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A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

Molecular Psychiatry volume 10, pages 758–764 (2005)Cite this article

Abstract

In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3′ end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.

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Acknowledgements

We are deeply indebted to the families who made this study possible. We greatly appreciate the pyrosequencing expertise of Dr Liying Yan from Biotage. We thank Colleen A Callahan, Roxann G Ingersoll, Abdulgafoor M Bachani, Hyon S Hwang and Marie Sonderman for technical assistance, Alka Ahuja for statistical advice, and Dr George A Vielhauer and Jeffrey M Catania for intellectual support. This work was supported, in part, by grants from the National Alliance for Research on Schizophrenia and Depression Young, Independent, and Distinguished Investigator Awards, grant T32MH15330 from the National Institutes of Health and the Stanley Medical Research Institute.

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Authors and Affiliations

  1. Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    N A Sachs, A Sawa, S E Holmes, C A Ross & R L Margolis

  2. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A Sawa & C A Ross

  3. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C A Ross & R L Margolis

  4. Program of Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    C A Ross & R L Margolis

  5. Department of Psychiatry, New York University, New York, NY, USA

    L E DeLisi

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  1. N A Sachs
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Correspondence to R L Margolis.

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Sachs, N., Sawa, A., Holmes, S. et al. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry 10, 758–764 (2005). https://doi.org/10.1038/sj.mp.4001667

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