Identification of rare missense variants reducing cathepsin O secretion in families with intracranial aneurysm
Year: 2026
Type: article
Abstract: AIMS: Intracranial aneurysm (IA) is a common cerebrovascular abnormality characterized by localized dilation and wall thinning in cerebral arteries, which can rupture and lead to fatal subarachnoid haemorrhage. Although genetic factors can contribute to IA, the genetic pre-disposition of IA is largely unknown. This study aims to identify rare functional variants associated with IA in families with multiple affected subjects and explore their impact on IA pathophysiology. METHODS AND RESULTS: By combining whole-exome sequencing and identity-by-descent analyses, we have identified two rare missense variants in the CTSO gene associated to IA in two large families with multiple affected subjects. We found that the cysteine-type papain-like cathepsin O (CTSO) encoded by CTSO is expressed in the circle of Willis of mice and in the wall of human IA domes. Stretching of vascular smooth muscle cells (VSMC) induced CTSO secretion. CTSO controls VSMC migration and adhesion to the extracellular matrix, and directly interacts with fibronectin (FN). CTSO depletion, or expression of the two CTSO variants, which are poorly secreted, increased the amount of FN. Moreover, CTSO depletion augmented VSMC stiffness, which was reduced by the addition of exogenous CTSO. CONCLUSION: Collectively, our findings identify CTSO as a potential new player in arterial remodelling, regulating FN deposition and VSMC function, supporting the causal role of rare coding CTSO variants in familial forms of IA.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvaf279
Authors: Milène Fréneau, Raphael Blanchet, Maxence Bodet, Sandro Benichi, Mary-Adel Mrad, Surya Prakash Rao Batta, Marc Rio, Stéphanie Bonnaud, Pierre Lindenbaum, Fabien Laporte, Stéphane Cuénot, Thibaud Quillard, Mike Maillasson, Sandrine Morel, Brenda R Kwak, Philippe Bijlenga, Jean-François Deleuze, Christian Dina, Stéphanie Chatel, Emmanuelle Bourcereau, Solène Jouan, Arturo Consoli, Cyril Dargazanli, Julien Ognard, Hubert Desal, Anne-Clémence Vion, Romain Bourcier, Gervaise Loirand, Richard Redon
Institutions: Centre National de la Recherche Scientifique, Inserm, Centre Hospitalier Universitaire de Nantes, Institut du Thorax, Nantes Université, Institut des Matériaux Jean Rouxel, UMS BioCore, University of Geneva, University Hospital of Geneva, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Centre National de Recherche en Génomique Humaine, Université de Versailles Saint-Quentin-en-Yvelines, Hôpital Foch, Centre Hospitalier Universitaire de Montpellier, Centre Hospitalier Régional Universitaire de Brest
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,329
Awards: NExT (I-SITE), IntraCranial ANeurysms: From familial forms to pathophysiological mechanisms, G2336319514, G5007498923, Cathepsin O and intracranial aneurysm, Institut français de bioinformatique, Mechanical forces in IntraCranial aneurysm: Understanding the role of Rho proteins signaling, genotype/phenotype correlations to alloW rupturE risk stratification of intraCranial Aneurysm, G7494494322
OpenAlex ID: W7119484553