Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes
Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes
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甘氨酸裂解系统基因的突变可能通过代谢组学的变化影响精神分裂症的阴性症状
DOI：
10.1111/pcn.12628
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发表时间：
2018
影响因子：
11.9
通讯作者：
Kakiuchi Chihiro
中科院分区：
文献类型：
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作者：
Yoshikawa Akane;Nishimura Fumichika;Inai Aya;Eriguchi Yosuke;Nishioka Masaki;Takaya Atsuhiko;Tochigi Mamoru;Kawamura Yoshiya;Umekage Tadashi;Kato Kayoko;Sasaki Tsukasa;Ohashi Yoshiaki;Iwamoto Kazuya;Kasai Kiyoto;Kakiuchi Chihiro
目的N-甲基-D-天冬氨酸受体（NMDAR）功能低下可能与精神分裂症（SCZ）的病理生理有关。最近，甘氨酸裂解系统（GCS）被证明影响脑中的NMDAR功能。GCS功能缺陷引起非酮症高甘氨酸血症，其非典型表型表现为与SCZ相似的精神症状。在这里，我们研究了参与GCS SCZ.MethodsFirst，以确定罕见的变异和外显子缺失，我们重新测序的所有编码外显子和剪接位点的4个GCS基因（GLDC，AMT，GCSH，和DLD）在474例SCZ患者和475名对照，并进行多重连接依赖性探针扩增分析SCZ。接下来，我们使用携带GCS变体的患者（n= 5）和对照（n= 5）的血浆，通过毛细管电泳飞行时间质谱法进行代谢组学分析。血浆代谢产物和阳性和阴性症状量表评分之间的相关性进行了进一步examined. ResultsPossible损害变异体观察SCZ：A203 V，S801 N在GLDC，附近的非典型非酮症高甘氨酸血症致病突变（A202 V，A802 V）; G825 D在GLDC，一个潜在的神经管缺陷致病突变;和R253 X在AMT。在携带GCS变体的患者中观察到血浆5-氧代脯氨酸（焦谷氨酸）、天冬氨酸和谷氨酸显著升高，这可能影响NMDAR功能。结论GCS罕见变异可能通过升高天冬氨酸水平影响SCZ阴性症状而参与SCZ的病理生理过程。
AimHypofunction ofN‐methyl‐D‐aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ.MethodsFirst, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC,AMT,GCSH, andDLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation‐dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n= 5) and controls (n= 5) by capillary electrophoresis time‐of‐flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined.ResultsPossibly damaging variants were observed in SCZ: A203V, S801N inGLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D inGLDC, a potential neural tube defect causative mutation; and R253X inAMT. Marked elevation of plasma 5‐oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r= −0.942,P= 0.0166).ConclusionThese results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.