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Human Molecular Genetics Advance Access published online on March 1, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl040
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received November 1, 2005
Revised February 8, 2006
Accepted February 21, 2006

Article

Expression of DISC1 Binding Partners Is Reduced in Schizophrenia and Associated with DISC1 SNPs

Barbara K. Lipska 1 *, Tricia Peters 2, Thomas M. Hyde 2, Nader Halim 2, Cara Horowitz 2, Shruti Mitkus 2, Cynthia Shannon Weickert 2, Mitsuyuki Matsumoto 3, Akira Sawa 4, Richard Straub 2, Radhakrishna Vakkalanka 2, Mary M. Herman 2, Daniel R. Weinberger 2, and Joel E. Kleinman 2

1 Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Rm. 4N306, Bethesda, MD 20892-1385, USA
2 Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1385, USA
3 Functional Genomics, Molecular Medicine Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305-8585, Japan
4 Division of Neurobiology and Departments of Psychiatry and Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA

* To whom correspondence should be addressed.
Barbara K. Lipska, E-mail: lipskab{at}intra.nimh.nih.gov


  Abstract

DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation, such as NUDEL, FEZ1 and LIS1. We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex (DLPFC) of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high risk DISC1 polymorphisms. Although many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.


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