Abstract
The human discs, large homolog 1 gene (DLG1) is mapped to the schizophrenia-susceptibility locus 3q29, and it encodes a scaffold protein that interacts with the N-methyl-D-aspartate receptor presumably dysregulated in schizophrenia. In the current study, we have newly identified a splicing variant of DLG1, which is transcribed from an unreported 95-base-pair exon (exon 3b) and is labeled 3b(+). We investigated the mRNA expression of 3b(+) in the post-mortem dorsolateral prefrontal cortices of patients with psychiatric disorders, obtained from The Stanley Medical Research Institute, and examined the potential association of the expression with the genotype of the single-nucleotide polymorphism (SNP) rs3915512 located within exon 3b. A real-time quantitative reverse transcriptase-polymerase chain reaction revealed that the mRNA levels of 3b(+) were significantly reduced in patients with early-onset schizophrenia (onset at <18 years old, P=0.0003) but not in those with non-early-onset schizophrenia, early-onset or non-early-onset bipolar disorder or in the controls. Furthermore, the genotype at the rs3915512 SNP was closely associated with the levels of 3b(+) mRNA expression. It is inferred that the T allele fails to meet the exonic splicing enhancer consensus, thus resulting in skipping of exon 3b, leading to the expression of 3b(−) (the previously known DLG1 variant) but not 3b(+). Because all the subjects with early-onset schizophrenia in the current study possess the T/T genotype, the reduced level of the DLG1 3b(+) transcript may be involved in the susceptibility and/or pathophysiology of early-onset schizophrenia.
Highlights
Schizophrenia is a serious psychiatric disorder with a high prevalence of nearly 1% and a wide variety of mental dysfunctions that are only partially ameliorated by current antipsychotic drugs
It has been widely accepted in recent decades that N-methyl-Daspartate glutamate receptor (NMDAR) hypofunction may be involved in the pathophysiology of schizophrenia because NMDAR antagonists and anti-NMDAR antibodies cause psychotomimetic effects,[1,2,3,4] which might provide a valuable clue to understand the molecular and cellular basis of this disorder for development of more effective therapeutic methods
The deduced amino-acid sequence of the putative protein significant differences in the levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in each translated from the 3b(+) DLG1 transcript variant indicated that diagnostic group compared with the controls in the study to the insertion of exon 3b between exons 3a (relabeled from the examine the expression of housekeeping genes (Supplementary original exon 3) and 4 might lead to a premature termination of Table S1), the GAPDH mRNA values were used to normalize the translation due to the in-frame stop codon in exon 3b (Figure 2a). data for 3b(+) and 3b( − )
Summary
Schizophrenia is a serious psychiatric disorder with a high prevalence of nearly 1% and a wide variety of mental dysfunctions that are only partially ameliorated by current antipsychotic drugs. In our previous studies based on this hypothesis, to screen for schizophrenia-related genes we chose candidate genes that were upregulated in brain tissues by phencyclidine administration after the above critical period, ~3 weeks after birth, but failed to have any effect before this period Among such genes, we have identified Dlg[1] (discs, large homolog 1 of Drosophila)/SAP97 (synapse-associated protein 97 (DLG1)), which encodes synaptic scaffold proteins interacting with ionotropic glutamate receptors including NMDAR.[12,13] we found a genetic association of schizophrenia with human DLG1 from our two separate cohort studies using single-nucleotide polymorphisms (SNPs).[14,15] In agreement with our results, expression changes in the DLG1 proteins were observed in brains of patients with schizophrenia post-mortem.[16,17] genome-wide analyses of the copynumber variation found a significant excess of deletions in schizophrenia at the chromosomal position 3q29, which includes the DLG1 gene.[18,19]. The pH values between the control (CT) and non-EOS groups, and (ii) similar expression levels of the housekeeping genes, GAPDH, ACTB, PGK1, 18S and 28S rRNA, observed across all the diagnostic groups, suggest that
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