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Human Molecular Genetics Advance Access originally published online on March 1, 2006
Human Molecular Genetics 2006 15(8):1245-1258; doi:10.1093/hmg/ddl040
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Published by Oxford University Press 2006

Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs

Barbara K. Lipska1,*, Tricia Peters1, Thomas M. Hyde1, Nader Halim1, Cara Horowitz1, Shruti Mitkus1, Cynthia Shannon Weickert1, Mitsuyuki Matsumoto2, Akira Sawa3, Richard E. Straub1, Radhakrishna Vakkalanka1, Mary M. Herman1, Daniel R. Weinberger1 and Joel E. Kleinman1

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

* To whom correspondence should be addressed at: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Building 10, Room 4N306, Bethesda, MD 20892-1385, USA. Tel: +1 3014969501; Fax: +1 3014022751; Email: lipskab{at}intra.nimh.nih.gov

Received November 1, 2005; Revised December 30, 2005; Accepted February 8, 2006

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 fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). 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 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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