Dataset Information

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 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.

SUBMITTER: Young TL

PROVIDER: S-EPMC7545080 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Young Terri L TL Whisenhunt Kristina N KN Jin Jing J LaMartina Sarah M SM Martin Sean M SM Souma Tomokazu T Limviphuvadh Vachiranee V Suri Fatemeh F Souzeau Emmanuelle E Zhang Xue X Dan Yongwook Y Anagnos Evie E Carmona Susana S Jody Nicole M NM Stangel Nickie N Higuchi Emily C EC Huang Samuel J SJ Siggs Owen M OM Simões Maria José MJ Lawson Brendan M BM Martin Jacob S JS Elahi Elahe E Narooie-Nejad Mehrnaz M Motlagh Behzad Fallahi BF Quaggin Susan E SE Potter Heather D HD Silva Eduardo D ED Craig Jamie E JE Egas Conceição C Maroofian Reza R Maurer-Stroh Sebastian S Bradfield Yasmin S YS Tompson Stuart W SW

Investigative ophthalmology & visual science 20201001 12

<h4>Purpose</h4>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 ...[more]

PMID: 33027505

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Project description:Glaucoma is an irreversible form of optic neuropathy in which the optic nerve suffers damage in a characteristic manner with optic nerve cupping and retinal ganglion cell death. Primary congenital glaucoma (PCG) is an idiopathic irreversible childhood blinding disorder which manifests at birth or within the first year of life. PCG presents with a classical triad of symptoms (viz epiphora, photophobia and blepharospasm) though there are many additional symptoms, including large eye ball and hazy cornea. The only anatomical anomaly found in PCG is trabecular meshwork (TM) dysgenesis. PCG is an inheritable disease with established genetic etiology. It transmits through autosomal recessive mode. A number of cases are sporadic also. Mutations in many genes have been found to be causative in PCG and many are yet to be found. Mutations in cytochrome P4501B1 (CYP1B1) gene have been found to be the predominant cause of PCG. Other genes that have been implicated in PCG etiology are myocilin, Forkhead-related transcription factor C1 (FOXC1) and latent transforming growth factor beta-binding protein 2 (LTBP2). Mutations in these genes have been reported from many parts of the world. In addition to this, mitochondrial genome mutations are also thought to be involved in its pathogenesis. There appears to be some mechanism involving more than one genetic factor. In this review, we will discuss the various clinical, biochemical and genetic aspects of PCG. We emphasize that etiology of PCG does not lie in a single gene or genetic factor. Research needs to be oriented into a direction where gene-gene interactions, ocular embryology, ophthalmic metabolism and systemic oxidative status need to be studied in order to understand this disorder. We also accentuate the need for ophthalmic genetic facilities in all ophthalmology setups. How to cite this article: Faiq M, Sharma R, Dada R, Mohanty K, Saluja D, Dada T. Genetic, Biochemical and Clinical Insights into Primary Congenital Glaucoma. J Current Glau Prac 2013;7(2):66-84.

Project description:BackgroundPrimary congenital glaucoma (PCG) manifests within the first few years of a child's life and is not associated with any other systemic or ocular abnormalities. PCG results in considerable morbidity even in developed countries. Several surgical techniques for treating this condition, and lowering the intraocular pressure (IOP) associated with it, have been described.ObjectivesTo compare the effectiveness and safety of different surgical techniques for PCG.Search methodsWe searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2014, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), (January 1982 to June 2014), PubMed (January 1946 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 23 June 2014.Selection criteriaWe included all randomized and quasi-randomized trials in which different types of surgical interventions were compared in children under five years of age with PCG.Data collection and analysisWe used standard methodological procedures specified by The Cochrane Collaboration.Main resultsWe included a total of six trials (four randomized and two quasi-randomized) with 102 eyes in 61 children. Two trials were conducted in the USA and one trial each in Egypt, Israel, Lebanon and Saudi Arabia. All trials included children aged younger than one year when diagnosed with PCG, and followed them for periods ranging from six months to five years.No two trials compared the same pair of surgical interventions, so we did not perform any meta-analysis. One trial compared trabeculotomy versus goniotomy; a second trial compared combined trabeculectomy-trabeculotomy with mitomycin C versus trabeculectomy-trabeculotomy with mitomycin C and deep sclerectomy; a third trial compared combined trabeculotomy-trabeculectomy versus trabeculotomy; a fourth trial compared one goniotomy versus two goniotomies; a fifth trial compared trabeculotomy versus viscocanalostomy; and the sixth trial compared surgical goniotomy versus neodymium-YAG laser goniotomy. For IOP change and surgical success (defined by IOP achieved), none of the trials reported a difference between pairs of surgical techniques. However, due to the limited sample sizes for all trials (average of 10 children per trial), the evidence as to whether a particular surgical technique is effective and which surgical technique is better still remains uncertain. Adverse events, such as choroidal detachment, shallow anterior chamber and hyphema, were reported from four trials. None of the trials reported quality of life or economic data.These trials were neither designed nor reported well overall. Two trials were quasi-randomized trials and judged to have high risk of selection bias; four trials were at unclear or high risk for performance bias and detection bias; and we judged one trial to have high risk of attrition bias due to high proportions of losses to follow-up. Due to poor study design and reporting, the reliability and applicability of evidence remain unclear.Authors' conclusionsNo conclusions could be drawn from the trials included in this review due to paucity of data. More research is needed to determine which of the many surgeries performed for PCG are effective.

Project description:PurposeTo screen mitochondrial DNA (mtDNA) for nucleotide variations in primary congenital glaucoma (PCG).MethodsThe entire coding region of the mitochondrial genome was amplified by polymerase chain reaction from 35 PCG patients and 40 controls. The full mtDNA genome except the D-loop was sequenced. All sequences were analyzed against mitochondrial reference sequence NC_012920.ResultsMtDNA sequencing revealed a total of 132 and 58 nucleotide variations in PCG and controls, respectively. Of 132 nucleotide variations, 42 (31.81%) were non-synonymous and 82 (62.12%) were synonymous changes, and 8 were in RNA genes. The highest number of nucleotide variations were recorded in complex I followed by complex IV, then complex V. Eight patients (22.85%) had potentially pathogenic mtDNA nucleotide changes and twenty (57.14%) had mtDNA sequence changes associated with elevated reactive oxygen species (ROS) production. Mitochondria not only constitute the energy-generating system in the cell, but are also critically involved in calcium signaling and apoptosis. Mitochondrial function can be affected by mutations in mitochondrial and nuclear DNA, chemical insults to components of the electron transport chain, and a lack of substrates such as oxygen. Mitochondrial dysfunction results in an excessive generation of free radicals and reduced mitochondrial respiration. Developing trabecular meshwork (TM) is deficient in antioxidant enzymes, and thus is more susceptible to oxidative stress (OS) induced damage. Previous studies have documented certain mtDNA sequence variations associated with elevated ROS levels and OS. Three such changes (G10398A, A12308G, and G13708A) were present in our patients. Elevated ROS may cause OS. This OS may further damage mtDNA and may cause decreased mitochondrial respiration. This may lead to impaired growth, development and differentiation of TM and consequently trabecular-dysgenesis, which is a characteristic feature of PCG. OS affects both TM and retinal ganglion cells (RGCs) and may be involved in the neuronal death affecting the optic nerve in glaucoma. There are several studies which point to mitochondrial dysfunction in different types of glaucoma and critically participate in RGC death. Recent studies also implicate mitochondrial dysfunction-associated OS as a risk factor for glaucoma patients. It has been reported that elevated hydrostatic pressure causes breakdown of the mitochondrial network by mitochondrial fission and induce cristae depletion and cellular ATP reduction in differentiated RGC-5 cells in vitro as well as in vivo.ConclusionsA total of 44 novel mtDNA variations were identified in this study. Non-synonymous mtDNA variations may adversely affect respiratory chain, impair OXPHOS pathway result in low ATP production, high ROS production and impair growth, development and differentiation of TM lead to trabecular-dysgenesis and consequently RGC's death. Such cases with mtDNA variations and consequent OS may benefit by early diagnosis and prompt management by antioxidant therapy. This may delay OS induced injury to TM and RGCs and hence improve visual prognosis.

Dataset Information

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

Publications

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

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