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.

RETRACTED: Identification of gene ontologies linked to prefrontal–hippocampal functional coupling in the human brain

“…There is increasing interest in the neuroligin family in schizophrenia because neuroligins form transsynaptic complexes with schizophreniaassociated neurexin (NRX) proteins (61,62). NLGN-NRX complexes are known to be important in brain development, and genetic variation in these genes has been associated with autism and schizophrenia (63)(64)(65)(66). The NLGN1-NRX complex has been found to specifically localize to glutamatergic synapses, where it helps stabilize the synapse and recruit additional synaptic proteins involved in synapse structure and function.…”

γ-Aminobutyric Acid Type A (GABAA) Receptor α Subunits Play a Direct Role in Synaptic Versus Extrasynaptic Targeting

“…3), providing an important research tool for future studies on different subtypes of receptors. Furthermore, we have recently demonstrated that such a model system is useful for the screening of human disease-related gene mutations by co-expressing GABA A -Rs with wild type or mutant NL2 identified from patients with schizophrenia (62). Our previous and current studies suggest that molecularly engineered hetero-synapses are a versatile model system that can be used to study not only synaptogenesis but also receptor targeting and functional deficits of gene mutations.…”

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome

“…Difference in the expression levels of specific KCC2 transcripts has been linked to schizophrenia and affective disorders (38). We have previously discovered a significant decrease of KCC2 expression induced by a neuroligin 2 mutation found in patients with schizophrenia (39,40), suggesting a potential role of KCC2 in the pathogenesis of schizophrenia. Altered KCC2 expression has also been implied in stress (41).…”