Abstract
Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.
Highlights
Schizophrenia typically develops after adolescence [1]
Based on this series of experiments using a DNA microarray technique, we detected as candidates for this type of novel schizophrenia-related genes the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1), whose mRNAs were up-regulated greater in the adult than in the infant rats by these schizophrenomimetics
A schematic representation of the structures of the human WDR3 and ALG1 genes and location of the single nucleotide polymorphisms (SNPs) are shown in Fig 1 and Table 1
Summary
Schizophrenia typically develops after adolescence [1]. Methamphetamine, an indirect dopamine agonist, and phencyclidine (PCP) and ketamine, antagonists of the N-methyl-D aspartate (NMDA) type glutamate receptor, are known to cause schizophrenia-like symptoms only after the adolescent period [2,3,4]. We have explored the gene transcripts that are developmentally regulated after methamphetamine and PCP administrations in the rat cerebral neocortex Based on this series of experiments using a DNA microarray technique, we detected as candidates for this type of novel schizophrenia-related genes the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1), whose mRNAs were up-regulated greater in the adult (postnatal days 50) than in the infant (postnatal days 8) rats by these schizophrenomimetics. WDR3, known as DIP2 and UTP12, is broadly expressed including in the brain [12] This protein is contained in the nuclear, nucleolus and the main component of the small 40S ribosome subunit [12,13,14]. WDR3 and ALG1 may be associated with the susceptibility and/or pathogenesis of schizophrenia
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