Mutations in FOXE3/Foxe3 Cause Familial Thoracic Aortic Aneurysms and Dissections. S. Q. Kuang1, O. Medina-Martinez22, D. C. Guo1, L. Gong1, E. S. Regalado1, C. Boileau4, G. Jondeau5, S. K. Prakash1, A. M. Peters1, H. Pannu1, M. J. Bamshad3, J. Shendure3, D. A. Nickerson3, C. L. Reynolds6, M. Jamrich2, D. M. Milewicz1 1) Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX; 2) Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; 3) 3Department of Genome Sciences, University of Washington, Seattle, Washington; 4) AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France; Université Paris 7, Paris, France; AP-HP, Hôpital Bichat, Laboratoire de Génétique moléculaire, Boulogne, France; INSERM, U1148, Paris, France; 5) AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France; Université Paris 7, Paris, France; AP-HP, Hôpital Bichat, Service de Cardiologie, Paris, France; INSERM, U1148, Paris, France; 6) Mouse Phenotyping Core, Baylor College of Medicine, Houston, Texas, USA.

   Mutations in FOXE3 cause lens defects due to lack of proliferation and differentiation of epithelial cells. Exome sequencing of a large family with autosomal dominant thoracic aortic aneurysms and dissections (TAAD) identified a rare variant in FOXE3, c.457G>C (p. D153H) that altered a conserved amino acid, was predicted to disrupt protein function, and segregated with TAAD in the family with decreased penetrance in women. Sequencing of 354 unrelated probands with TAAD identified three additional FOXE3 variants, p.D156N, p.G137D, and p.R164S, which were novel and predicted to be damaging. These families did not have lens defects, and the mutations were in a different region of the DNA binding domain compared with mutations that cause lens defects. Morpholino (MO) knockdown of foxe3 in zebrafish disrupted aortic arch development in 70% of embryos. Co-injection of wild-type but not mutant foxe3 RNA resulted in partial rescue of the phenotype. Foxe3 is not expressed in adult mouse aortas but in situ hybridization detected Foxe3 expression in the mouse embryo pharyngeal arches from E9.5 to E10.5, suggesting that Foxe3 is involved in establishing neural crest-derived aortic smooth muscle cells (SMCs). Aortas from 4 week old Foxe3-/- mice had reduced SMC density and decreased differentiation of SMCs, but the mice did not form aneurysms. When exposed to increased pressures by constricting the transverse aorta (TAC), Foxe3-/- mice developed larger aneurysms compared with wildtype (WT) mice and aortic rupture occurred in 50% of Foxe3-/- mice. TUNEL staining of the ascending aorta showed more SMC apoptosis in the Foxe3-/- mice than WT mice (p<0.05). To drive cellular survival pathways, p53 activity was disrupted by administration of an inhibitor (pifithrin-) or crossing the Foxe3-/- mice into p53-/- mice, and both rescued aortic SMC apoptosis and aortic rupture in TAC-challenged Foxe3-/- mice. Aortic SMC density and differentiation were also rescued to WT levels in 4 week old Foxe3-/-p53-/- mice. These data indicate that loss of Foxe3 leads to decreased numbers and de-differentiated SMCs in the ascending aorta, and SMC apoptosis and aortic rupture with increased biomechanical stress in the adult ascending aorta. Interestingly, blocking p53 in the Foxe3-/- mice rescued these phenotypes by driving survival and differentiation of the SMCs.

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