Vol 8, No 3 - Drug Discovery and Proof of Concept
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chizophrenia is a syndrome characterized by psy- chotic symptoms (hallucinations, delusions, thought disor- der, and  cognitive  impairment), with  a  prevalence approaching 1% worldwide. Schizophrenia is clearly a genetic disorder. Results from twin and adoption studies show a heritability estimate for schizophrenia of 70% to 90%.1-3 However, analysis of recurrence risk estimates in families with one or more affected individuals clearly argues against schizophrenia being a single-gene disorder, even with the possibility of incomplete penetrance.4 As in other psychiatric disorders, the mode of transmission for schizophrenia is complex and multifactorial, with the pos- sibility of a number of genes conferring varying degrees of susceptibility.With this in mind, efforts have been directed at identifying allelic variants in genes that may confer increased risk for schizophrenia. Identification of schizo- phrenia susceptibility genes will also increase our under- standing of the molecular pathways involved in the etiol- ogy of the disorder, and may offer new therapeutic targets. DISC1 gene The disrupted in schizophrenia 1 (DISC1) gene is a 414.3 kb gene located on chromosomal region 1q42.2, and con- sists of 13 exons. DISC1 was originally identified as a can- didate gene for schizophrenia in a large Scottish family, in F r e e p a p e r Copyright © 2006 LLS SAS.  All rights reserved www.dialogues-cns.org Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia Barbara K. Lipska, PhD; Shruti N. Mitkus, PhD; Shiny V. Mathew, PhD; Robert Fatula; Thomas M. Hyde, MD, PhD; Daniel R. Weinberger, MD; Joel E. Kleinman, MD, PhD S Keywords: schizophrenia;  gene;  pathophysiology;  functional  genomics;  pre- frontal cortex; hippocampus; postmortem human brain Author affiliations: Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Md, USA   Address for correspondence: 10 Center Drive, Bldg 10, Rm 4N306, Bethesda, MD 20892-1385, USA (e-mail:lipskab@intra.nimh.nih.gov) The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) associ- ation studies and clinical data, suggesting that risk SNPs impact  on  hippocampal  structure  and  function.  We hypothesized that altered expression of DISC1 and/or its molecular  partners  (nuclear  distribution  element-like [NUDEL],  fasciculation  and  elongation  protein  zeta-1 [FEZ1], and lissencephaly 1 [LIS1]) may underlie its path- ogenic role in schizophrenia and explain its genetic asso- ciation. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizo- phrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression  of  each  showed  association  with  high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.   © 2006, LLS SAS Dialogues Clin Neurosci. 2006;8:353-357.