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Stuart William Tompson, Kristina Whisenhunt, Sarah M LaMartina, Sean M Martin, Tomokazu Souma, Vachiranee Limviphuvadh, Jing Jin, Nicole M Jody, Samuel J Huang, Brendan M Lawson, Jacob S Martin, Sebastian Maurer-Stroh, Heather D Potter, Yasmin S Bradfield, Terri L Young; SVEP1 as a genetic modifier of TEK-related primary congenital glaucoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3519.
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© ARVO (1962-2015); The Authors (2016-present)
Affecting children by age 3, primary congenital glaucoma (PCG) is a debilitating form of vision loss caused by developmental impairment of aqueous drainage resulting in high intraocular pressure, globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in heterogeneous populations, but is associated with low penetrance and variable expressivity due to variable dysgenesis of Schlemm’s canal (SC). In a multi-generational family with higher disease penetrance (6 affected), we identified rare variants in TEK and SVEP1. As Svep1-/- mice are reported to show reduced Tek expression in lymphatic endothelia, we investigated SVEP1 as a potential modifier of TEK-related PCG.
Three affected individuals were exome sequenced to identify shared variants with an allele frequency less than 0.0001 (gnomAD global data). Variants were genotyped in all available family members by Sanger sequencing. Protein functions were assessed by variant/wild-type over-expression in HEK293 cells: TEK receptor activation (phosphorylation) was evaluated by Western blot, and the effect of exogenous SVEP1 protein on HUVEC TEK expression was measured by TaqMan assay. SVEP1 expression in developing ocular outflow tissues was detected by flat-mount immunofluorescent staining of 7-day mouse anterior segments. Histology was performed on an enucleated globe from the affected proband.
A rare TEK:p.(A841V) variant was identified in all 5 available affected individuals, of which 4 also harbored a rare SVEP1:p.(R997C) variant. TEK-A841V receptors were unable to phosphorylate, confirming the TEK mutation as a loss-of-function allele. SVEP1-R997C protein stimulated HUVEC expression of TEK to a lesser extent than wild-type SVEP1, suggesting the mutation is hypomorphic. In 1-week-old wild-type mice, SVEP1 was expressed in the developing ocular outflow tissues, where it is in close apposition to the developing SC. Pathology of an enucleated eye from the proband showed complete absence of SC and the overlying trabecular meshwork, analogous to murine eyes lacking a functional Tek allele.
We report a family with TEK-related PCG and higher disease penetrance. Our results are consistent with an additional rare variant in SVEP1 acting as a modifier of PCG severity, further reducing functional TEK levels during the development of SC, and exacerbating the mechanisms of disease.
This is a 2020 ARVO Annual Meeting abstract.
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