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Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulating N-methyl-d-aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients (n = 1,140) and controls (n = 1,140). We identified eight missense variants, of which four were previously unreported. Case–control genetic association analysis of these variants in a larger cohort (n = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed.

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Acknowledgement

This study was supported in part by Grants-in-Aid for Scientific Research (T.Y.) and by Grant-in-Aid for Scientific Research on Innovative Areas (T.Y.), from the Japan Society for the Promotion of Science (JSPS), Japan. In addition, this study was supported by RIKEN Brain Science Institute Funds (T.Y.), and a part of this study is the result of the “Development of biomarker candidates for social behavior” project, carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.Y.).

Conflict of interest

The authors declare that they have no potential conflicts of interest.

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Authors and Affiliations

  1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Shabeesh Balan, Yoshimi Iwayama, Kazuo Yamada, Tomoko Toyota, Tetsuo Ohnishi, Manabu Toyoshima, Chie Shimamoto, Takeo Yoshikawa & Motoko Maekawa

  2. Department of Life Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan

    Chie Shimamoto

  3. Division of Clinical Medicine, Department of Psychiatry, University of Tsukuba, Ibaraki, Japan

    Masayuki Ide

  4. Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Shizuoka, Japan

    Yasuhide Iwata & Katsuaki Suzuki

  5. Department of Psychiatry and Neurobiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

    Mitsuru Kikuchi

  6. Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan

    Tasuku Hashimoto & Nobuhisa Kanahara

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  1. Shabeesh Balan
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  2. Yoshimi Iwayama
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Correspondence to Takeo Yoshikawa.

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Balan, S., Iwayama, Y., Yamada, K. et al. Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia. J Neural Transm 122, 477–485 (2015). https://doi.org/10.1007/s00702-014-1269-0

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