Human Molecular Genetics, 2000, Vol. 9, No. 9 1415-1423
© 2000 Oxford University Press
Disruption of two novel genes by a translocation co-segregating with schizophrenia
1Medical Genetics Section, Department of Medical Sciences, The University of Edinburgh, Molecular Medicine Centre and MRC Human Genetics Unit, both at Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK, 2The Department of Mental Health, University Medical Building, The University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, UK and 3Department of Psychiatry, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK
A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 (DISC1 and DISC2). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.
+ To whom correspondence should be addressed at: Medical Genetics Section, Department of Medical Sciences, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK. Tel: +44 131 650 1000; Fax: +44 651 1059; Email: kirsty.millar@ed.ac.uk
§ Present address: Molecular Genetics of Cancer Division, WEHI, Royal Melbourne Hospital, Victoria 3050, Australia
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D. F. Levinson, P. A. Holmans, C. Laurent, B. Riley, A. E. Pulver, P. V. Gejman, S. G. Schwab, N. M. Williams, M. J. Owen, D. B. Wildenauer, et al. No Major Schizophrenia Locus Detected on Chromosome 1q in a Large Multicenter Sample Science, April 26, 2002; 296(5568): 739 - 741. [Abstract] [Full Text] [PDF]
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D. H. R. BLACKWOOD, P. M. VISSCHER, and W. J. MUIR Genetic studies of bipolar affective disorder in large families The British Journal of Psychiatry, June 1, 2001; 178 (41): s134 - s136. [Abstract] [Full Text] [PDF]
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V. A. Erdmann, M. Z. Barciszewska, M. Szymanski, A. Hochberg, N. d. Groot, and J. Barciszewski The non-coding RNAs as riboregulators Nucleic Acids Res., January 1, 2001; 29(1): 189 - 193. [Abstract] [Full Text] [PDF]
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