RAVA

We identified loss-of-function pathogenic variants in the THSD4 gene encoding ADAMTSL6. ADAMTSL6 is a microfibril-associated protein known to bind directly to fibrillin-1 and to promote fibrillin-1 matrix assembly. We showed that PTC and missense variants in THSD4 lead to haploinsufficiency of ADAMTSL6 and/or impaired assembly of fibrillin-1 microfibrils. Furthermore, we confirmed our results with a Thsd4+/- mouse model that showed progressive aortic dilation at the level of the thoracic aorta that increased significantly over time compared with control mice. All these data in patients and mice support that ADAMTSL6 is a novel protagonist in the pathophysiology of TAAD. Moreover, it was shown that using a TWAS, a decrease in predicted THSD4 expression was linked to an increase in aortic diameter. However, the exact role of ADAMTSL6 in the aorta and the development of this disease is still not clear. Our hypothesis is that ADAMTSL6 has the role of modulator of the ECM assembly in the VSMC. The project divided into 4 work packages (WP) aims at identifying a common process of TAAD development from different etiologies involving ADAMTSL6 using mouse models and human tissues. This project will allow both to highlight a major actor of TAAD development, ADAMTSL6, but also provide needed additional insight into the mechanisms underlying the development of aortic dilatations. This project enables us to adequately explore our hypothesis of a common TAAD pathogenic signature.