Abstract
How can we hope to explain mechanistically the schizophrenic phenotype? Perhaps through the reductionist approach of genetics, which is beginning to yield biological clues. Growing evidence supports the view that the well-established genetic risk factor DISC1 plays an important role in schizophrenia biology by interacting with FEZ1 and NDEL1 during neurodevelopment and with the phosphodiesterase PDE4B in neuronal cell signalling. Thus, DISC1 and its pathways support the neurodevelopmental hypothesis of schizophrenia and provide a mechanistic explanation for the characteristic cognitive deficits. Genetic variants of DISC1 also predispose to related affective (mood) disorders. As a consequence, we can speculate on the mechanisms of DISC1 action and possible routes to treatment for these common, debilitating brain disorders.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / genetics
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism
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Adaptor Proteins, Signal Transducing
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Animals
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Brain / embryology*
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Brain / growth & development*
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Brain / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 4
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Developmental / genetics
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Genetic Predisposition to Disease / genetics*
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Humans
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Models, Neurological
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Schizophrenia / genetics
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Schizophrenia / metabolism
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Schizophrenia / physiopathology*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DISC1 protein, human
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DNA-Binding Proteins
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FEZ1 protein, human
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LZTS1 protein, human
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NDEL1 protein, human
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Nerve Tissue Proteins
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Tumor Suppressor Proteins
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, human