Biol Chem. 2008 Oct 10;283(41):27534-27546
references.pmid: 18640976
references.citation: J Inherit Metab Dis. 2000 Jul;23(5):441-7
references.pmid: 10947197
references.citation: Chembiochem. 2009 Jun 15;10(9):1431-42
references.pmid: 19437530
references.citation: EMBO J. 2004 Jun 16;23(12):2381-91
references.pmid: 15175653
references.citation: Brain Res Bull. 2001 Oct-Nov 1;56(3-4):273-80
references.pmid: 11719261
references.citation: J Biol Chem. 1997 Jul 4;272(27):17070-7
references.pmid: 9202023
references.citation: Proteins. 2008 Aug;72(2):779-92
references.pmid: 18260110
references.citation: Bioessays. 2008 Jan;30(1):1-4
references.pmid: 18081004
references.citation: Adv Neurol. 1999;79:399-409
references.pmid: 10514829
references.citation: Dev Cell. 2002 Mar;2(3):251-2
references.pmid: 11879627
references.citation: Protein Sci. 2009 Aug;18(8):1806-13
references.pmid: 19565466
references.citation: Protein Sci. 2006 Oct;15(10):2278-89
references.pmid: 16963647
references.citation: Nucleic Acids Res. 1999 May 1;27(9):1957-65
references.pmid: 10198427
references.citation: Hum Mol Genet. 2003 Apr 1;12(7):711-25
references.pmid: 12651867
references.citation: Gene. 2000 Oct 17;257(1):33-43
references.pmid: 11054566
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Int J Biochem Cell Biol. 2008;40(4):776-88
references.pmid: 18060825
references.citation: J Biol Chem. 1997 Sep 26;272(39):24105-8
references.pmid: 9305852
references.citation: J Biol Chem. 2005 Nov 18;280(46):38862-9
references.pmid: 16162498
references.citation: Neuron. 2002 May 30;34(5):701-13
references.pmid: 12062018
references.citation: Dev Dyn. 2009 Oct;238(10):2471-8
references.pmid: 19681162
references.citation: Nucleic Acids Res. 1990 Oct 25;18(20):6097-100
references.pmid: 2172928
references.citation: Biochem J. 2004 Feb 15;378(Pt 1):229-38
references.pmid: 14640981
references.citation: Biochemistry. 1999 Oct 26;38(43):14338-51
references.pmid: 10572009
references.citation: Nat Genet. 2003 Dec;35(4):313-5
references.pmid: 14634649
references.citation: Nature. 2003 Dec 18;426(6968):905-9
references.pmid: 14685252
references.citation: Eur J Hum Genet. 2006 Apr;14(4):418-25
references.pmid: 16493439
references.citation: Hum Mol Genet. 2009 Nov 15;18(22):4239-54
references.pmid: 19661183
references.citation: Am J Hum Genet. 2004 Apr;74(4):777-80
references.pmid: 15024694
references.citation: Am J Med Genet A. 2005 May 1;134(4):415-21
references.pmid: 15782410