Fishing for genes: a disease transgressing approach to unravel the genetic basis of thoracic aortic aneurysm

Datum: 18 april 2016

Locatie: UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 WILRIJK

Tijdstip: 16.30 uur

Promovendus: Dorien Schepers

Promotor: Prof B. Loeys & Prof L. Van Laer

Korte beschrijving: PhD defence Dorien Schepers - Faculty of Medicine and Health Sciences


An aortic aneurysm is an enlargement or dilatation of the main artery in the human body. If left untreated, it can result in aortic dissection and rupture, making it one of the most life threatening forms of cardiovascular disease.

Thoracic aortic aneurysm (TAA) is a prominent clinical feature of several hereditary connective tissue disorders, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Because of the relatively high incidence and the lethality of the disease, there is an increased need for therapies based on the underlying molecular defect. Therefore, unraveling the genetic basis of TAA is necessary in order to completely understand the pathogenesis of aortic aneurysm in general and TAA in particular. Through the elucidation of the genetic basis of different hereditary disorders associated with TAA, such as LDS, Shprintzen-Goldberg syndrome (SGS) and autosomal dominant polycystic kidney disease (ADPKD), we delivered an important contribution to this objective.

In this thesis we have identified heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand causing a phenotype within the LDS spectrum. Additionally, we show upregulation of TGF-β signaling in aortic tissue from affected individuals and haploinsufficient Tgfb2+/- mice. Additionally, we have identified causative variations in several individuals with SGS in the proto-oncogene SKI, which is a known repressor of TGF-β activity and show that increased TGF-β signaling is also involved in the pathogenetic mechanism underlying SGS. Moreover, we identify a mutational hotspot in the first half of exon 1 of SKI. ADPKD, which is caused by mutations in PKD1 or PKD2, two polycystin encoding genes, has
a clinical overlap with MFS. Aortic and arterial aneurysms occur in ADPKD patients more often compared to the general population and vice versa, kidneys cysts are more frequently observed in MFS patients.

In a family presenting with both TAA and mild cystic kidneys, we have identified two duplicated regions in the genome, containing seven genes. By overexpressing these genes separately and in combination with each other in zebrafish, we have revealed a potential role for FOXF1 in cyst formation since FOXF1 overexpression zebrafish develop ectopic branching of the pronephros. Whether FOXF1 overexpression also contributes to aneurysm formation is currently being investigated by overexpressing FOXF1 in tg(fli:egpf) zebrafish, which harbours a reporter for the cardiovascular system.