| 1 | Hum. Genet. 2011 Oct 130: 563-73 |
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| PMID | 21424692 |
| Title | Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. |
| Abstract | Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders. |
| SCZ Keywords | schizophrenia |
| 2 | Hum. Mol. Genet. 2011 Aug 20: 3042-51 |
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| PMID | 21551456 |
| Title | Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia. |
| Abstract | schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution. |
| SCZ Keywords | schizophrenia |
| 3 | Behav. Brain Res. 2013 Aug 251: 50-64 |
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| PMID | 22820233 |
| Title | Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2. |
| Abstract | Mutations in neurexin and neuroligin genes have been associated with neurodevelopmental disabilities including autism. Autism spectrum disorder is diagnosed by aberrant reciprocal social interactions, deficits in social communication, and repetitive, stereotyped patterns of behaviors, along with narrow restricted interests. Mouse models have been successfully used to study physiological and behavioral outcomes of mutations in the trans-synaptic neurexin-neuroligin complex. To further understand the behavioral consequences of Neuroligin2 (NLGN2) mutations, we assessed several behavioral phenotypes relevant to autism in neuroligin2 null (NLGN2(-/-)), heterozygote (NLGN2(+/-)), and wildtype (NLGN2(+/+)) littermate control mice. Reduced breeding efficiency and high reactivity to handling was observed in NLGN2(-/-) mice, resulting in low numbers of adult mice available for behavioral assessment. Consistent with previous findings, NLGN2(-/-) mice displayed normal social behaviors, concomitant with reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones. No spontaneous stereotypies or repetitive behaviors were detected. Acoustic, tactile, and olfactory sensory information processing as well as sensorimotor gating were not affected. NLGN2(-/-) pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than NLGN2(+/+) littermate controls. The present findings add to the growing literature on the role of neurexins and neuroligins in physiology and behavior relevant to neurodevelopmental disorders. |
| SCZ Keywords | schizophrenia |
| 4 | Hum. Mol. Genet. 2013 May 22: 2055-66 |
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| PMID | 23393157 |
| Title | Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. |
| Abstract | The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions. |
| SCZ Keywords | schizophrenia |
| 5 | PLoS ONE 2013 -1 8: e56871 |
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| PMID | 23451101 |
| Title | Hippocampal neuroligin-2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. |
| Abstract | Disturbances of the excitation/inhibition (E/I) balance in the brain were recently suggested as potential factors underlying disorders like autism and schizophrenia resulting in associated behavioral alterations including changes in social and emotional behavior as well as abnormal aggression. Neuronal cell adhesion molecules (nCAMs) and mutations in these genes were found to be strongly implicated in the pathophysiology of these disorders. Neuroligin2 (NLGN2) is a postsynaptic cell adhesion molecule, which is predominantly expressed at inhibitory synapses and required for synapse specification and stabilization. Changes in the expression of NLGN2 were shown to result in alterations of social behavior as well as altered inhibitory synaptic transmission, hence modifying the E/I balance. In our study, we focused on the role of NLGN2 in the dorsal hippocampus in the regulation of emotional and social behaviors. To this purpose, we injected an AAV construct overexpressing NLGN2 in the hippocampus of rats and investigated the effects on behavior and on markers for the E/I ratio. We could show an increase in GAD65, a GABA-synthesizing protein in neuronal terminals, and furthermore, reduced exploration of novel stimuli and less offensive behavior. Our data suggest NLGN2 in the hippocampus to be strongly implicated in maintaining the E/I balance in the brain and thereby modulating social and emotional behavior. |
| SCZ Keywords | schizophrenia |
| 6 | J. Biol. Chem. 2014 Oct 289: 27585-603 |
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| PMID | 25157101 |
| Title | Dystroglycan binding to ?-neurexin competes with neurexophilin-1 and neuroligin in the brain. |
| Abstract | ?-Neurexins (?-Nrxn) are mostly presynaptic cell surface molecules essential for neurotransmission that are linked to neuro-developmental disorders as autism or schizophrenia. Several interaction partners of ?-Nrxn are identified that depend on alternative splicing, including neuroligins (Nlgn) and dystroglycan (?DAG). The trans-synaptic complex with Nlgn1 was extensively characterized and shown to partially mediate ?-Nrxn function. However, the interactions of ?-Nrxn with ?DAG, neurexophilins (Nxph1) and NLGN2, ligands that occur specifically at inhibitory synapses, are incompletely understood. Using site-directed mutagenesis, we demonstrate the exact binding epitopes of ?DAG and Nxph1 on Nrxn1? and show that their binding is mutually exclusive. Identification of an unusual cysteine bridge pattern and complex type glycans in Nxph1 ensure binding to the second laminin/neurexin/sex hormone binding (LNS2) domain of Nrxn1?, but this association does not interfere with Nlgn binding at LNS6. ?DAG, in contrast, interacts with both LNS2 and LNS6 domains without inserts in splice sites SS#2 or SS#4 mostly via LARGE (like-acetylglucosaminyltransferase)-dependent glycans attached to the mucin region. Unexpectedly, binding of ?DAG at LNS2 prevents interaction of Nlgn at LNS6 with or without splice insert in SS#4, presumably by sterically hindering each other in the u-form conformation of ?-Nrxn. Thus, expression of ?DAG and Nxph1 together with alternative splicing in Nrxn1? may prevent or facilitate formation of distinct trans-synaptic Nrxn·Nlgn complexes, revealing an unanticipated way to contribute to the identity of synaptic subpopulations. |
| SCZ Keywords | schizophrenia |
| 7 | Ann. Hum. Genet. 2016 Jan 80: 38-49 |
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| PMID | 26474449 |
| Title | Practical Experience of the Application of a Weighted Burden Test to Whole Exome Sequence Data for Obesity and Schizophrenia. |
| Abstract | For biological and statistical reasons it makes sense to combine information from variants at the level of the gene. One may wish to give more weight to variants which are rare and those that are more likely to affect function. A combined weighting scheme, implemented in the SCOREASSOC program, was applied to whole exome sequence data for 1392 subjects with schizophrenia and 982 with obesity from the UK10K project. Results conformed fairly well with null hypothesis expectations and no individual gene was strongly implicated. However, a number of the higher ranked genes appear plausible candidates as being involved in one or other phenotype and may warrant further investigation. These include MC4R, NLGN2, CRP, DONSON, GTF3A, IL36B, ADCYAP1R1, ARSA, DLG1, SIK2, SLAIN1, UBE2Q2, ZNF507, CRHR1, MUSK, NSF, SNORD115, GDF3 and HIBADH. Some individual variants in these genes have different frequencies between cohorts and could be genotyped in additional subjects. For other genes, there is a general excess of variants at many different sites so attempts at replication would be more difficult. Overall, the weighted burden test provides a convenient method for using sequence data to highlight genes of interest. |
| SCZ Keywords | schizophrenia |
| 8 | Neuropharmacology 2016 Jan 100: 56-65 |
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| PMID | 26142252 |
| Title | Neuroligin 2 deletion alters inhibitory synapse function and anxiety-associated neuronal activation in the amygdala. |
| Abstract | Neuroligin 2 (NLGN2) is a synaptic adhesion protein that plays a central role in the maturation and function of inhibitory synapses. NLGN2 mutations have been associated with psychiatric disorders such as schizophrenia, and in mice, deletion of NLGN2 results in a pronounced anxiety phenotype. To date, however, the molecular and cellular mechanisms linking NLGN2 deletion to psychiatric phenotypes remain completely unknown. The aim of this study was therefore to define the role of NLGN2 in anxiety-related neural circuits. To this end, we used a combination of behavioral, immunohistochemical, and electrophysiological approaches in NLGN2 knockout (KO) mice to expand the behavioral characterization of these mice and to assess the functional consequences of NLGN2 deletion in the amygdala. Moreover, we investigated the differential activation of anxiety-related circuits in NLGN2 KO mice using a cFOS activation assay following exposure to an anxiogenic stimulus. We found that NLGN2 is present at the majority of inhibitory synapses in the basal amygdala, where its deletion affects postsynaptic structures specifically at perisomatic sites and leads to impaired inhibitory synaptic transmission. Following exposure to an anxiogenic environment, NLGN2 KO mice show a robust anxiety phenotype as well as exacerbated induction of cFOS expression specifically in CaMKII-positive projection neurons, but not in parvalbumin- or somatostatin-positive interneurons. Our data indicate that NLGN2 deletion predominantly affects inhibitory synapses onto projection neurons in basal amygdala, resulting in decreased inhibitory drive onto these neurons and leading to their excessive activation under anxiogenic conditions. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. |
| SCZ Keywords | schizophrenia |