A Mutation in NPAS3 That Segregates with Schizophrenia in a Small Family Leads to Protein Aggregation.

Schizophrenia and other major mental illnesses result from a complex interplay of genetic and environmental factors. We previously identified a mutation in NPAS3 that results in a valine to isoleucine (V304I) amino acid substitution segregating with schizophrenia in a small family. The amino acid change occurs in a potentially critical region for protein function. Furthermore, the same amino acid substitution in proteins related to familial Alzheimer's disease and transthyretin amyloidosis has been associated with protein aggregation. In this study, we demonstrate that NPAS3 is prone to aggregation, and that the V304I mutation in NPAS3 increases this propensity in both bacterial and mammalian expression systems. We also show that NPAS3-V304I reduces soluble endogenous NPAS3, and increases insoluble endogenous NPAS3 and leads to alteration of transcriptional activity. These results suggest that protein aggregation, potentially leading to cell dysfunction via a loss of protein function through sequestration, may contribute to the pathogenesis of schizophrenia and other forms of mental illness. Further exploration of the mechanisms leading to abnormal protein quality control could lead to new therapeutic targets.