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 Rusk, Deepa Gopalan, Philip Twiss, Jacob J. Visser, Martin Goddard, Samer A. M. Nashef, Robin Heijmen, Paul Clift, Sanjay Sinha, James P. Pirruccello, Patrick T. Ellinor, Elisabeth M. Busch-Nentwich, Ramiro Ramirez-Solis, Michael P. Murphy, Luca Persani, Martin Bennett and Krishna Chatterjee ()
Additional contact information
Erik Schoenmakers: University of Cambridge
Federica Marelli: Istituto Auxologico Italiano IRCCS
Helle F. Jørgensen: University of Cambridge
W. Edward Visser: Erasmus University Medical Center
Carla Moran: University of Cambridge
Stefan Groeneweg: Erasmus University Medical Center
Carolina Avalos: Clinica Alemana de Santiago
Sean J. Jurgens: The Broad Institute of MIT and Harvard
Nichola Figg: University of Cambridge
Alison Finigan: University of Cambridge
Neha Wali: Wellcome Genome Campus
Maura Agostini: University of Cambridge
Hannah Wardle-Jones: Wellcome Genome Campus
Greta Lyons: University of Cambridge
Rosemary Rusk: Addenbrookes Hospital
Deepa Gopalan: Addenbrookes Hospital
Philip Twiss: Addenbrookes Hospital
Jacob J. Visser: Erasmus University Medical Center
Martin Goddard: Royal Papworth Hospital
Samer A. M. Nashef: Royal Papworth Hospital
Robin Heijmen: Radboud University Medical Center
Paul Clift: Queen Elizabeth Hospital
Sanjay Sinha: University of Cambridge
James P. Pirruccello: The Broad Institute of MIT and Harvard
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Elisabeth M. Busch-Nentwich: Queen Mary University of London
Ramiro Ramirez-Solis: Wellcome Genome Campus
Michael P. Murphy: University of Cambridge
Luca Persani: Istituto Auxologico Italiano IRCCS
Martin Bennett: University of Cambridge
Krishna Chatterjee: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43851-6

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