GENOMIC DUPLICATION · Genetic basis of disorders and genomic duplications: anxiety disorders and other chromosome 15 rearrangements
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-04-01 → 2005-03-31
- EU contribution
- €36,010
- Participants
- 1
- Scheme
- ERG
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
The goal of this research project is to investigate the association between genomic rearrangements caused by segmental duplications and the pathogenesis of human genetic disease. In particular we will focus on the analysis of the anxiety disorders, wich ar e complex and common psychiatric diseases associated with high morbidity and social cost. We have recently identified a genomic duplication on chromosome 15q24-26 (DUP25), which is a genetic susceptibility factor for these pathologies. The most likely mech anism causing anxiety disorders is the overexpression of specific genes on DUP 25. For this reason, one of the main objectives of this project is the analysis of gene dosage variation as a consequence of DUP25. We have developed murine models of overexpres sion of some of the genes contained in the duplicated region. Overexpression of one of these genes shows an anxiety phenotype in the murine model. Furthermore, the pathologic phenotypes could also be a consequence of the variation of global gene expression caused by these genomic mutations. In order to investigate this hypothesis, the consequences of DUP25 on the rest of the transcriptome will be evaluated throughout microarrays. Comparative hybridisation using microarrays should allow us the identification of genes responsible for these disorders that will be the object of further investigation. Finally we also plan the study of other genomic rearrangements associated with human chromosome 15 alterations, such as the case of the 15q11-13 deletions in Prader -Willi and Angelman syndrome. The investigation and understanding of the genomic organization of these duplicated genomic regions, covering all the aspects of the variability, should seed light on the mechanisms that lead to these human genomic disorders, and to understand the consequences of such rearrangements at the tissue and organ level. The identification of the underlying molecular causes of these genomic disorders should also facilitate their preventi#
Original text from CORDIS.
Participants
- FUNDACIO CENTRE DE REGULACIO GENOMICA · BARCELONACoordinatorSpain
Links
Data: CORDIS, © European Union