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

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          Abstract

          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.

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          Most cited references46

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          Rare and common variants: twenty arguments.

          Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk. The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect. Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled.
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            Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series.

            Voltage-gated potassium channels are thought to be the target of antibodies associated with limbic encephalitis. However, antibody testing using cells expressing voltage-gated potassium channels is negative; hence, we aimed to identify the real autoantigen associated with limbic encephalitis. We analysed sera and CSF of 57 patients with limbic encephalitis and antibodies attributed to voltage-gated potassium channels and 148 control individuals who had other disorders with or without antibodies against voltage-gated potassium channels. Immunohistochemistry, immunoprecipitation, and mass spectrometry were used to characterise the antigen. An assay with HEK293 cells transfected with leucine-rich, glioma-inactivated 1 (LGI1) and disintegrin and metalloproteinase domain-containing protein 22 (ADAM22) or ADAM23 was used as a serological test. The identity of the autoantigen was confirmed by immunoabsorption studies and immunostaining of Lgi1-null mice. Immunoprecipitation and mass spectrometry analyses showed that antibodies from patients with limbic encephalitis previously attributed to voltage-gated potassium channels recognise LGI1, a neuronal secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22. Immunostaining of HEK293 cells transfected with LGI1 showed that sera or CSF from patients, but not those from control individuals, recognised LGI1. Co-transfection of LGI1 with its receptors, ADAM22 or ADAM23, changed the pattern of reactivity and improved detection. LGI1 was confirmed as the autoantigen by specific abrogation of reactivity of sera and CSF from patients after immunoabsorption with LGI1-expressing cells and by comparative immunostaining of wild-type and Lgi1-null mice, which showed selective lack of reactivity in brains of Lgi1-null mice. One patient with limbic encephalitis and antibodies against LGI1 also had antibodies against CASPR2, an autoantigen we identified in some patients with encephalitis and seizures, Morvan's syndrome, and neuromyotonia. LGI1 is the autoantigen associated with limbic encephalitis previously attributed to voltage-gated potassium channels. The term limbic encephalitis associated with antibodies against voltage-gated potassium channels should be changed to limbic encephalitis associated with LGI1 antibodies, and this disorder should be classed as an autoimmune synaptic encephalopathy. National Institutes of Health, National Cancer Institute, and Euroimmun. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration.

              Nogo has been identified as a component of the central nervous system (CNS) myelin that prevents axonal regeneration in the adult vertebrate CNS. Analysis of Nogo-A has shown that an axon-inhibiting domain of 66 amino acids is expressed at the extracellular surface and at the endoplasmic reticulum lumen of transfected cells and oligodendrocytes. The acidic amino terminus of Nogo-A is detected at the cytosolic face of cellular membranes and may contribute to inhibition of axon regeneration at sites of oligodendrocyte injury. Here we show that the extracellular domain of Nogo (Nogo-66) inhibits axonal extension, but does not alter non-neuronal cell morphology. In contrast, a multivalent form of the N terminus of Nogo-A affects the morphology of both neurons and other cell types. Here we identify a brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo-66. Cleavage of the Nogo-66 receptor and other glycophosphatidylinositol-linked proteins from axonal surfaces renders neurons insensitive to Nogo-66. Nogo-66 receptor expression is sufficient to impart Nogo-66 axonal inhibition to unresponsive neurons. Disruption of the interaction between Nogo-66 and its receptor provides the potential for enhanced recovery after human CNS injury.
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                Author and article information

                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                11 March 2016
                July 2016
                : 4
                : 4 ( doiID: 10.1002/mgg3.2016.4.issue-4 )
                : 447-456
                Affiliations
                [ 1 ] Department of Neurology and NeurosurgeryMontreal Neurological Institute McGill University 3801 University Montreal Quebec H3A 2B4Canada
                [ 2 ] Department of Human GeneticsMcGill University 1205 Dr Penfield Avenue Montreal Quebec H3A 1B1Canada
                [ 3 ] Department of BiologyUniversity of British Columbia Kelowna BC. V1V 1V7Canada
                Author notes
                [*] [* ] Correspondence

                Philip A. Barker , Department of Biology , University of British Columbia , Kelowna B.C., Canada. Tel: (514) 807 9582; Fax: (514) 807 2376; E‐mail: philip.barker@ 123456ubc.ca

                Article
                MGG3215
                10.1002/mgg3.215
                4947863
                27468420
                669981d1-6840-4cfb-91a0-c412f7ead36a
                © 2016 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 December 2015
                : 17 February 2016
                : 19 February 2016
                Page count
                Pages: 10
                Funding
                Funded by: Canadian Institutes of Health Research
                Award ID: 37850
                Funded by: Fonds de Recherche du Québec Santé (FRQS)
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                mgg3215
                July 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:18.07.2016

                lgi1,ngr1,rhoa,rtn4r,schizophrenia,synapse formation
                lgi1, ngr1, rhoa, rtn4r, schizophrenia, synapse formation

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