Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1–LGI1 signaling

BACKGROUND: The protein NgR1 is encoded by RTN4R, a gene linked to schizophrenia. We previously reported NgR1 as receptor for the epilepsy‐linked protein LGI1. NgR1 regulates synapse number and synaptic plasticity, whereas LGI1 antagonizes NgR1 signaling and promotes synapse formation. Impairments in synapse formation are common in neurological disease and we hypothesized that an LGI1–NgR1 signaling pathway may contribute to the development of schizophrenia. METHODS: We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1 using whole exome sequencing and Sanger sequencing. We tested the ability of LGI1 to bind rare coding variants of NgR1 using a cell surface binding assays and the signaling ability of NgR1 using COS7 cell‐spreading assays. RESULTS: We observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W). We report the first LGI1 mutations to be identified in individuals with schizophrenia. Three different LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M), and an intronic variant (g.897T>C) that likely leads to a protein truncation. We found NgR1(R119W) and NgR1(277C) have a reduced ability to bind LGI1 in a cell surface binding assay. COS7 cell‐spreading assays reveal that NgR1 mutants are impaired in their ability to mediate RhoA activation. CONCLUSION: Variants in NgR1 and LGI1 may be associated with schizophrenia and variants in NgR1 found in schizophrenic patients have impaired LGI1–NgR1 signaling. Impaired LGI1–NgR1 signaling may contribute to disease progression.