Rare coding variants in CTSO, a potential new actor of arterial remodeling, are associated to familial intracranial aneurysm

Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, which can rupture and lead to fatal subarachnoid hemorrhage. Although the pathophysiology of IA remains largely unknown, increasing evidence suggests that genetic susceptibility plays a predominant role. Here, we combined whole exome sequencing and identity-by-descent analyses with functional investigations to identify rare functional variants associated to IA in families with multiple affected subjects. We identified two rare missense variants in the CTSO gene in two large pedigrees. We found that the cysteine-type papain-like cathepsin O (CTSO) encoded by CTSO is expressed in the wall of human IA domes. Stretching of vascular smooth muscle cells (VSMC) induced secretion of CTSO, which acted as an extracellular protease controlling VSMC migration and adhesion to the extracellular matrix. CTSO depletion, as well as expression of the two CTSO variants, which are poorly secreted, increased the amount of fibronectin. In addition, CTSO depletion increased VSMC stiffness, which was reduced by the addition of exogenous CTSO. Collectively, our findings identify CTSO as a potential new player in arterial remodeling, regulating fibronectin deposition and VSMC function, supporting the causal role of rare coding CTSO variants in familial forms of IA.