Uezato A, Yamamoto N, Iwayama Y, Hiraoka S, Hiraaki E, Umino A, Haramo E, Umino M, Yoshikawa T, Nishikawa T
Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
Transl Psychiatry. 2015 Oct 6;5(10):e654. doi: 10.1038/tp.2015.154.
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.
人类盘状大同源物1基因（DLG1）定位于精神分裂症易感位点3q29，它编码一种支架蛋白，该蛋白与在精神分裂症中可能失调的N-甲基-D-天冬氨酸受体相互作用。在本研究中，我们新鉴定出一种DLG1的剪接变体，它从一个未报道的95个碱基对的外显子（外显子3b）转录而来，并标记为3b(+)。我们研究了从斯坦利医学研究所获得的患有精神疾病患者的死后背外侧前额叶皮质中3b(+)的mRNA表达，并检测了该表达与位于外显子3b内的单核苷酸多态性（SNP）rs3915512基因型的潜在关联。实时定量逆转录聚合酶链反应显示，早发性精神分裂症患者（发病年龄<18岁，P=0.0003）中3b(+)的mRNA水平显著降低，但非早发性精神分裂症患者、早发性或非早发性双相情感障碍患者以及对照组中则未降低。此外，rs3915512 SNP的基因型与3b(+) mRNA表达水平密切相关。据推测，T等位基因不符合外显子剪接增强子共识，从而导致外显子3b跳跃，导致3b(-)（先前已知的DLG1变体）而非3b(+)的表达。由于本研究中所有早发性精神分裂症患者均具有T/T基因型，DLG1 3b(+)转录本水平降低可能与早发性精神分裂症的易感性和/或病理生理学有关。
