Repository logo

Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

Published version

Repository DOI

Change log



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 seleno- cysteine 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. Anti- oxidant 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.


Acknowledgements: Our research is supported by a Wellcome Trust Investigator Award (210755/Z/18/Z) and Medical Research Council funding ((MRC_MC_UU_00014/40) to KC, British Heart Foundation (BHF) grants (RG/13/14/30314, RG/20/2/34763, PG/6/24/32090, PG/16/11/32021, PG/13/14/30314; BHF Centre for Research Excellence RE/18/1/34212CH/2000003) and NIHR Senior Investigator award (NF-SI-0616-10036) to MB, Italian Ministry of Health grant (TRANSTIR, # 05C501_2015 and PNRR-MR1-2022-12375726) to LP, Erasmus MC fellowship to WEV and the NIHR Cambridge Biomedical Research Centre. SJJ is supported by an Amsterdam UMC Doctoral Fellowship, and by the Dutch Heart Foundation (Nederlandse Hartstichting 03-007-2022-0035). PTE is supported by the National Institutes of Health (1R01HL092577, 5RO1HL139731, 1R01HL157635), the American Heart Association (18SFRN34110082) and by the European Union (MAESTRIA 965286). JPP is supported by the John S. LaDue Memorial Fellowship for Cardiovascular Research and by the National Institutes of Health (5K08HL159346). Work in the MPM lab is supported by the Medical Research Council UK (MC_UU_00028/4) and by a Wellcome Trust Investigator award (220257/Z/20/Z). Our murine disease model, histopathology and imaging core facilities are supported by MRC Metabolic Diseases Unit [MC_UU_00014/5] and Wellcome Trust funding [208363/Z/17/Z].

Funder: Amsterdam UMC Doctoral Fellowship and Dutch Heart Foundation (Nederlandse Hartstichting 03-007-2022-0035)

Funder: John S LaDue Memorial Fellowship for Cardiovascular Research

Funder: European Union (MAESTRIA 965286)

Funder: Italian Ministry of Health (TRANSTIR, 05C501_2015) and PNRR-MR1-2022-12375726


Humans, Male, Mice, Animals, Zebrafish, Selenocysteine, Muscle, Smooth, Vascular, Aortic Aneurysm, Selenoproteins, Myocytes, Smooth Muscle

Journal Title

Nature Communications

Conference Name

Journal ISSN


Volume Title



Nature Portfolio
Wellcome Trust (095564/Z/11/Z)
Medical Research Council (MC_UU_12012/5)
British Heart Foundation (None)
British Heart Foundation (PG/16/11/32021)
Wellcome Trust (208363/Z/17/Z)
Wellcome Trust (210755/Z/18/Z)
British Heart Foundation (RG/20/2/34763)
Wellcome Trust (220257/Z/20/Z)
MRC (MC_UU_00014/5)
British Heart Foundation (CH/2000003/12800)
British Heart Foundation (PG/16/24/32090)
British Heart Foundation (PG/16/63/32307)
Medical Research Council (MC_PC_12012)