SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma

Abstract

PURPOSE. Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. METHODS. Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in constructtransfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. RESULTS. Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent-child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. CONCLUSIONS. We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity.

Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

“…Recent findings have solidified our understanding of SC as a unique “hybrid” endothelium with aspects of both blood and lymphatic vascular identity and have highlighted the importance of lymphatic signaling molecules such as PROX1 and FLT4 in canal regulation 5 , 34 . In a further example of the similarity between lymphatic and SC biology, a likely loss-of-function variant in SVEP1 , encoding an extracellular matrix protein required for lymphatic development and valve formation, was recently identified as a modifier of PCG disease in a large family with five affected generations 22 . In addition, a common SVEP1 variant (rs61751937) has been identified via GWAS as a risk allele for POAG, further supporting a role for SVEP1 in IOP homeostasis 23 .…”

“…One such gene is SVEP1 (Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1), encoding a large extracellular matrix protein also known as Polydom which is expressed in the TM and has been reported to bind ANGPT1 in vitro 20 , 21 . SVEP1 is essential for lymphatic development and was linked to PCG via a large family containing five generations of affected individuals also harboring a heterozygous loss of function variant in TEK 22 and has been associated with POAG in a large multi-ethnic cohort 23 .…”

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

“…Lyphangiogenesis has an important role in the development of Schlemm’s canal required for outflow of fluid from the eye 47 , 48 , and two other genes necessary for lyphangiogenesis and Schlemm’s canal development ( TEK, ANGPT1 ) cause childhood glaucoma 49 , 50 . Interestingly, SVEP1 was shown to be a modifier of TEK -related primary congenital glaucoma 51 . VCAM1 is an extracellular matrix cell adhesion molecule involved in angiogenesis and possibly regulation of fluid flow from the eye 52 .…”

Childhood and Early Onset Glaucoma Classification and Genetic Profile in a Large Australasian Disease Registry

“…The median age of diagnosis of disease also reached statistical significance between groups (p=0.03). Those with non-acquired systemic disease had the youngest median age of disease diagnosis (23 [21][22][23][24][25][26][27][28][29][30] years) but post-hoc analyses did not show statistical significance between specific groups.…”