Identification of rare missense variants reducing cathepsin O secretion in families with intracranial aneurysm

Abstract

Background: Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in intracranial arteries, that frequently leads to fatal vascular rupture. The mechanisms underlying IA formation, growth and rupture are mostly unknown, and while increasing evidence suggest a genetic component of IA, identification of specific genes or causal molecular pathways remains largely inconclusive and only a small fraction of the risk attributable to genetics for IA in the general population. Methods: Here, we combined whole exome sequencing and identity-by -descent analyses with functional investigations to identify rare IA predisposing variants in familial forms of IA and understand their contribution to the pathophysiology of IA. Results: We identified two rare missense variants in the CTSO gene shared by all the affected relatives in two large pedigrees with multiple IA-affected relative. CTSO encodes for the cysteine-type papain-like cathepsin CTSO. Functional analyses revealed that CTSO acts as an extracellular protease controlling vascular smooth muscle cell migration and adhesion to the extracellular matrix. CTSO depletion, as well as expression of the two CTSO variants, which were poorly secreted, led to increase the amount of fibronectin. This effect is associated with a marked increase in VSMC stiffness which was rescued by exogenous CTSO. Conclusions: This report identifies rare CTSO variants in familial IA patients and suggests that the increased susceptibility to IA induced by these variants is likely related to their primary effects on the vascular tissue, and more particularly on the media layer of the wall of cerebral arteries.