Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia

• Published in: Human molecular genetics Vol. 20; no. 15; pp. 3042 - 3051
• Main Authors: Sun, Chicheng, Cheng, Min-Chih, Qin, Rosie, Liao, Ding-Lieh, Chen, Tzu-Ting, Koong, Farn-Jong, Chen, Gong, Chen, Chia-Hsiang
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.2011
• Subjects: Adult; Adult and adolescent clinical studies; Benign; Biological and medical sciences; Blotting, Western; Brain; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - genetics; Cell Aggregation - genetics; Cell Aggregation - physiology; Cell Line; Cell membranes; Electrophysiological recording; Electrophysiology; Endoplasmic reticulum; Etiology; Exons; Family studies; Female; Fundamental and applied biological sciences. Psychology; gamma -Aminobutyric acid; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunocytochemistry; Immunohistochemistry; Male; Medical sciences; Mental disorders; Missense mutation; Molecular and cellular biology; Mutation; Nerve Tissue Proteins - genetics; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length - genetics; Promoters; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Schizophrenia; Schizophrenia - genetics; Synaptogenesis; Psychosis; Characterization; Gene; Schizophrenia; Genetics; Identification; Mutation
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddr208

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.