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

Publication ,  Journal Article
Young, TL; Whisenhunt, KN; Jin, J; LaMartina, SM; Martin, SM; Souma, T; Limviphuvadh, V; Suri, F; Souzeau, E; Zhang, X; Dan, Y; Anagnos, E ...
Published in: Invest Ophthalmol Vis Sci
October 1, 2020

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 construct-transfected 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.

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Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

October 1, 2020

Volume

61

Issue

12

Start / End Page

6

Location

United States

Related Subject Headings

  • Receptor, TIE-2
  • Protein Isoforms
  • Phosphorylation
  • Penetrance
  • Pedigree
  • Ophthalmology & Optometry
  • Mutation, Missense
  • Middle Aged
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Young, T. L., Whisenhunt, K. N., Jin, J., LaMartina, S. M., Martin, S. M., Souma, T., … Tompson, S. W. (2020). SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. Invest Ophthalmol Vis Sci, 61(12), 6. https://doi.org/10.1167/iovs.61.12.6
Young, Terri L., Kristina N. Whisenhunt, Jing Jin, Sarah M. LaMartina, Sean M. Martin, Tomokazu Souma, Vachiranee Limviphuvadh, et al. “SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.Invest Ophthalmol Vis Sci 61, no. 12 (October 1, 2020): 6. https://doi.org/10.1167/iovs.61.12.6.
Young TL, Whisenhunt KN, Jin J, LaMartina SM, Martin SM, Souma T, et al. SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):6.
Young, Terri L., et al. “SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.Invest Ophthalmol Vis Sci, vol. 61, no. 12, Oct. 2020, p. 6. Pubmed, doi:10.1167/iovs.61.12.6.
Young TL, Whisenhunt KN, Jin J, LaMartina SM, Martin SM, Souma T, Limviphuvadh V, Suri F, Souzeau E, Zhang X, Dan Y, Anagnos E, Carmona S, Jody NM, Stangel N, Higuchi EC, Huang SJ, Siggs OM, Simões MJ, Lawson BM, Martin JS, Elahi E, Narooie-Nejad M, Motlagh BF, Quaggin SE, Potter HD, Silva ED, Craig JE, Egas C, Maroofian R, Maurer-Stroh S, Bradfield YS, Tompson SW. SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma. Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):6.

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

October 1, 2020

Volume

61

Issue

12

Start / End Page

6

Location

United States

Related Subject Headings

  • Receptor, TIE-2
  • Protein Isoforms
  • Phosphorylation
  • Penetrance
  • Pedigree
  • Ophthalmology & Optometry
  • Mutation, Missense
  • Middle Aged
  • Mice
  • Male