Characterization of 7q11.23 reciprocal aneusomy syndromes: from patients to functional pathways (and back)

Informations projet

7DUP

N° de convention de subvention: 656359

DOI

10.3030/656359

Projet clôturé

Date de signature de la CE 17 Avril 2015

Date de début 1 Avril 2016

Date de fin 31 Mars 2018

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 158 121,60

Contribution de l’UE

€ 158 121,60

Coordonné par

UNIVERSIDAD POMPEU FABRA
Spain

Periodic Reporting for period 1 - 7DUP (Characterization of 7q11.23 reciprocal aneusomy syndromes: from patients to functional pathways (and back))

Période du rapport: 2016-04-01 au 2018-03-31

Résumé du contexte et des objectifs généraux du projet

Williams-Beuren Syndrome (WBS) and 7q11.23 microduplication syndrome (7dup) are two rare developmental disorders caused by the deletion or duplication, respectively, of a chromosome region at 7q11.23. Patients present opposite craniofacial characteristic ad cardiac alterations, and both have intellectual disability. These rearrangements expand 1.55-1.83 Mb and include 26-28 genes.
To better understand the pathophysiological mechanisms disrupted in patients carrying 7q11.23 alterations, we proposed a combined experimental and systems biology analytical approach with the following specific aims: (1) Identify and characterize patients with 7q11.23 CNVs; (2) Create reciprocal genetic models of 7q11.23 CNVs by generating induced pluripotent stem cells derived from patients and identify transcriptional alterations in differentiated neural precursors and mature neurons; and (3) Identify key functional pathways commonly and/or symmetrically disturbed across patient-specific neurons of 7q11.23 CNVs.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

In this project, we have characterized at molecular level large collections of patients with variations in the number of copies of 7q11.23. In particular, we have demonstrated that the mechanisms leading to 7q11.23 microduplications are the reciprocal of the deletion events. In addition, we have identified recombination hotspots in a repetitive region that flanks the deleted/duplicated genes.
In the second aim of this project, we have created reciprocal genetic models of 7q11.23 copy number variants by generating patient-derived induced Pluripotent Stem Cells (iPSC) that were differentiated to neural precursors and differentiated neurons. We then studied the changes in the transcriptome of these in vitro models of brain to investigate the genes that are altered by these alterations at 7q11.23.
Finally, we used a Systems Biology approach integrating multiple sources of biological evidence to identify genes deregulated and pathways altered in these disorders. We identified multiple genes differentially expressed in specific types of neurons that warrant further investigation.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

These cellular models are now a very valuable resource for future studies for 7q11.23 syndromes and associated brain disorders as autism spectrum disorders. Further studies will include the analyses of morphology and functionality of these neurons, and assays or in vitro drug testing.

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