Nature Communications (Dec 2023)
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,
- Krishna Chatterjee
Affiliations
- Erik Schoenmakers
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
- Federica Marelli
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS
- Helle F. Jørgensen
- Section of Cardiorespiratory Medicine, University of Cambridge
- W. Edward Visser
- Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center
- Carla Moran
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
- Stefan Groeneweg
- Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus University Medical Center
- Carolina Avalos
- Department of Paediatric Endocrinology, Clinica Alemana de Santiago
- Sean J. Jurgens
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard
- Nichola Figg
- Section of Cardiorespiratory Medicine, University of Cambridge
- Alison Finigan
- Section of Cardiorespiratory Medicine, University of Cambridge
- Neha Wali
- Wellcome Sanger Institute, Wellcome Genome Campus
- Maura Agostini
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
- Hannah Wardle-Jones
- Wellcome Sanger Institute, Wellcome Genome Campus
- Greta Lyons
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
- Rosemary Rusk
- Department of Cardiology, Addenbrookes Hospital
- Deepa Gopalan
- Department of Radiology, Addenbrookes Hospital
- Philip Twiss
- Cambridge Genomics Laboratory, Addenbrookes Hospital
- Jacob J. Visser
- Department of Radiology, Erasmus University Medical Center
- Martin Goddard
- Department of Pathology, Royal Papworth Hospital
- Samer A. M. Nashef
- Department of Cardiothoracic Surgery, Royal Papworth Hospital
- Robin Heijmen
- Department of Cardiothoracic Surgery, Radboud University Medical Center
- Paul Clift
- Department of Cardiology, Queen Elizabeth Hospital
- Sanjay Sinha
- Section of Cardiorespiratory Medicine, University of Cambridge
- James P. Pirruccello
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard
- Patrick T. Ellinor
- Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard
- Elisabeth M. Busch-Nentwich
- School of Biological and Behavioural Sciences, Queen Mary University of London
- Ramiro Ramirez-Solis
- Wellcome Sanger Institute, Wellcome Genome Campus
- Michael P. Murphy
- MRC Mitochondrial Biology Unit, University of Cambridge
- Luca Persani
- Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS
- Martin Bennett
- Section of Cardiorespiratory Medicine, University of Cambridge
- Krishna Chatterjee
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge
- DOI
- https://doi.org/10.1038/s41467-023-43851-6
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
