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Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes
Author(s) -
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
Publication year - 2018
Publication title -
psychiatry and clinical neurosciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.609
H-Index - 74
eISSN - 1440-1819
pISSN - 1323-1316
DOI - 10.1111/pcn.12628
Subject(s) - affect (linguistics) , glycine , schizophrenia (object oriented programming) , metabolomics , gene , cleavage (geology) , genetics , chemistry , biology , bioinformatics , psychology , psychiatry , amino acid , communication , paleontology , fracture (geology)
Aim Hypofunction of N ‐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. Methods First, 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 , and DLD ) 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. Results Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC , near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC , a potential neural tube defect causative mutation; and R253X in AMT . 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). Conclusion These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.