Novel IL1RAP mutation associated with schizophrenia interferes with neuronal growth and related NF-κB signal pathways

Abstract

Schizophrenia is a complex, severe psychiatric disorder with a high heritability that affects approximately 1% of the world’s population. Numerous schizophrenia-related risk genes have been reported in large-scale studies, but the role of most genetic abnormalities in the pathogenesis of the disease is still obscure. In this study, using whole-exome sequencing, we identified a novel nonsense mutation c.1324C > T in the Interleukin 1 receptor accessory protein (IL1RAP) gene in four affected individuals with schizophrenia of a Chinese family. IL1RAP was found involved in initiating the immune responses and regulating synaptic formation. Considering that schizophrenia has been hypothesized to be neurodevelopment disorder for decades, we further explored the influence of altered expression of IL1RAP gene on neuronal growth, and assessed whether this mutation affects the function of IL1RAP protein in IL-1 signaling pathway. We used lentivirus-mediated shRNA to knockdown the IL1RAP gene expression, which suppressed the axon and dendrites growth of cultured mouse cortical neurons. These defects can be recovered by human IL1RAP wild type construct, but not the R442* mutant construct. Furthermore, this mutant even inhibited neuronal growth and IL-1β-induced JNK phosphorylation when overexpressed in cortical neurons. Although overexpression of this mutant in HePG2 cells did not change IL1RAP protein expression, it partially prohibited the IL-1β-induced nuclear translocation of transcript factor NF-κB, indicating that IL1RAP c.1324C > T is a loss-of-function mutation. Our findings show that IL1RAP plays an important role in early stages of neurodevelopment, and the mutation c.1324C > T may contribute to the pathogenesis of schizophrenia.