Whole-Exome Sequencing of 677 Unrelated Aneurysm Patients Identifies Multiple Rare Variants of the Proprotein Convertase Furin Causing Impaired TGFB Signaling

Background: Aortic aneurysms are characterized by remodeling of the extracellular matrix and weakening of the aorta wall. It is caused by interactions between genetic predispositions and risk factors like aging, gender, smoking, and hypertension. At present, all known aneurysm genes explain less than 5% of aortic aneurysms. Finding novel genetic predispositions for aneurysms may therefor help to identify risk profiles for patients and their relatives.

Methods: Whole-exome-sequencing (WES) data of 677 unrelated abdominal aorta aneurysm patients and their affected relatives were used to identify FURIN as a new genetic predisposition for aortic aneurysms. The effects of variants in the FURIN gene were investigated by structural modeling of protein domains, protein maturation and -activity assays. Using patient-derived fibroblasts, the effects on intracellular signaling and downstream gene expression were studied using immunoblotting and gene expression analysis.

Results: Thirty-one (4.6%) unrelated patients had 15 different rare heterozygous variants in FURIN, encoding the proprotein convertase FURIN. Of these 31 patients, 21 had multiple aneurysms, 5 had a rupture and 3 an aortic dissection. Twelve patients had a thoracic aneurysms were observed. Structural and functional studies showed alterations in protein function and downstream signaling pathways resulting in the identification of FURIN as a novel aneurysm gene. The steady-state protein levels, protease activity and shedding of FURIN variants were affected. Maturation of pro-TGFB1, phosphorylation of its downstream targets SMAD2 and ERK1/2 and gene expression of TGFB1-responsive ACTA2 and COL4A1 were impaired in patient fibroblasts, indicating that TGFB family actions are dysregulated in these patients. Moreover, we showed influences of individual genetic backgrounds with a range of effects of the recurrent missense pR745Q FURIN in fibroblasts of 5 different patients.

Conclusion: FURIN is a novel genetic predisposition for aorta aneurysm, presenting with abdominal, thoracic and multiple aortic aneurysm, ruptures and dissections, through TGFB dysregulation.

Publication History

Article published online:
10 June 2022