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A schizophrenia-linked KALRN coding variant alters neuron morphology, protein function, and transcript stability
Biological Psychiatry ( IF 9.6 ) Pub Date : 2018-03-01 , DOI: 10.1016/j.biopsych.2017.10.024
Theron A Russell 1 , Melanie J Grubisha 2 , Christine L Remmers 1 , Seok Kyu Kang 1 , Marc P Forrest 1 , Katharine R Smith 1 , Katherine J Kopeikina 1 , Ruoqi Gao 1 , Robert A Sweet 3 , Peter Penzes 4
Affiliation  

BACKGROUND Large-scale genetic studies have revealed that rare sequence variants, including single nucleotide variants (SNVs), in glutamatergic synaptic genes are enriched in schizophrenia patients. However, the majority are too rare to show any association with disease and have not been examined functionally. One such SNV, KALRN-P2255T, displays a penetrance that greatly exceeds that of previously identified schizophrenia-associated SNVs. Therefore, we sought to characterize its effects on the function of kalirin (Kal)-9, a dual Ras-related C3 botulinum toxin substrate 1 and Ras homologue gene family, member A (RhoA) guanine nucleotide exchange factor, upregulated in human schizophrenia brain tissue. METHODS Kal9 was overexpressed in primary rat cortical neurons or human embryonic kidney 293 (HEK293) cells. The effects of the P2255T variant on dendritic branching, dendritic spine morphology, protein and messenger RNA stability, and catalytic activity were examined. RESULTS Kal9-P2255T leads to diminished basal dendritic branching and dendritic spine size, compared with wild-type Kal9. The P2255T SNV directly affected Kal9 protein function, causing increased RhoA activation in HEK293 cells, but had no effect on Ras-related C3 botulinum toxin substrate 1 activation. Consistent with human postmortem findings, we found that Kal9-P2255T protein levels were higher than those of wild-type Kal9 in neurons. Increased messenger RNA stability was detected in HEK293 cells, indicating that this was the cause of the higher protein levels. When analyzed together, increased intrinsic RhoA guanine nucleotide exchange factor catalytic activity combined with increased messenger RNA expression led to net enhancement of RhoA activation, known to negatively impact neuronal morphology. CONCLUSIONS Taken together, our data reveal a novel mechanism for disease-associated SNVs and provide a platform for modeling morphological changes in mental disorders.

中文翻译:

精神分裂症相关的 KALRN 编码变体改变神经元形态、蛋白质功能和转录本稳定性

背景技术大规模遗传学研究表明,谷氨酸能突触基因中的稀有序列变异,包括单核苷酸变异 (SNV),在精神分裂症患者中富集。然而,大多数都非常罕见,无法显示与疾病有任何关联,并且尚未进行功能检查。一个这样的 SNV,KALRN-P2255T,显示出的外显率大大超过了先前发现的精神分裂症相关 SNV。因此,我们试图描述其对 kalirin (Kal)-9 功能的影响,kalirin (Kal)-9 是一种双 Ras 相关的 C3 肉毒杆菌毒素底物 1 和 Ras 同源基因家族,成员 A (RhoA) 鸟嘌呤核苷酸交换因子,在人类精神分裂症大脑中上调组织。方法 Kal9 在原代大鼠皮层神经元或人胚肾 293 (HEK293) 细胞中过表达。研究了 P2255T 变体对树突分支、树突棘形态、蛋白质和信使 RNA 稳定性以及催化活性的影响。结果与野生型 Kal9 相比,Kal9-P2255T 导致基础树突分支和树突棘大小减少。P2255T SNV 直接影响 Kal9 蛋白功能,导致 HEK293 细胞中 RhoA 活化增加,但对 Ras 相关的 C3 肉毒杆菌毒素底物 1 活化没有影响。与人类尸检发现一致,我们发现 Kal9-P2255T 蛋白水平高于神经元中的野生型 Kal9。在 HEK293 细胞中检测到信使 RNA 稳定性增加,表明这是蛋白质水平较高的原因。一起分析时,增加的内在 RhoA 鸟嘌呤核苷酸交换因子催化活性与增加的信使 RNA 表达相结合导致 RhoA 激活的净增强,已知会对神经元形态产生负面影响。结论 综上所述,我们的数据揭示了一种与疾病相关的 SNV 的新机制,并为模拟精神障碍的形态学变化提供了一个平台。
更新日期:2018-03-01
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