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Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

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Peer-reviewed

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Article

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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 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.

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Journal Title

Nature Communications

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Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Nature Portfolio
Sponsorship
Wellcome Trust (095564/Z/11/Z)
Medical Research Council (MC_UU_12012/5)