Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia
Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia
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DOI：
10.1093/hmg/ddr208
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发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Chen, Chia-Hsiang
中科院分区：
文献类型：
--
作者：
Sun, Chicheng;Cheng, Min-Chih;Chen, Chia-Hsiang
精神分裂症是一种严重的慢性精神障碍，其病因具有高度的遗传成分。多项研究表明，突触功能障碍可能是精神分裂症发病机制的基础。 Neuroligin 蛋白在突触后膜上充当细胞粘附分子，在突触发生和突触成熟中发挥关键作用。在这项研究中，我们对来自台湾的 584 名精神分裂症患者和 549 名对照受试者样本中的 Neuroligin-2 (NLGN2) 基因的所有外显子和启动子区域进行了系统测序。我们总共鉴定了 19 个基因变异，包括 6 种罕见的错义突变，例如 R215H（一名患者）、V510M（两名患者）、R621H（一名患者）、A637T（两名患者）、P800L（一名患者和一名对照）和 A819S（一名患者和一名对照）。计算机分析预测，两种患者特异性错义突变 R215H 和 R621H 具有破坏性作用，而其他错义突变是良性的。重要的是，免疫细胞化学和电生理记录的功能分析将 R215H 突变体鉴定为诱导 GABA 能突触发生的功能丧失突变体。从机制上讲，R215H突变体的突触发生缺陷是由于其滞留在内质网内并且无法转运至细胞膜。我们的研究表明，大脑中 GABA 能突触形成的缺陷可能是精神分裂症发病的一个重要因素。在对该突变的家族研究中，我们发现他的哥哥也携带该突变，但没有精神症状，表明该突变具有不完全外显率，因此应谨慎解释该突变的临床相关性。
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.