Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Lilly-Molecular Psychiatry Award Winner
  • Published:

Lilly-Molecular Psychiatry Award, Winner

β-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation

Molecular Psychiatry volume 8, pages 654–663 (2003)Cite this article

Abstract

We have mapped and sequenced both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis. Bioinformatics analysis of the regions revealed a number of confirmed and predicted transcripts. No confirmed transcripts are disrupted by either breakpoint. The chromosome 6 breakpoint region is gene poor, the closest transcript being the serotonin receptor 1E (HTR1E) at 625 kb telomeric to the breakpoint. The chromosome 11 breakpoint is situated close to the telomere. The closest gene, β-1,3-glucuronyltransferase (B3GAT1 or GlcAT-P), is 299 kb centromeric to the breakpoint. B3GAT1 is the key enzyme during the biosynthesis of the carbohydrate epitope HNK-1, which is present on a number of cell adhesion molecules important in neurodevelopment. Mice deleted for the B3GAT1 gene show defects in hippocampal long-term potentiation and in spatial memory formation. We propose that the translocation causes a positional effect on B3GAT1, affecting expression levels and making it a plausible candidate for the psychosis found in this family. More generally, regions close to telomeres are highly polymorphic in both sequence and length in the general population and several studies have implicated subtelomeric deletions as a common cause of idiopathic mental retardation. This leads us to the hypothesis that polymorphic or other variation of the 11q telomere may affect the activity of B3GAT1 and be a risk factor for schizophrenia and related psychoses in the general population.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Prescott CA, Gottesman II . Genetically mediated vulnerability to schizophrenia. Psychiatr Clin North Am 1993; 16: 245–267.

    Article  CAS  PubMed  Google Scholar 

  2. McGuffin P, Owen MJ, Farmer AE . Genetic-basis of schizophrenia. Lancet 1995; 346: 678–682.

    Article  CAS  PubMed  Google Scholar 

  3. Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet 1993; 3: 20–25.

    Article  CAS  PubMed  Google Scholar 

  4. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP . A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001; 413: 519–523.

    Article  CAS  PubMed  Google Scholar 

  5. Holland T, Gosden C . A balanced chromosomal translocation partially co-segregating with psychotic illness in a family. Psychiatry Res 1990; 32: 1–8.

    Article  CAS  PubMed  Google Scholar 

  6. Sinnett D, Richer C, Baccichet A . Isolation of stable bacterial artificial chromosome DNA using a modified alkaline lysis method. Biotechniques 1998; 24: 752–754.

    Article  CAS  PubMed  Google Scholar 

  7. Carter NP . Bivariate chromosome analysis using a commercial flow cytometer. Methods Mol Biol 1994; 29: 187–204.

    CAS  PubMed  Google Scholar 

  8. Telenius H, Carter NP, Bebb CE, Nordenskjold M, Ponder BA, Tunnacliffe A . Degenerate oligonucleotide-primed PCR: general amplification of target DNA by a single degenerate primer. Genomics 1992; 13: 718–725.

    Article  CAS  PubMed  Google Scholar 

  9. Green P . Documentation for Phrap. Genome Center, University of Washington, 1996.

  10. Mungall AJ, Edwards CA, Ranby SA, Humphray SJ, Heathcott RW, Clee CM et al. Physical mapping of chromosome 6: a strategy for the rapid generation of sequence-ready contigs. DNA Seq 1996; 7: 47–49.

    Article  CAS  PubMed  Google Scholar 

  11. Soderlund C, Longden I, Mott R . FPC: a system for building contigs from restriction fingerprinted clones. Comput Appl Biosci 1997; 13: 523–535.

    CAS  PubMed  Google Scholar 

  12. Osoegawa K, Mammoser AG, Wu C, Frengen E, Zeng C, Catanese JJ et al. A bacterial artificial chromosome library for sequencing the complete human genome. Genome Res 2001; 11: 483–496.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gregory SG, Howell GR, Bentley DR . Genome mapping by fluorescent fingerprinting. Genome Res 1997; 7: 1162–1168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhao S . Human BAC ends. Nucleic Acids Res 2000; 28: 129–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McPherson JD, Marra M, Hillier L, Waterston RH, Chinwalla A, Wallis J et al. A physical map of the human genome. Nature 2001; 409: 934–941.

    Article  CAS  PubMed  Google Scholar 

  16. Marra MA, Kucaba TA, Dietrich NL, Green ED, Brownstein B, Wilson RK et al. High throughput fingerprint analysis of large-insert clones. Genome Res 1997; 7: 1072–1084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Church GM, Gilbert W . Genomic sequencing. Proc Natl Acad Sci USA 1984; 81: 1991–1995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gordon D, Abajian C, Green P . Consed: a graphical tool for sequence finishing. Genome Res 1998; 8: 195–202.

    Article  CAS  PubMed  Google Scholar 

  19. Sonnhammer EL, Durbin R . A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. Gene 1995; 167G: C1–C10.

    Google Scholar 

  20. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860–921.

    Article  CAS  PubMed  Google Scholar 

  21. Riethman HC, Xiang Z, Paul S, Morse E, Hu XL, Flint J et al. Integration of telomere sequences with the draft human genome sequence. Nature 2001; 409: 948–951.

    Article  CAS  PubMed  Google Scholar 

  22. Burge C, Karlin S . Prediction of complete gene structures in human genomic DNA. J Mol Biol 1997; 268: 78–94.

    Article  CAS  PubMed  Google Scholar 

  23. Kleinjan DJ, van Heyningen V . Position effect in human genetic disease. Hum Mol Genet 1998; 7: 1611–1618.

    Article  CAS  PubMed  Google Scholar 

  24. Pfeifer D, Kist R, Dewar K, Devon K, Lander ES, Birren B et al. Campomelic dysplasia translocation breakpoints are scattered over 1 Mb proximal to SOX9: evidence for an extended control region. Am J Hum Genet 1999; 65: 111–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Calabretta B, Robberson DL, Barrera-Saldana HA, Lambrou TP, Saunders GF . Genome instability in a region of human DNA enriched in Alu repeat sequences. Nature 1982; 296: 219–225.

    Article  CAS  PubMed  Google Scholar 

  26. Deininger PL, Batzer MA . Alu repeats and human disease. Mol Genet Metab 1999; 67: 183–193.

    Article  CAS  PubMed  Google Scholar 

  27. Edelmann L, Spiteri E, Koren K, Pulijaal V, Bialer MG, Shanske A et al. AT-rich palindromes mediate the constitutional t(11;22) translocation. Am J Hum Genet 2001; 68: 1–13.

    Article  CAS  PubMed  Google Scholar 

  28. Jeggo PA . DNA-PK: at the cross-roads of biochemistry and genetics. Mutat Res 1997; 384: 1–14.

    Article  CAS  PubMed  Google Scholar 

  29. Roth DB, Porter TN, Wilson JH . Mechanisms of nonhomologous recombination in mammalian cells. Mol Cell Biol 1985; 5: 2599–2607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roth DB, Wilson JH . Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol Cell Biol 1986; 6: 4295–4304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. Genomics 1997; 43: 1–8.

    Article  CAS  PubMed  Google Scholar 

  32. Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q. Am J Med Genet 1999; 88: 337–343.

    Article  CAS  PubMed  Google Scholar 

  33. Kaufmann CA, Suarez B, Malaspina D, Pepple J, Svrakic D, Markel PD et al. NIMH genetics initiative millenium schizophrenia consortium: linkage analysis of African-American pedigrees. Am J Med Genet 1998; 81: 282–289.

    Article  CAS  PubMed  Google Scholar 

  34. Axelsson R, Wahlstrom J . Chromosome aberrations in patients with paranoid psychosis. Hereditas 1984; 100: 29–31.

    Article  CAS  PubMed  Google Scholar 

  35. Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. DeLisi LE, Craddock NJ, Detera-Wadleigh S, Foroud T, Gejman P, Kennedy JL et al. Update on chromosomal locations for psychiatric disorders: report of the interim meeting of chromosome workshop chairpersons from the VIIth World Congress of Psychiatric Genetics, Monterey, CA, October 14–18, 1999. Am J Med Genet 2000; 96: 434–449.

    Article  CAS  PubMed  Google Scholar 

  37. McAllister G, Charlesworth A, Snodin C, Beer MS, Noble AJ, Middlemiss DN et al. Molecular cloning of a serotonin receptor from human brain (5HT1E): a fifth 5HT1-like subtype. Proc Natl Acad Sci USA 1992; 89: 5517–5521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Levy FO, Holtgreve-Grez H, Tasken K, Solberg R, Ried T, Gudermann T . Assignment of the gene encoding the 5-HT1E serotonin receptor (S31) (locus HTR1E) to human chromosome 6q14–q15. Genomics 1994; 22: 637–640.

    Article  CAS  PubMed  Google Scholar 

  39. Adham N, Vaysse PJ, Weinshank RL, Branchek TA . The cloned human 5-HT1E receptor couples to inhibition and activation of adenylyl cyclase via two distinct pathways in transfected BS-C-1 cells. Neuropharmacology 1994; 33: 403–410.

    Article  CAS  PubMed  Google Scholar 

  40. Bruinvels AT, Landwehrmeyer B, Gustafson EL, Durkin MM, Mengod G, Branchek TA et al. Localization of 5-HT1B, 5-HT1D alpha, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain. Neuropharmacology 1994; 33: 367–386.

    Article  CAS  PubMed  Google Scholar 

  41. Bruinvels AT, Landwehrmeyer B, Probst A, Palacios JM, Hoyer D . A comparative autoradiographic study of 5-HT1D binding sites in human and guinea-pig brain using different radioligands. Brain Res Mol Brain Res 1994; 21: 19–29.

    Article  CAS  PubMed  Google Scholar 

  42. Terayama K, Oka S, Seiki T, Miki Y, Nakamura A, Kozutsumi Y et al. Cloning and functional expression of a novel glucuronyltransferase involved in the biosynthesis of the carbohydrate epitope HNK-1. Proc Natl Acad Sci USA 1997; 94: 6093–6098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Terayama K, Seiki T, Nakamura A, Matsumori K, Ohta S, Oka S et al. Purification and characterization of a glucuronyltransferase involved in the biosynthesis of the HNK-1 epitope on glycoproteins from rat brain. J Biol Chem 1998; 273: 30295–30300.

    Article  CAS  PubMed  Google Scholar 

  44. Schwarting GA, Jungalwala FB, Chou DK, Boyer AM, Yamamoto M . Sulfated glucuronic acid-containing glycoconjugates are temporally and spatially regulated antigens in the developing mammalian nervous system. Dev Biol 1987; 120: 65–76.

    Article  CAS  PubMed  Google Scholar 

  45. Yoshihara Y, Oka S, Watanabe Y, Mori K . Developmentally and spatially regulated expression of HNK-1 carbohydrate antigen on a novel phosphatidylinositol-anchored glycoprotein in rat brain. J Cell Biol 1991; 115: 731–744.

    Article  CAS  PubMed  Google Scholar 

  46. Bronner-Fraser M . Perturbation of cranial neural crest migration by the HNK-1 antibody. Dev Biol 1987; 123: 321–331.

    Article  CAS  PubMed  Google Scholar 

  47. Keilhauer G, Faissner A, Schachner M . Differential inhibition of neurone–neurone, neurone–astrocyte and astrocyte–astrocyte adhesion by L1, L2 and N-CAM antibodies. Nature 1985; 316: 728–730.

    Article  CAS  PubMed  Google Scholar 

  48. Kunemund V, Jungalwala FB, Fischer G, Chou DK, Keilhauer G, Schachner M . The L2/HNK-1 carbohydrate of neural cell adhesion molecules is involved in cell interactions. J Cell Biol 1988; 106: 213–223.

    Article  CAS  PubMed  Google Scholar 

  49. Chou DK, Ilyas AA, Evans JE, Costello C, Quarles RH, Jungalwala FB . Structure of sulfated glucuronyl glycolipids in the nervous system reacting with HNK-1 antibody and some IgM paraproteins in neuropathy. J Biol Chem 1986; 261: 11717–11725.

    CAS  PubMed  Google Scholar 

  50. Kruse J, Mailhammer R, Wernecke H, Faissner A, Sommer I, Goridis C et al. Neural cell adhesion molecules and myelin-associated glycoprotein share a common carbohydrate moiety recognized by monoclonal antibodies L2 and HNK-1. Nature 1984; 311: 153–155.

    Article  CAS  PubMed  Google Scholar 

  51. Schachner M, Martini R . Glycans and the modulation of neural-recognition molecule function. Trends Neurosci 1995; 18: 183–191.

    Article  CAS  PubMed  Google Scholar 

  52. Yamamoto S, Oka S, Inoue M, Shimuta M, Manabe T, Takahashi H et al. Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning. J Biol Chem 2002; 277: 27227–27231.

    Article  CAS  PubMed  Google Scholar 

  53. Senn C, Kutsche M, Saghatelyan A, Bosl M, Lohler J, Bartsch U et al. Mice deficient for the HNK-1 sulfotransferase show alterations in synaptic efficacy and spatial learning and memory. Mol Cell Neurosci 2002; 20: 712.

    Article  CAS  PubMed  Google Scholar 

  54. Saghatelyan AK, Gorissen S, Albert M, Hertlein B, Schachner M, Dityatev A . The extracellular matrix molecule tenascin-R and its HNK-1 carbohydrate modulate perisomatic inhibition and long-term potentiation in the CA1 region of the hippocampus. Eur J Neurosci 2000; 12: 3331–3342.

    Article  CAS  PubMed  Google Scholar 

  55. Colter N, Battal S, Crow TJ, Johnstone EC, Brown R, Bruton C . White matter reduction in the parahippocampal gyrus of patients with schizophrenia. Arch Gen Psychiatry 1987; 44: 1023.

    Article  CAS  PubMed  Google Scholar 

  56. Heckers S, Heinsen H, Geiger B, Beckmann H . Hippocampal neuron number in schizophrenia. A stereological study. Arch Gen Psychiatry 1991; 48: 1002–1008.

    Article  CAS  PubMed  Google Scholar 

  57. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ . Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 1998; 55: 433–440.

    Article  CAS  PubMed  Google Scholar 

  58. Port RL, Seybold KS . Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis. Biol Psychiatry 1995; 37: 318–324.

    Article  CAS  PubMed  Google Scholar 

  59. Park S, Holzman PS . Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992; 49: 975–982.

    Article  CAS  PubMed  Google Scholar 

  60. Vawter MP . Dysregulation of the neural cell adhesion molecule and neuropsychiatric disorders. Eur J Pharmacol 2000; 405: 385–395.

    Article  CAS  PubMed  Google Scholar 

  61. Poltorak M, Wright R, Hemperly JJ, Torrey EF, Issa F, Wyatt RJ et al. Monozygotic twins discordant for schizophrenia are discordant for N-CAM and L1 in CSF. Brain Res 1997; 751: 152–154.

    Article  CAS  PubMed  Google Scholar 

  62. Brown WR, MacKinnon PJ, Villasante A, Spurr N, Buckle VJ, Dobson MJ . Structure and polymorphism of human telomere-associated DNA. Cell 1990; 63: 119–132.

    Article  CAS  PubMed  Google Scholar 

  63. Wilkie AO, Higgs DR, Rack KA, Buckle VJ, Spurr NK, Fischel-Ghodsian N et al. Stable length polymorphism of up to 260 kb at the tip of the short arm of human chromosome 16. Cell 1991; 64: 595–606.

    Article  CAS  PubMed  Google Scholar 

  64. Ijdo JW, Lindsay EA, Wells RA, Baldini A . Multiple variants in subtelomeric regions of normal karyotypes. Genomics 1992; 14: 1019–1025.

    Article  CAS  PubMed  Google Scholar 

  65. Joyce CA, Dennis NR, Cooper S, Browne CE . Subtelomeric rearrangements: results from a study of selected and unselected probands with idiopathic mental retardation and control individuals by using high-resolution G-banding and FISH. Hum Genet 2001; 109: 440–451.

    Article  CAS  PubMed  Google Scholar 

  66. Anderlid BM, Schoumans J, Anneren G, Sahlen S, Kyllerman M, Vujic M et al. Subtelomeric rearrangements detected in patients with idiopathic mental retardation. Am J Med Genet 2002; 107: 275–284.

    Article  PubMed  Google Scholar 

  67. Baker E, Hinton L, Callen DF, Altree M, Dobbie A, Eyre HJ et al. Study of 250 children with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies. Am J Med Genet 2002; 107: 285–293.

    Article  PubMed  Google Scholar 

  68. Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE . The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 1995; 9: 132–140.

    Article  CAS  PubMed  Google Scholar 

  69. Knight SJ, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999; 354: 1676–1681.

    Article  CAS  PubMed  Google Scholar 

  70. Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG et al. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet 1992; 2: 26–30.

    Article  CAS  PubMed  Google Scholar 

  71. Trask B, Fertitta A, Christensen M, Youngblom J, Bergmann A, Copeland A et al. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 1993; 15: 133–145.

    Article  CAS  PubMed  Google Scholar 

  72. Trask BJ, Friedman C, Martin-Gallardo A, Rowen L, Akinbami C, Blankenship J et al. Members of the olfactory receptor gene family are contained in large blocks of DNA duplicated polymorphically near the ends of human chromosomes. Hum Mol Genet 1998; 7: 13–26.

    Article  CAS  PubMed  Google Scholar 

  73. Gottschling DE, Aparicio OM, Billington BL, Zakian VA . Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 1990; 63: 751–762.

    Article  CAS  PubMed  Google Scholar 

  74. Baur JA, Zou Y, Shay JW, Wright WE . Telomere position effect in human cells. Science 2001; 292: 2075–2077.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all members, past and present, at the Cytogenetics department of the Sanger Institute, especially Nigel Carter and Sheila Clegg, for their continued teaching/help and resources for the FISH work. Thanks also to all those involved in the chromosome 6 project at the Sanger Institute, in particular Graeme Bethel for the fingerprint analysis and John Collins for bioinformatics help. This study was funded by a Medical Research Council postgraduate studentship.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Institute of Psychiatry (King's College London), Denmark Hill, London, UK

    A R Jeffries & J F Powell

  2. The Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    A J Mungall, E Dawson, K Halls, C F Langford & I Dunham

  3. Department of Psychological Medicine, Institute of Psychiatry (King's College London), Denmark Hill, London, UK

    R M Murray

Authors
  1. A R Jeffries
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A J Mungall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Dawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Halls
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C F Langford
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R M Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I Dunham
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J F Powell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A R Jeffries.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeffries, A., Mungall, A., Dawson, E. et al. β-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol Psychiatry 8, 654–663 (2003). https://doi.org/10.1038/sj.mp.4001382

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001382

Keywords

This article is cited by

Search

Advanced search

Quick links