title: Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.
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.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
authors.forename: Shabeesh
authors.initials: S
authors.lastname: Balan
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Manabu
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Chie
authors.initials: C
authors.lastname: Shimamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ide
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Iwata
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Suzuki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kikuchi
authors.forename: Tasuku
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Kanahara
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; C498710:PAG1 protein, human; D012333:RNA, Messenger