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Stuart W. J. Tompson, Tomokazu Souma, Owen M. Siggs, Sebastian Maurer-Stroh, Kristina N. Whisenhunt, Janey L Wiggs, Francesca Pasutto, Jamie E Craig, Susan E. Quaggin, Terri L Young; Mutations in a new gene cause glaucoma with variable onset. Invest. Ophthalmol. Vis. Sci. 2016;57(12):799. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Primary congenital glaucoma (PCG) accounts for 5% of childhood blindness and results from defects in the aqueous outflow system of the eye leading to high intraocular pressure (IOP), corneal/globe expansion, and optic neuropathy. CYP1B1 mutations are responsible for 15-20% of cases in ethnically diverse populations. Reports have also suggested a limited involvement from LTBP2, FOXC1 and MYOC variants. We aimed to identify novel candidate genes for PCG using exome sequencing in unsolved families.
An international multi-center cohort of 189 PCG families was assembled, all of which were Sanger sequenced and mutation negative for the 4 known genes. Exome sequencing was performed on 105 families using various platforms. Common and unrelated variants were filtered using the ExAC database and 119 in-house control exomes, respectively. Short-listed variants were validated by Sanger sequencing. Further candidate gene variants were identified in 84 additional PCG families by directly sequencing the coding exons and promoter. The functional impact of each variant was predicted using Polyphen, SIFT and FoldX and assayed in HEK293 and HUVEC cells using mutant and wild-type over-expression constructs.
Heterozygosity for 10 novel/rare variants in TIE2/TEK (tunica interna endothelial cell kinase) was identified in 10 of 189 unrelated PCG families. Among these 10 families, 13 of the 22 mutation carriers were affected by PCG, 2 did not develop glaucoma until the 5th or 6th decades, and 7 did not show signs of glaucoma, suggesting variable expressivity, reduced penetrance and/or oligogenic effects. Importantly, every individual affected by glaucoma in these 10 families carried a TEK mutation. In silico analysis predicted the mutations to have a detrimental effect on protein function. Cell-based over-expression assays in HEK293 and HUVECs demonstrated that the mutations were loss-of-function (LOF).
We report heterozygous LOF mutations in TEK that appear to predispose individuals to PCG or later-onset forms of open-angle glaucoma. Strong supporting evidence comes from previous reports that mice with disrupted ANGPT-TEK signaling also present with a glaucomatous phenotype, due to severe defects in the development of Schlemm’s canal. Our data suggests a requirement for vigilant glaucoma screening in relatives of patients carrying a TEK mutation, as they may develop glaucoma in later years.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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