Aberrant
neuregulin 1-ErbB4 signaling has been implicated in
schizophrenia. We previously identified a novel
schizophrenia-associated missense mutation (
valine to
leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (
Val/Leu) and non-carriers (
Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (
Val/Val N = 6,
Val/Leu N = 5, T test, FDR (1 %), α = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed
inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling,
protein kinase C (
PKC)-eta (PRKCH) and non-
receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (
serine/
threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35
peptides. IPA showed neurite outgrowth (six
peptides) as the top annotated function. Phosphorylation of these
peptides was significantly decreased in ErbB4-treated
Val/Val but not in
Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to
schizophrenia pathophysiology.