Selenoprotein deficiency disorder predisposes to aortic aneurysm formation

Objectives: Mutations in SECISBP2 cause deficiency of selenoproteins, resulting in a multisystem disorder with abnormal circulating thyroid hormone and selenium levels and features due to lack of specific selenoproteins or loss of antioxidant selenoenzymes. Having observed early-onset, aneurysmal thoracic aortic dilatation in four patients with this disorder, we studied zebrafish and murine Secisbp2 mutant models to determine whether the aortic phenotype and selenoprotein deficiency are causally related. Methods: Analyses of histology, selenoprotein deficiencies, oxidative stress, DNA damage and apoptosis in aortae and aortic vascular smooth muscle cells (VSMCs) from two patients following surgery, and in aortae from zebrafish Secisbp2 mutant and morpholino knockdown or VSMC-targeted, Secisbp2-deficient mouse models, were undertaken. Results: Progressive, early-onset (age 10 to 41yrs) aneurysmal ascending aortic dilatation occurred in four patients with biallelic mutations in SECISBP2, but without defects in known, thoracic aortopathy, genes. Histology of aneurysmal aortae showed cystic medial necrosis, with deficiency of antioxidant selenoenzymes, oxidative membrane lipid and DNA damage and apoptosis in both medial wall of aorta and cultured, medial VSMCs. Ventral aortic dilatation increased tissue H202 content, lipid peroxidation and DNA damage were observed in adult, Secisbp2Q333X/Q333X mutant and embryonic Secisbp2 morpholino-knockdown zebrafish, with coexpression of Secisbp2 mRNA in the morpholino model rescuing these abnormalities. Tamoxifen treatment of Myh11-CreERt2/ Secisbp2flox/flox mice, conditionally abolished Secisbp2 and selenoprotein expression in the medial layer of murine aortae. Infusion of angiotensin II, an established model of thoracic aortic aneurysm (TAA) formation, caused markedly diminished survival (60%) of homozygous mice compared to wild-type or heterozygous littermates (90%), due to development of TAAs with aortic cystic medial necrosis. Loss of antioxidant selenoenzymes, oxidative stress, DNA damage and apoptosis, were features common to aortae from patients, zebrafish and mouse models of SECISBP2 deficiency. Reversal of oxidative damage and apoptosis by exposure of human aortic VSMCs to antioxidants, implicates excess ROS in their pathogenesis. Conclusions: We have documented thoracic aortic aneurysm formation in patients with SECISBP2 mutations and similar aortopathy in zebrafish or mice with global or VSMC-targeted inactivation of Secisbp2. We suggest that SECISBP2 is a novel genetic aetiology of TAA, with oxidative stress and cell death secondary to deficiency of antioxidant selenoenzymes mediating aortic degeneration.