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Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism


Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan–Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361*, in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan–Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.

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  1. Ropers HH, Hamel BC . X-linked mental retardation. Nat Genet 2005; 6: 46–57.

    Article  CAS  Google Scholar 

  2. Graves JA, Gécz J, Hameister H . Evolution of the human X, a smart and sexy chromosome that controls speciation and development. Cytogenet Genome Res 2002; 99: 141–145.

    Article  CAS  Google Scholar 

  3. Chiurazzi P, Schwartz CE, Gecz J, Neri G . XLMR genes: update 2007. Eur J Hum Genet 2008; 16: 422–434.

    Article  CAS  Google Scholar 

  4. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 2005; 77: 442–453.

    Article  CAS  Google Scholar 

  5. Froyen G, Van Esch H, Bauters M, Hollanders K, Frints SG, Vermeesch JR et al. Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes. Hum Mutat 2007; 28: 1034–1042.

    Article  CAS  Google Scholar 

  6. Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C et al. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. Am J Hum Genet 2008; 82: 432–443.

    Article  CAS  Google Scholar 

  7. Tarpey PS, Stevens C, Teague J, Edkins S, O’Meara S, Avis T et al. Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation. Am J Hum Genet 2006; 79: 1119–1124.

    Article  CAS  Google Scholar 

  8. Tarpey PS, Raymond FL, O’Meara S, Edkins S, Teague J, Butler A et al. Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor. Am J Hum Genet 2007; 80: 345–352.

    Article  CAS  Google Scholar 

  9. Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L et al. Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation. Nat Genet 2007; 39: 1127–1133.

    Article  CAS  Google Scholar 

  10. Inlow JK, Restifo LL . Molecular and comparative genetics of mental retardation. Genetics 2004; 166: 835–881.

    Article  CAS  Google Scholar 

  11. Chelly J, Khelfaoui M, Francis F, Beldjord C, Bienvenu T . Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006; 14: 701–713.

    Article  CAS  Google Scholar 

  12. Laumonnier F, Cuthbert PC, Grant SG . The role of neuronal complexes in human X-linked brain diseases. Am J Hum Genet 2007; 80: 205–220.

    Article  CAS  Google Scholar 

  13. de Brouwer AP, Yntema HG, Kleefstra T, Lugtenberg D, Oudakker AR, de Vries BB et al. Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium. Hum Mutat 2007; 28: 207–208.

    Article  Google Scholar 

  14. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW . Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992; 51: 1229–1239.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Neitzel H . A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 1986; 73: 320–326.

    Article  CAS  Google Scholar 

  16. Raynaud M, Moizard MP, Dessay B, Briault S, Toutain A, Gendrot C et al. Systematic analysis of X-inactivation in 19 XLMR families: extremely skewed profiles in carriers in three families. Eur J Hum Genet 2000; 8: 253–258.

    Article  CAS  Google Scholar 

  17. Lykke-Andersen J, Shu MD, Steiz JA . Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 2000; 22: 1121–1131.

    Article  Google Scholar 

  18. Berglund L, Björling E, Oksvold P, Fagerberg L, Asplund A, Al-Khalili Szigyarto C et al. A gene-centric human protein atlas for expression profiles based on antibodies. Mol Cell Proteomics 2008; 7: 2019–2027.

    Article  CAS  Google Scholar 

  19. Ropers HH . X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev 2006; 16: 260–269.

    Article  CAS  Google Scholar 

  20. Ropers HH . Genetics of intellectual disability. Curr Opin Genet Dev 2008; 18: 241–250.

    Article  CAS  Google Scholar 

  21. Lugtenberg D, Veltman JA, van Bokhoven H . High-resolution genomic microarrays for X-linked mental retardation. Genet Med 2007; 9: 560–565.

    Article  CAS  Google Scholar 

  22. Madrigal I, Rodríguez-Revenga L, Armengol L, González E, Rodriguez B, Badenas C et al. X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation. BMC Genomics 2007; 8: 443.

    Article  CAS  Google Scholar 

  23. Van Buggenhout G, Fryns JP . Lujan–Fryns syndrome (mental retardation, X-linked, marfanoid habitus). Orphanet J Rare Dis 2006; 1: 26.

    Article  Google Scholar 

  24. Gehring NH, Neu-Yilik G, Schell T, Hentze MW, Kulozik AE . Y14 and hUpf3b form an NMD-activating complex. Mol Cell 2003; 11: 939–949.

    Article  CAS  Google Scholar 

  25. Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 2004; 74: 552–557.

    Article  CAS  Google Scholar 

  26. Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR . X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12–q21.31 by X inactivation and linkage analysis. Am J Hum Genet 1992; 51: 1136–1149.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Hatakeyama C, Anderson CL, Beever CL, Penaherrera MS, Brown CJ, Robinson WP . The dynamics of X-inactivation skewing as women age. Clin Genet 2004; 66: 327–332.

    Article  CAS  Google Scholar 

  28. Chang YF, Imam JS, Wilkinson MF . The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 2007; 76: 51–74.

    Article  CAS  Google Scholar 

  29. Conti E, Izzauralde E . Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 2005; 17: 316–325.

    Article  CAS  Google Scholar 

  30. Gehring NH, Kunz JB, Neu-Yilik G, Breit S, Viegas MH, Hentze MW et al. Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol Cell 2005; 20: 65–75.

    Article  CAS  Google Scholar 

  31. Kunz JB, Neu-Yilik G, Hentze MW, Kulozik AE, Gehring NH . Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 2006; 12: 1015–1022.

    Article  CAS  Google Scholar 

  32. Chan WK, Huang L, Gudikote JP, Chang YF, Imam JS, MacLean II JA et al. An alternative branch of the nonsense-mediated decay pathway. EMBO J 2007; 26: 1820–1830.

    Article  CAS  Google Scholar 

  33. Ivanov PV, Gehring NH, Kunz JB, Hentze MW, Kulozik AE . Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J 2008; 27: 736–747.

    Article  CAS  Google Scholar 

  34. Motazacker MM, Rost BR, Hucho T, Garshasbi M, Kahrizi K, Ullmann R et al. A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am J Hum Genet 2007; 81: 792–798.

    Article  CAS  Google Scholar 

  35. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007; 39: 25–27.

    Article  CAS  Google Scholar 

  36. Nakanishi S, Nakajima Y, Masu M, Ueda Y, Nakahara K, Watanabe D et al. Glutamate receptors: brain function and signal transduction. Brain Res Brain Res Rev 1998; 26: 230–235.

    Article  Google Scholar 

  37. Boeckers TM, Kreutz MR, Winter C, Zuschratter W, Smalla K-H, Sanmarti-Vila L et al. Proline-rich synapse-associated protein-1/cortactin binding protein 1 (ProSAP1/CortBP1) is a PDZ-domain protein highly enriched in the postsynaptic density. J Neurosci 1999; 19: 6506–6518.

    Article  CAS  Google Scholar 

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We thank the patients and their family members, the XLMR European Consortium for their participation in this study. We also thank Rose-Anne Thépault, Brigitte Jauffrion and Lucianne Vandeleur for help with sequencing reactions and cell culture. This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM) and the University of Tours, by the European Union (grant QLG3-CT-2002-01810), by Australian NHMRC Project grant 453457 (JG) and senior research fellowship (JG).

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Correspondence to F Laumonnier.

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Laumonnier, F., Shoubridge, C., Antar, C. et al. Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. Mol Psychiatry 15, 767–776 (2010).

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  • autism
  • mental retardation
  • nonsense-mediated mRNA decay
  • neuronal expression
  • X chromosome

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