An Assessment of GUCA1C Variants in Primary Congenital Glaucoma.
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ABSTRACT:
SUBMITTER: Souzeau E
PROVIDER: S-EPMC7998521 | biostudies-literature | 2021 Mar
REPOSITORIES: biostudies-literature
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An Assessment of GUCA1C Variants in Primary Congenital Glaucoma.
Souzeau Emmanuelle E Weisschuh Nicole N Craig Jamie E JE Pasutto Francesca F Koch Karl-Wilhelm KW
Genes 20210302 3
In the special issue "Molecular Genetics of Retinal Dystrophies", Morales-Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG) [...]. ...[more]
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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.
| S-EPMC4438567 | biostudies-literature
Project description: Not available
| S-EPMC8094178 | biostudies-literature
Project description:ImportanceBoth primary and secondary forms of childhood glaucoma have many distinct causative mechanisms, and in many cases a cause is not immediately clear. The broad phenotypic spectrum of secondary glaucoma, particularly in individuals with variants in FOXC1 or PITX2 genes associated with Axenfeld-Rieger syndrome, makes it more difficult to diagnose patients with milder phenotypes. These cases are occasionally classified and managed as primary congenital glaucoma.ObjectiveTo investigate the prevalence of FOXC1 variants in participants with a suspected diagnosis of primary congenital glaucoma.Design, setting, and participantsAustralian and Italian cohorts were recruited from January 1, 2007, through March 1, 2016. Australian individuals were recruited through the Australian and New Zealand Registry of Advanced Glaucoma and Italian individuals through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Milan, Italy. We performed exome sequencing, in combination with Sanger sequencing and multiplex ligation-dependent probe amplification, to detect variants of FOXC1 in individuals with a suspected diagnosis of primary congenital glaucoma established by their treating specialist. Data analysis was completed from June 2015 to November 2017.Main outcome and measuresIdentification of single-nucleotide and copy number variants in FOXC1, along with phenotypic characterization of the individuals who carried them.ResultsA total of 131 individuals with a suspected diagnosis of primary congenital glaucoma were included. The mean (SD) age at recruitment in the Australian cohort was 24.3 (18.1) years; 37 of 84 Australian participants (44.0%) were female, and 71 of 84 (84.5%) were of European ancestry. The mean (SD) age at recruitment was 22.5 (18.4) years in the Italian cohort; 21 of 47 Italian participants (44.7%) were female, and 45 of 47 (95.7%) were of European ancestry. We observed rare, predicted deleterious FOXC1 variants in 8 of 131 participants (6.1%), or 8 of 166 participants (4.8%) when including those explained by variants in CYP1B1. On reexamination or reinvestigation, all of these individuals had at least 1 detectable ocular and/or systemic feature associated with Axenfeld-Rieger syndrome.Conclusions and relevanceThese data highlight the genetic and phenotypic heterogeneity of childhood glaucoma and support the use of gene panels incorporating FOXC1 as a diagnostic aid, especially because clinical features of Axenfeld-Rieger syndrome can be subtle. Further replication of these results will be needed to support the future use of such panels.
| S-EPMC6459212 | biostudies-literature
Project description:PurposePrimary congenital glaucoma (PCG) is a clinically and genetically heterogeneous disease. The present study was undertaken to find the genetic causes of PCG segregating in 36 large consanguineous Pakistani families.MethodsOphthalmic examination including fundoscopy, or slit-lamp microscopy was performed to clinically characterize the PCG phenotype. Genomic nucleotide sequences of the CYP1B1 and LTBP2 genes were analyzed with either Sanger or whole exome sequencing. In silico prediction programs were used to assess the pathogenicity of identified alleles. ClustalW alignments were performed to determine evolutionary conservation, and three-dimensional (3D) modeling was performed using HOPE and Phyre2 software.ResultsAmong the known loci, mutations in CYP1B1 and LTBP2 are the common causes of PCG. Therefore, we analyzed the genomic nucleotide sequences of CYP1B1 and LTBP2, and detected probable pathogenic variants cosegregating with PCG in 14 families. These included the three novel (c.542T>A, c.1436A>G, and c.1325delC) and five known (c.868dupC, c.1168C>T, c.1169G>A, c.1209InsTCATGCCACC, and c.1310C>T) variants in CYP1B1. Two of the novel variants are missense substitutions [p.(Leu181Gln), p.(Gln479Arg)], which replaced evolutionary conserved amino acids, and are predicted to be pathogenic by various in silico programs, while the third variant (c.1325delC) is predicted to cause reading frameshift and premature truncation of the protein. A single mutation, p.(Arg390His), causes PCG in six (~43%) of the 14 CYP1B1 mutations harboring families, and thus, is the most common variant in this cohort. Surprisingly, we did not find any LTBP2 pathogenic variants in the families, which further supports the genetic heterogeneity of PCG in the Pakistani population.ConclusionsIn conclusion, results of the present study enhance our understanding of the genetic basis of PCG, support the notion of a genetic modifier of CYP1B1, and contribute to the development of genetic testing protocols and genetic counseling for PCG in Pakistani families.
| S-EPMC6386514 | biostudies-literature
Project description:CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80.
| S-EPMC4779945 | biostudies-literature
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.
| S-EPMC2846849 | biostudies-literature
Project description:Cytochrome P450 1B1 (Cyp1b1) belongs to the CYP450 superfamily of heme-binding mono-oxygenases which catalyze oxidation of various endogenous and exogenous substrates. The expression of Cyp1b1 plays an important role in the modulation of development and functions of the trabecular meshwork (TM). Mutations in Cyp1b1 have been reported in patients with primary congenital glaucoma (PCG). Mice lacking Cyp1b1 also exhibit developmental defects in the TM similar to those reported in congenital glaucoma patients. However, how Cyp1b1 deficiency contributes to TM dysgenesis remains unknown. In the present review, we will address the significance of Cyp1b1 expression and/or its function in anterior segment development. Cyp1b1-deficient (Cyp1b1 (-/-)) mice are discussed as a promising model for an oxidative stress-induced model of PCG, in which Cyp1b1 activity is revealed as an important modulator of oxidative homeostasis contributing to the development and structural function of the TM. This conclusion suggests a possible clinical intervention for individuals who are genetically at high risk of developing PCG.
| S-EPMC4424721 | biostudies-literature
Project description:Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.
| S-EPMC2680998 | biostudies-literature
Project description:PurposeTo compare posterior corneal morphology between older treated and younger untreated children with primary congenital glaucoma (PCG) using anterior segment optical coherence tomography (ASOCT) and intraoperative OCT (iOCT), respectively.MethodsIn this comparative study, ASOCT of older PCG children were compared with iOCT of younger untreated PCG patients. Differences between the two groups with respect to posterior corneal morphology were studied.ResultsObserved morphological patterns within posterior cornea in older treated (age: 72-300 months) children (87 eyes) included Descemet's membrane (DM) excrescences (70%), thickened DM (35%), intracameral twin protuberances (92%), and DM detachment (26%). Changes within pre-Descemet's layer (PDL) (28%) included thickening, breaks, and detachments. Extent of Haab's striae was associated with thickness of DM/PDL complex (P = 0.008) when analyzed in the treated group. In contrast, in the untreated group (n = 53 eyes, age 1-63 months), posterior corneal changes were limited to diffuse hyper-reflectivity of the DM/PDL complex, with absence of DM tears.ConclusionPosterior cornea thickens and Haab's striae become more circumscribed in eyes of older treated children compared to untreated PCG eyes, probably reflecting a healing response of posterior cornea over time.
| S-EPMC9426191 | biostudies-literature
Project description:PurposeTo investigate the potential of handheld optical coherence tomography (HH-OCT) in assessing the anterior segment of the eye in patients with primary congenital glaucoma.DesignA prospective, case-controlled observational study.ParticipantsTwenty-two patients with primary congenital glaucoma (PCG, 9 females and 13 males; mean age 4.36 ± 3.4 years) and age-, gender- and ethnicity-matched healthy participants.MethodsAnterior OCT was performed in all participants using a high-resolution HH SD-OCT device (Envisu 2300, Leica Microsystems, Germany) without anaesthesia or sedation.ResultsAnterior HH-OCT in PCG visualised Haab's striae in 14.3%, uneven internal cornea in 9.5% and epithelial thickening in 11.9% of patients with central corneal thickening (CCT, p < 0.001). CCT was significantly correlated with the intraocular pressure (IOP, p < 0.001). The flat iris with a thin collarette zone was found in 59.5%, anterior iris insertion in 11.90% of eyes affected by PCG. Two independent examiners showed sensitivity and specificity of 87% and 77%, respectively, by instating iris thinning and flattening of the anterior profile.ConclusionsAnterior HH-OCT has significant potential to improve diagnosis and management of PCG. Clinically relevant information can be obtained non-invasively and without sedation. High specificity makes anterior HH-OCT an important adjunct for management of PCG. Excellent visualisation of the iris insertion on OCT indicates potential for AS OCT to assist with surgical planning, including decision on the type of surgery and location of the incision.
| S-EPMC7005739 | biostudies-literature