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首页> 外文期刊>Human mutation >Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders.
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Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders.

机译：神经营养蛋白3受体基因（NTRK3）的功能MicroRNA靶位点中的等位基因变异作为焦虑症的易感因素。

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摘要

Genetic and functional data indicate that variation in the expression of the neurotrophin-3 receptor gene (NTRK3) may have an impact on neuronal plasticity, suggesting a role for NTRK3 in the pathophysiology of anxiety disorders. MicroRNA (miRNA) posttranscriptional gene regulators act by base-pairing to specific sequence sites, usually at the 3'UTR of the target mRNA. Variants at these sites might result in gene expression changes contributing to disease susceptibility. We investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by resequencing their 3'UTRs in patients with panic disorder (PD), obsessive-compulsive disorder (OCD), and in controls. We have found the C allele of rs28521337, located in a functional target site for miR-485-3p in the truncated isoform of NTRK3, to be significantly associated with the hoarding phenotype of OCD. We have also identified two new rare variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in one chromosome of a patient with PD. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two miRNAs, miR-509 and miR-128, the latter being a brain-enriched miRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the miRNA-mediated regulation of NTRK3, resulting in recovery of gene expression. These data implicate miRNAs as key posttranscriptional regulators of NTRK3 and provide a framework for allele-specific miRNA regulation of NTRK3 in anxiety disorders.
机译：遗传和功能数据表明，神经营养蛋白3受体基因（NTRK3）表达的变化可能对神经元可塑性产生影响，表明NTRK3在焦虑症的病理生理学中具有作用。 MicroRNA（miRNA）转录后基因调节剂通过与特定序列位点碱基配对起作用，通常在靶mRNA的3'UTR处。这些位点的变异可能导致基因表达改变，从而导致疾病易感性。我们通过对恐慌症（PD），强迫症（OCD）和对照患者的3'UTRs进行重新测序，研究了两种不同的NTRK3亚型作为焦虑症的候选易感性因素的遗传变异。我们发现rs28521337的C等位基因位于NTRK3截短亚型中miR-485-3p的功能性靶位，与OCD的ho积表型显着相关。我们还确定了NTRK3的3'UTR中的两个新的罕见变体ss102661458和ss102661460，它们各自仅存在于PD患者的一条染色体上。 ss102661458变体位于miR-765的功能性靶位点中，而ss102661460则位于两个miRNA（miR-509和miR-128）的功能性靶位点中，后者是大脑丰富的miRNA，参与神经元分化和突触加工。有趣的是，这两个变体显着改变了miRNA介导的NTRK3调控，从而恢复了基因表达。这些数据表明miRNA是NTRK3的关键转录后调控因子，并为焦虑症中NTRK3的等位基因特异性miRNA调控提供了框架。

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