Selenoprotein deficiency disorder predisposes to aortic aneurysm formation
Erik Schoenmakers, Federica Marelli, Helle F. Jørgensen, W. Edward Visser, Carla Moran, Stefan Groeneweg, Carolina Avalos, Sean J. Jurgens, Nichola Figg, Alison Finigan, Neha Wali, Maura Agostini, Hannah Wardle‐Jones, Greta Lyons, Rosemary A. Rusk, Deepa Gopalan, Philip Twiss, Jacob J. Visser, Martin Goddard, Samer A.M. Nashef, Robin H. Heijmen, Paul Clift, Sanjay Sinha, James P. Pirruccello, Patrick T. Ellinor, Elisabeth M. Busch‐Nentwich, Ramiro Ramírez‐Solis, Michael P. Murphy, Luca Persani, Martin R. Bennett, Krishna Chatterjee
Abstract
Aortic aneurysms, which may dissect or rupture acutely and be lethal, can be a part of multisystem disorders that have a heritable basis. We report four patients with deficiency of selenocysteine-containing proteins due to selenocysteine Insertion Sequence Binding Protein 2 (SECISBP2) mutations who show early-onset, progressive, aneurysmal dilatation of the ascending aorta due to cystic medial necrosis. Zebrafish and male mice with global or vascular smooth muscle cell (VSMC)-targeted disruption of Secisbp2 respectively show similar aortopathy. Aortas from patients and animal models exhibit raised cellular reactive oxygen species, oxidative DNA damage and VSMC apoptosis. Antioxidant exposure or chelation of iron prevents oxidative damage in patient's cells and aortopathy in the zebrafish model. Our observations suggest a key role for oxidative stress and cell death, including via ferroptosis, in mediating aortic degeneration.