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The regulation of tetraspanin 8 gene expression-A potential new mechanism in the pathogenesis of bipolar disorder.

Am J Med Genet B Neuropsychiatr Genet. 2017 Oct;174(7):740-750. doi:10.1002/ajmg.b.32571. Epub 2017 Aug 04
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摘要


In a previous study, we identified the single nucleotide polymorphism (SNP) rs4500567, located in the upstream region of tetraspanin 8 to be associated with bipolar disorder (BD). Due to its proximal position, the SNP might have an impact on promoter activity, thus on gene expression. We investigated the impact of rs4500567 on Tduanyu1842N8 expression in vitro with luciferase-based promoter assays in human embryonic kidney (HEK293) and neuroblastoma cells (SH-SY5Y), and its effect on expression of downstream associated genes by microarray-based transcriptome analyses. Immunohistochemical localization studies on murine brain slices served to identify possible target regions of altered Tduanyu1842N8 expression in the brain. Promoter assays revealed decreased Tduanyu1842N8 expression in presence of the minor allele. Transcriptome analyses of cells, mirroring the effects of putatively reduced Tduanyu1842N8 expression in minor allele carriers, resulted in 231 differentially expressed genes with enrichments of relevant signaling pathways for psychiatric disorders and neuronal development. Finally, we demonstrate Tspan8 abundance in mouse cerebellum and hippocampus. These findings point to a role of Tduanyu1842N8 in neuronal function or development. Considering a rather protective effect of the minor allele of rs4500567, our findings reveal a possible novel mechanism that contributes to the development of BD.

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