Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.
This study was funded by NIH R01 HL124120 (S.E. Quaggin); NIH R01 EY014685, the Research to Prevent Blindness Inc. Lew R. Wasserman Award, the Duke–National University of Singapore Core Grant, and the University of Wisconsin Centennial Scholars Award (T.L. Young); and NIH Career Development Award K12, 1K23EY020554 (T.L. Yanovitch). This work was also supported by grants from the March of Dimes Foundation (J.L. Wiggs), Howard Hughes Medical Center and EY 11721 (S. John and K. Kizhatil), the Ophthalmic Research Institute of Australia, the Channel Seven Children’s Research Foundation, Department of Innovation, Industry, Science and Research, and the National Health and Medical Research Council
of Australia (NHMRC). T. Souma is supported by fellowship grants from the Japan Society for the Promotion of Science and Mallinckrodt Pharmaceuticals. B.R. Thomson is supported by the Canadian Institute of Health Research. K.P. Burdon, J.E. Craig, and D.N. Azmanov are supported by fellowships from the NHMRC. Imaging was performed at the Northwestern University Center for Advanced Microscopy supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We also acknowledge support from Vision Core Grant NEI P30EY016665 of the University of Wisconsin–Madison Department of Ophthalmology and Visual Sciences. Proteomics analyses were supported by the Northwestern University Proteomics Core. We thank Dhaval Nanavati (Northwestern University, Proteomics Core) for technical support and helpful discussions.