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Genetic basis of disorders and genomic duplications: anxiety disorders and other chromosome 15 rearrangements

Final Activity Report Summary - GENOMIC DUPLICATION (Genetic basis of disorders and genomic duplications: anxiety disorders and other chromosome 15 rearrangements)

The main objective of this research project was to investigate the association between genomic rearrangements caused by segmental duplications and the pathogenesis of human psychiatric disorders, such as panic disorders. We firstly wanted to focus on the study of the DUP25 paramutable region, 15q24-26, characterising the genomic organisation of this duplication and studying the genes that it contained. We were particularly interested in the study of the neurothrophin-3 receptor gene (NTRK3), because of its potential role in the pathophysiology of panic disorder and in the analysis of a transgenic mouse model of overexpression of this gene which was generated in our laboratory, namely tgNTRK3.

In order to study the consequences of NTRK3 overexpression on the transcriptome we firstly set up a custom oligo microarray, assembling a catalogue of about 900 candidate genes that were either known to be involved in psychiatric disorders or had important roles in development, apoptosis, tyrosine kinase signalling, neurotrophic signalling and synaptic plasticity. This array was used for the study of the tgNTRK3 model in basal conditions as well as in different conditions of stress and pharmacological treatments. As a previous step to the use of this specific neuroarray we also studied the effect of overexpression of NTRK3 on the transcriptome using whole genome commercial arrays, namely the agilent mouse 22k oligo array. We could detect variations in genes involved in neuropeptide signalling and hormonal activity, some of which seemed to be implicated in anxiety and mood disorders. For example, neuromedin B (NMB) and its receptor (NMBR) were involved in stress responses and the family of Bombesin-like peptides to which NMB belonged were thought to modulate stress, fear and anxiety responses. Galanin coexisted with NA in the LC, seemed to exert anxiolytic actions under conditions of stress and its function manipulation, either genetic or pharmacological, altered anxiety-related responses. Transthyretin was involved in depression-like behaviour and probably acted as a modulator of the noradrenergic system, whereas angiotensinogen-related genes seemed to be associated with panic disorder in humans.

Finally, we worked towards the development of comparative genomic hybridisation (CGH) arrays for the characterisation of genomic rearrangements involved in human disease. A whole genome array and a specific chip for chromosome 15 were built.