Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia

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.

PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior

“…Considering that deletions in the 3q29 region occur at different break points in patients, resulting in deletions of varying number of genes in each case (Mulle et al, 2010;Pollazzon et al, 2009;Quintero-Rivera et al, 2010;Seo et al, 2010), it is possible that the multiple clinical features in this syndrome are synergistically caused by PAK2 and other genes in this region. This may be supported by a recent study, in which DLG1, another gene located in the 3q29 deletion region, was found to be involved in early-onset schizophrenia (Toyooka et al, 2002;Uezato et al, 2015).…”

Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study

“…Generally, early-onset schizophrenia (EOS) is intractable and the prognosis is poor compared with non-early-onset schizophrenia (non-EOS). In addition, in our previous clinical genetic study in consideration of the onset age, gene expression related to glutamate neurotransmission was different between EOS and non-EOS [31]. Findings observed in these and our studies suggested that heterogeneity of the system related to glutamate neurotransmission appears as a differences in the onset age of schizophrenia and influences response to treatment.…”

The DLGAP family: neuronal expression, function and role in brain disorders

“…Another study demonstrated increased expression of DLGAP1 in the nucleus accumbens [ 9 ]. Moreover, the expression level of DLG1 and DLG2 was also found to be significantly skewed in a schizophrenia rat model and in schizophrenic patients [ 32 , 96 – 98 ]. The deregulation of DLGs and DLGAP1 in these patients could be an indication of malfunction of NMDA receptors.…”