title: 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Uezato
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwayama
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hiraoka
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Hiraaki
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Umino
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Haramo
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Umino
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nishikawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017668:Age of Onset; D000074288:Discs Large Homolog 1 Protein; D005091:Exons; D005260:Female; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger