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

Projektinformationen

7DUP

ID Finanzhilfevereinbarung: 656359

DOI

10.3030/656359

Projekt abgeschlossen

EK-Unterschriftsdatum 17 April 2015

Startdatum 1 April 2016

Enddatum 31 März 2018

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 158 121,60

EU-Beitrag

€ 158 121,60

Koordiniert durch

UNIVERSIDAD POMPEU FABRA
Spain

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

Berichtszeitraum: 2016-04-01 bis 2018-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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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