Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia (original) (raw)

Molecular Psychiatry volume 6, pages 173–178 (2001)Cite this article

Abstract

Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

251,40 € per year

only 20,95 € per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. McGuffin P, Owen MJ, Farmer AE . Genetic basis of schizophrenia Lancet 1995 346: 678–682
    Article CAS PubMed Google Scholar
  2. StClair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G et al. Association within a family of a balanced translocation with major mental illness Lancet 1990 336: 13–16
    Article CAS Google Scholar
  3. Devon RS, Evans KL, Maule JC, Christie S, Anderson S, Brown J et al. Novel transcribed sequences neighbouring a translocation breakpoint associated with schizophrenia Am J Med Genet 1997 74: 82–90
    Article CAS PubMed Google Scholar
  4. Millar JK, Brown J, Maule JC, Shibasaki Y, Christie S, Lawson D et al. A long-range restriction map across 3Mb of the chromosome 11 breakpoint region of a translocation linked to schizophrenia: localisation of the breakpoint and the search for neighbouring genes Psychiatr Genet 1998 8: 175–181
    Article CAS PubMed Google Scholar
  5. Devon RS, Porteous DJ . Physical mapping of a glutamate receptor gene in relation to a balanced translocation associated with schizophrenia in a large Scottish family Psychiatr Genet 1997 7: 165–169
    Article CAS PubMed Google Scholar
  6. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, CAM Semple et al. Disruption of two novel genes by a translocation cosegregating with schizophrenia Hum Mol Genet 2000 9: 1415–1423
    Article CAS PubMed Google Scholar
  7. Dolnick BJ . Naturally occuring antisense RNA Pharmacol Ther 1997 75: 179–184
    Article CAS PubMed Google Scholar
  8. Knee R, Murphy PR . Regulation of gene expression by natural antisense RNA transcripts Neurochem Int 1997 31: 379–392
    Article CAS PubMed Google Scholar
  9. Constancia M, Pickard B, Kelsey G, Reik W . Imprinting mechanisms Genome Res 1998 8: 881–900
    Article CAS PubMed Google Scholar
  10. Ioannou PA, de Jong PJ . Construction of bacterial artificial chromosome libraries using the modified P1 (PAC) System In: Dracopoli NC, Haines JL, Korf BR, Moir DT, Morton CC, Seidman CE et al (eds). Current Protocols in Human Genetics John Wiley and Sons, New York 1996
  11. Fletcher JM, Evans K, Baillie D, Byrd P, Hanratty D, Leach S et al. Schizophrenia-associated chromosome 11q21 translocation: identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources Am J Hum Genet 1993 52: 478–490
    CAS PubMed PubMed Central Google Scholar
  12. Evans KL, Brown J, Shibasaki Y, Devon RS, He L, Arveiler B et al. A contiguous clone map over 3 Mb on the long arm of chromosome 11 across a balanced translocation associated with schizophrenia Genomics 1995 28: 420–428
    Article CAS PubMed Google Scholar
  13. Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning. A Laboratory Manual CSH Laboratory Press, Cold Spring Harbor 1989
    Google Scholar
  14. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller A et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs Nucleic Acids Res 1997 25: 3389–3402
    Article CAS PubMed PubMed Central Google Scholar
  15. Tarn WY, Steitz JA . Pre-mRNA splicing: the discovery of a new spliceosome doubles the challenge Trends Biochem Sci 1997 22: 132–137
    Article CAS PubMed Google Scholar
  16. Ekelund J, Lichtermann D, Hovatta L, Ellonen P, Suvisaari J, Terwilliger JD et al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22 Hum Mol Genet 2000 9: 1049–1057
    Article CAS PubMed Google Scholar
  17. Gejman PV, Martinez M, Cao Q, Friedman E, Berrettini WH, Goldin LR et al. Linkage analysis of fifty-seven microsatellite loci to bipolar disorder Neuropsychopharmacology 1993 9: 31–40
    Article CAS PubMed Google Scholar
  18. LaBuda MC, Maldonado M, Marshall D, Otten K, Gerhard DS . A follow-up report of a genome search for affective disorder predisposition loci in the Old Order Amish Am J Hum Genet 1996 59: 1343–1362
    CAS PubMed PubMed Central Google Scholar
  19. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2 Proc Natl Acad Sci 1999 96: 5604–5609
    Article CAS PubMed PubMed Central Google Scholar
  20. Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R et al. A genome wide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci Am J Hum Genet 1999 65: 1114–1124
    Article CAS PubMed PubMed Central Google Scholar

Download references

Acknowledgements

We thank Kathy Evans for many useful discussions and Caroline Lamb for her contribution to determining the splice site sequences of DISC1. This work was supported by the United Kingdom Medical Research Council and NV Organon.

Author information

Authors and Affiliations

  1. Medical Genetics Section. The University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland and MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland
    J K Millar, S Christie, S Anderson, D Lawson, D Hsiao-Wei Loh, R S Devon, W J Muir, D H R Blackwood & D J Porteous
  2. Laboratoire de Pathologie Moleculaire et Therapie Genique, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, Bordeaux, 33076, Cedex, France
    B Arveiler
  3. Department of Psychiatry, Royal Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF, Scotland
    W J Muir & D H R Blackwood

Authors

  1. J K Millar
    You can also search for this author inPubMed Google Scholar
  2. S Christie
    You can also search for this author inPubMed Google Scholar
  3. S Anderson
    You can also search for this author inPubMed Google Scholar
  4. D Lawson
    You can also search for this author inPubMed Google Scholar
  5. D Hsiao-Wei Loh
    You can also search for this author inPubMed Google Scholar
  6. R S Devon
    You can also search for this author inPubMed Google Scholar
  7. B Arveiler
    You can also search for this author inPubMed Google Scholar
  8. W J Muir
    You can also search for this author inPubMed Google Scholar
  9. D H R Blackwood
    You can also search for this author inPubMed Google Scholar
  10. D J Porteous
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toJ K Millar.

Rights and permissions

About this article

Cite this article

Millar, J., Christie, S., Anderson, S. et al. Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia.Mol Psychiatry 6, 173–178 (2001). https://doi.org/10.1038/sj.mp.4000784

Download citation

Keywords

This article is cited by