Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia.
Reduced cortical expression of a newly identified splicing variant of the DLG1 gene in patients with early-onset schizophrenia.
复制标题
DOI：
10.1038/tp.2015.154
复制
发表时间：
2015-10-06
影响因子：
6.8
通讯作者：
Nishikawa T
中科院分区：
文献类型：
--
作者：
Uezato A;Yamamoto N;Iwayama Y;Hiraoka S;Hiraaki E;Umino A;Haramo E;Umino M;Yoshikawa T;Nishikawa T
人类椎间盘，大同源1基因（DLG 1）定位于精神分裂症易感基因座3q 29，它编码一种支架蛋白，该蛋白与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。在目前的研究中，我们新发现了DLG 1的一个剪接变体，它是从一个未报道的95个碱基对外显子（外显子3b）转录的，标记为3b（+）。我们研究了来自斯坦利医学研究所的精神疾病患者死后背外侧前额叶皮质中3b（+）的mRNA表达，并检查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，3b（+）mRNA水平在早发性精神分裂症患者（发病年龄<18岁，P=0.0003）中显著降低，但在非早发性精神分裂症、早发性或非早发性双相情感障碍患者或对照组中则无显著降低。此外，rs3915512 SNP的基因型与3b（+）mRNA表达水平密切相关。推测T等位基因未能满足外显子剪接增强子共识，从而导致外显子3b的跳跃，导致3b（-）（之前已知的DLG 1变体）而不是3b（+）的表达。由于本研究中早发性精神分裂症患者均为T/T基因型，故DLG 1 3b（+）转录水平的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。
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.