Grant: Operating Grant

Schizophrenia (SC) is a debilitating chronic condition with symptoms that include hallucinations, delusions and social withdrawal. Family members of individuals with SC are at higher risk of developing SC than the general population, suggesting a genetic contribution. In 2003, we identified members of a family that carried an abnormal chromosome 14 and were diagnosed with SC. Using DNA from the affected mother and one daughter, we identified a disrupted gene on chromosome 14, the neuronal PAS3 gene, NPAS3. NPAS3 is a transcription factor that may help the growth of new neurons in the brain. The break in the NPAS3 gene is expected to lead to production of an inactive NPAS3 protein and this may lead to SC. The NPAS3 gene is expressed in some of the same brain regions that are altered in patients with SC. Other studies in mice show that 'knocking-out' Npas3 causes changes in behavior and brain structure similar to SC in humans. Our objective is to identify changes in the NPAS3 gene that contribute to schizophrenia. We have analysed the NPAS3 gene in people with SC, and found changes in the NPAS3 DNA sequence that may lead to production of abnormal NPAS3 protein. We will identify genes controlled by NPAS3 and find out how the DNA changes we have seen in people with SC affect NPAS3 function. One important aspect of SC management is early identification to allow treatment before the disorder has a serious impact on the life of the individual. We now need to know if the changes seen in NPAS3 can be used to identify people at risk for SC in the early stages of their disease. We will screen a larger number of individuals with SC for NPAS3 changes. We will correlate our genetic findings with clinical and psychological data. These studies will aid in the early detection of SC and the development of effective therapies.