No abstract

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. MicroRNAs are post-transcriptional gene regulators that act by base pairing to specific sequences, usually at the 3'UTR of the target mRNA. Nucleotide variants at these sites might result in changes of gene expression contributing to disease susceptibility. We have investigated genetic variation in two different isoforms of NTRK3 as candidate susceptibility factors for anxiety by re-sequencing their 3'UTRs in patients with panic disorder, obsessive-compulsive disorder and 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 obsessive-compulsive disorder. Furthermore, we have also identified two new rare allelic variants in the 3'UTR of NTRK3, ss102661458 and ss102661460, each present only in a chomosome of a patient with panic disorder. The ss102661458 variant is located in a functional target site for miR-765, and the ss102661460 in functional target sites for two microRNAs, miR-509 and miR-128, the latter being a brain-enriched microRNA involved in neuronal differentiation and synaptic processing. Interestingly, these two variants significantly alter the microRNA-mediated regulation of NTRK3 and result in the recovery of gene expression. The reported data implicate microRNAs as key post-transcriptional regulators of NTRK3 and provide a framework for allele-specific microRNA regulation of NTRK3 in anxiety disorders.