Muiños-Gimeno Margarita, Guidi Monica, Kagerbauer Birgit, Martín-Santos Rocío, Navinés Ricard, Alonso Pino, Menchón José M, Gratacòs Mònica, Estivill Xavier, Espinosa-Parrilla Yolanda
Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
Hum Mutat. 2009 Jul;30(7):1062-71. doi: 10.1002/humu.21005.
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.
遗传和功能数据表明，神经营养因子3受体基因（NTRK3）表达的变化可能会影响神经元可塑性，这表明NTRK3在焦虑症的病理生理学中发挥作用。微小RNA（miRNA）通过与特定序列位点碱基配对发挥转录后基因调节作用，这些位点通常位于靶mRNA的3'非翻译区（3'UTR）。这些位点的变异可能导致基因表达变化，进而影响疾病易感性。我们通过对惊恐障碍（PD）、强迫症（OCD）患者以及对照人群的NTRK3基因的两种不同异构体的3'UTR进行重测序，研究其作为焦虑症候选易感因素的遗传变异情况。我们发现，位于NTRK3截短异构体中miR - 485 - 3p功能靶位点的rs28521337的C等位基因与OCD的囤积表型显著相关。我们还在NTRK3的3'UTR中鉴定出两个新的罕见变异体，即ss102661458和ss102661460，每个变异体仅存在于一名PD患者的一条染色体上。ss102661458变异体位于miR - 765的功能靶位点，而ss102661460位于miR - 509和miR - 128两种miRNA的功能靶位点，后者是一种在大脑中富集、参与神经元分化和突触加工的miRNA。有趣的是，这两个变异体显著改变了miRNA对NTRK3的介导调节作用，导致基因表达恢复。这些数据表明miRNA是NTRK3关键的转录后调节因子，并为焦虑症中NTRK3的等位基因特异性miRNA调节提供了一个框架。
