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

Informazioni relative al progetto

7DUP

ID dell’accordo di sovvenzione: 656359

DOI

10.3030/656359

Progetto chiuso

Data della firma CE 17 Aprile 2015

Data di avvio 1 Aprile 2016

Data di completamento 31 Marzo 2018

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 158 121,60

Contributo UE

€ 158 121,60

Coordinato da

UNIVERSIDAD POMPEU FABRA
Spain

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

Periodo di rendicontazione: 2016-04-01 al 2018-03-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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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