1. ¹Division of Neurobiology, Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
2. ²Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
3. ³Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
4. ⁴Program of Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
5. ⁵Department of Psychiatry, New York University, New York, NY, USA

Correspondence: Dr RL Margolis, MD, Department of Psychiatry, The Johns Hopkins University School of Medicine, Meyer 2-181, 600 N Wolfe Street, Baltimore, MD 21287, USA. E-mail: rmargoli@jhmi.edu

Received 29 October 2004; Revised 2 February 2005; Accepted 24 February 2005; Published online 10 May 2005.

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.