Thomas Rhalena A, Ambalavanan Amirthagowri, Rouleau Guy A, Barker Philip A
Department of Neurology and Neurosurgery Montreal Neurological Institute McGill University 3801 University Montreal Quebec H3A 2B4 Canada.
Department of Human Genetics McGill University 1205 Dr Penfield Avenue Montreal Quebec H3A 1B1 Canada.
Mol Genet Genomic Med. 2016 Mar 11;4(4):447-56. doi: 10.1002/mgg3.215. eCollection 2016 Jul.
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.
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.
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.
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.
蛋白质NgR1由RTN4R编码，RTN4R是一个与精神分裂症相关的基因。我们之前报道NgR1是与癫痫相关的蛋白质LGI1的受体。NgR1调节突触数量和突触可塑性，而LGI1拮抗NgR1信号传导并促进突触形成。突触形成受损在神经疾病中很常见，我们推测LGI1 - NgR1信号通路可能与精神分裂症的发病有关。
我们使用全外显子组测序和桑格测序，在两个无亲缘关系的精神分裂症患者群体中筛查RTN4R和LGI1的变异。我们使用细胞表面结合试验检测LGI1与NgR1罕见编码变异的结合能力，并使用COS7细胞铺展试验检测NgR1的信号传导能力。
我们观察到RTN4R中一个先前报道的罕见编码变异（c.1195C>T，pR399W）。我们报道了在精神分裂症患者中首次鉴定出的LGI1突变。发现了三种不同的LGI1突变，两个错义突变（c.205G>A，p.V69I）和（c.313G>A，V105M），以及一个可能导致蛋白质截短的内含子变异（g.897T>C）。我们发现在细胞表面结合试验中，NgR1(R119W)和NgR1(277C)与LGI1的结合能力降低。COS7细胞铺展试验表明，NgR1突变体介导RhoA激活的能力受损。
NgR1和LGI1的变异可能与精神分裂症有关，在精神分裂症患者中发现的NgR1变异会损害LGI1 - NgR1信号传导。受损的LGI1 - NgR1信号传导可能导致疾病进展。
