TY - JOUR
T1 - SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma
AU - Young, Terri
AU - Whisenhunt, Kristina
AU - Jin, Jing
AU - LaMartina, Sarah M.
AU - Martin, Sean
AU - Souma, Tomokazu
AU - Limviphuvadh, Vachiranee
AU - Suri, Fatemeh
AU - Souzeau, Emmanuelle
AU - Zhang, Xue
AU - Dan, Yongwook
AU - Anagnos, Evie
AU - Carmona, Susana
AU - Jody, Nicole M.
AU - Stangel, Nickie
AU - Higuchi, Emily C.
AU - Huang, Samuel J.
AU - Siggs, Owen
AU - Simoes, Maria Jose
AU - Lawson, Brendan M.
AU - Martin, Jacob S.
AU - Elahi, Elahe
AU - Narooie-Nejad, Mehrnaz
AU - Motlagh, Behzad Fallahi
AU - Quaggin, Susan
AU - Potter, Heather D.
AU - Silva, Eduardo D.
AU - Craig, Jamie
AU - Egas, Conceicao
AU - Maroofian, Reza
AU - Maurer-Stroh, Sebastian
AU - Bradfield, Yasmin
AU - Tompson, Stuart
N1 - Copyright 2020 The Authors
This work is licensed under a Creative Commons Attribution 4.0 International License. [CC BY]
PY - 2020/10/1
Y1 - 2020/10/1
N2 - AbstractPurpose: 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.
AB - AbstractPurpose: 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.
KW - Genetics
KW - Eye Anatomy and Disorders
KW - Glaucoma
KW - SVEP1
KW - Genetic Modifiers
KW - TEK-Related Primary Congenital Glaucoma
KW - primary congenital glaucoma (PCG)
KW - TEK haploinsufficiency
KW - variable dysgenesis
KW - Schlemm's canal (SC)
KW - TEK
KW - Modifier
KW - Schlemm’s canal
UR - http://purl.org/au-research/grants/NHMRC/1116360
UR - http://purl.org/au-research/grants/NHMRC/1107098
UR - http://purl.org/au-research/grants/NHMRC/1154824
UR - http://www.scopus.com/inward/record.url?scp=85092684994&partnerID=8YFLogxK
U2 - 10.1167/iovs.61.12.6
DO - 10.1167/iovs.61.12.6
M3 - Article
SN - 1552-5783
VL - 61
SP - 6
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 12
M1 - 6
ER -