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Ocular findings of a patient with Marfan syndrome. Slit lamp photo of the patient with Marfan syndrome reveals pronounced iris transillumination defects as red color (A). The anterior chamber angles are open and iris sustains a back-bowing configuration demonstrated by anterior segment optic coherence tomography (B).
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Mutations in fibrillin-1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin-1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well-character...
Contexts in source publication
Context 1
... syndrome in both eyes, including pigment accumulation on the posterior surface of the central cornea in a vertical pattern (Krukenberg's spindle), deep anterior chamber both centrally and peripherally, iris transillumination defect in a radial spoke- like pattern in the mid-periphery of the iris and a back-bowing configuration of the iris (Fig. 1A). Both lenses appeared normal in size and shape, with no indications of ectopia lentis or cataract. Gonioscopic examination showed a wide open angle with a dense and homogeneous band of dark pigment in the full circumference of the trabecular meshwork. The open angle and concave config- uration of the iris was further confirmed by ...Context 2
... with no indications of ectopia lentis or cataract. Gonioscopic examination showed a wide open angle with a dense and homogeneous band of dark pigment in the full circumference of the trabecular meshwork. The open angle and concave config- uration of the iris was further confirmed by anterior segment optic coherence tomography (Visante OCT; Zeiss) (Fig. 1B). Based on the presence of optic nerve damage, elevated IOP with open angles and clear signs of iris pigment dispersion, the patient was diagnosed with pigmentary ...Citations
... Hyperhomocysteinemia, particularly in the context of the MTHFR C677T mutation, is highlighted as a risk factor for ocular pathologies [32]. While PDS/PG features in syndromic diseases like Knobloch syndrome, linked to COL18A1 mutations, and potentially in Marfan syndrome, conclusive genetic causality is yet to be established [51][52][53][54][55]. ...
Pigment Dispersion Syndrome (PDS) and Pigmentary Glaucoma (PG) comprise a spectrum of ocular disorders characterized by iris pigment dispersion and trabecular meshwork changes, resulting in increased intraocular pressure and potential glaucomatous optic neuropathy. This review summarizes recent progress in PDS/PG genetics including rare pathogenic protein coding alterations (PMEL) and susceptibility loci identified from genome-wide association studies (GSAP and GRM5/TYR). Areas for future research are also identified, especially the development of efficient model systems. While substantial strides have been made in understanding the genetics of PDS/PG, our review identifies key gaps and outlines the future directions necessary for further advancing this important field of ocular genetics.
... Similarly, patients with MFS and Weill-Marchesani type 2 syndrome with mutations in FBN1 often develop elevated IOP as a result of glaucoma. 14,15,50,54,55 In contrast with the fbn1 zebrafish mutants, the Fbn1 mouse mutants did not show a significant increase in IOP, except for two animals suffering from strongly cataractous lenses. 35 Finally, the fbn1 fish mutants showed a decreased number of ETMs per 15-second interval, indicating a decrease in spatial vision capability, similar to MFS patients. ...
Purpose:
To establish a set of assays that allow the in vivo screening of candidate genes for ocular diseases in zebrafish, with an emphasis on refractive error.
Methods:
Our pipeline includes the most relevant ocular screening measurements to assess (1) ocular biometry using spectral domain optical coherence tomography, (2) refractive status using an eccentric photorefractor, (3) intraocular pressure by tonometry, and (4) optokinetic response to study visual capability in zebrafish. To validate our pipeline and to demonstrate the potential of zebrafish as a valid animal model, we chose two well-characterized genes with an ocular phenotype (PRSS56 and FBN1) and generated two mutant zebrafish lines (prss56 and fbn1). Mutant fish were assessed at 2, 4, and 6 months after fertilization.
Results:
With the proposed phenotyping pipeline, we showed that ocular biometry, refractive status, intraocular pressure, and visual function can be studied in zebrafish. In the prss56 mutant, the pipeline revealed a dramatic decrease in axial length, mainly owing to a decreased vitreous chamber depth, whereas in the fbn1 mutant, ectopia lentis was the most distinctive ocular phenotype observed. Tonometry in both mutant lines showed an increase in intraocular pressure.
Conclusions:
The proposed pipeline was applied successfully in zebrafish and can be used for future genetic screenings of candidate genes. While validating our pipeline, we found a close resemblance between the ocular manifestations in the zebrafish mutants and patients harboring mutations in PRSS56 and FBN1. Our results support the validity of our pipeline and highlight the potential of zebrafish as an animal model for in vivo screening of candidate genes for ocular diseases.
... Other ocular diseases that affect the elastic component, and more specifically the microfibrils of FBN1, include myopia and ectopia lentis; both ophthalmological pathologies are frequently observed in Marfan syndrome, which involves defects in the microfibrils of FBN1. Glaucoma is also associated with this syndrome, although the form of this pathology has not been well characterized [95]. ...
Pterygium is a benign fibrovascular lesion of the bulbar conjunctiva with frequent involvement of the corneal limbus. Its pathogenesis has been mainly attributed to sun exposure to ultraviolet-B radiation. Obtained evidence has shown that it is a complex and multifactorial process which involves multiple mechanisms such as oxidative stress, dysregulation of cell cycle checkpoints, induction of inflammatory mediators and growth factors, angiogenic stimulation, extracellular matrix (ECM) disorders, and, most likely, viruses and hereditary changes. In this review, we aim to collect all authors’ experiences and our own, with respect to the study of fibroelastic ECM of pterygium. Collagen and elastin are intrinsic indicators of physiological and pathological states. Here, we focus on an in-depth analysis of collagen (types I and III), as well as the main constituents of elastic fibers (tropoelastin (TE), fibrillins (FBNs), and fibulins (FBLNs)) and the enzymes (lysyl oxidases (LOXs)) that carry out their assembly or crosslinking. All the studies established that changes in the fibroelastic ECM occur in pterygium, based on the following facts: An increase in the synthesis and deposition of an immature form of collagen type III, which showed the process of tissue remodeling. An increase in protein levels in most of the constituents necessary for the development of elastic fibers, except FBLN4, whose biological roles are critical in the binding of the enzyme LOX, as well as FBN1 for the development of stable elastin. There was gene overexpression of TE, FBN1, FBLN5, and LOXL1, while the expression of LOX and FBLN2 and -4 remained stable. In conclusion, collagen and elastin, as well as several constituents involved in elastic fiber assembly are overexpressed in human pterygium, thus, supporting the hypothesis that there is dysregulation in the synthesis and crosslinking of the fibroelastic component, constituting an important pathogenetic mechanism for the development of the disease.
... MS can involve numerous organ systems; however in terms of ocular manifestations, common associations include ectopia lentis, (Fuchs, 1997;Maumenee, 1981;Meire et al., 1991) thinning and curvature flattening of the cornea (Heur et al., 2008;Sultan et al., 2002), early cataracts, (Biro et al., 2014) glaucoma, (Izquierdo et al., 1992;Kuchtey et al., 2013) and retinal detachment (Abboud, 1998;Loewenstein et al., 2000;Sharma et al., 2002). While very little is known on the actual MS pathobiology, it has been found that MS patients lack expression of fibrillin-1 to the superficial capsule and the ciliary epithelial surface (Kohnen et al., 2003;Nemet et al., 2006;Wheatley et al., 1995). ...
"The Diseases of the Horny-coat of The Eye", known today as keratoconus, is a progressive, multifactorial, non-inflammatory ectatic corneal disorder that is characterized by steepening (bulging) and thinning of the cornea, irregular astigmatism, myopia, and scarring that can cause devastating vision loss. The significant socioeconomic impact of the disease is immeasurable, as patients with keratoconus can have difficulties securing certain jobs or even joining the military. Despite the introduction of corneal crosslinking and improvements in scleral contact lens designs, corneal transplants remain the main surgical intervention for treating keratoconus refractory to medical therapy and visual rehabilitation. To-date, the etiology and pathogenesis of keratoconus remains unclear. Research studies have increased exponentially over the years, highlighting the clinical significance and international interest in this disease. Hormonal imbalances have been linked to keratoconus, both clinically and experimentally, with both sexes affected. However, it is unclear how (molecular/cellular signaling) or when (age/disease stage(s)) those hormones affect the keratoconic cornea. Previous studies have categorized the human cornea as an extragonadal tissue, showing modulation of the gonadotropins, specifically luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Studies herein provide new data (both in vitro and in vivo) to further delineate the role of hormones/gonadotropins in the keratoconus pathobiology, and propose the existence of a new axis named the Hypothalamic-Pituitary-Adrenal-Corneal (HPAC) axis.
... Glaucoma-related proteins of the elastic tendon network include fibrillin-1, fibrillin-2, versican, latent TGFβ-binding proteins, and microfibrillar-associated proteins. Gonzalez et al., 2012;Kuchtey et al., 2013;Vranka et al., 2015;Filla et al., 2017;Papadopoulou et al., 2017). ...
We propose an integrated model of aqueous outflow control that employs a pump-conduit system in this article. Our model exploits accepted physiologic regulatory mechanisms such as those of the arterial, venous, and lymphatic systems. Here, we also provide a framework for developing novel diagnostic and therapeutic strategies to improve glaucoma patient care. In the model, the trabecular meshwork distends and recoils in response to continuous physiologic IOP transients like the ocular pulse, blinking, and eye movement. The elasticity of the trabecular meshwork determines cyclic volume changes in Schlemm's canal (SC). Tube-like SC inlet valves provide aqueous entry into the canal, and outlet valve leaflets at collector channels control aqueous exit from SC. Connections between the pressure-sensing trabecular meshwork and the outlet valve leaflets dynamically control flow from SC. Normal function requires regulation of the trabecular meshwork properties that determine distention and recoil. The aqueous pump-conduit provides short-term pressure control by varying stroke volume in response to pressure changes. Modulating TM constituents that regulate stroke volume provides long-term control. The aqueous outflow pump fails in glaucoma due to the loss of trabecular tissue elastance, as well as alterations in ciliary body tension. These processes lead to SC wall apposition and loss of motion. Visible evidence of pump failure includes a lack of pulsatile aqueous discharge into aqueous veins and reduced ability to reflux blood into SC. These alterations in the functional properties are challenging to monitor clinically. Phase-sensitive OCT now permits noninvasive, quantitative measurement of pulse-dependent TM motion in humans. This proposed conceptual model and related techniques offer a novel framework for understanding mechanisms, improving management, and development of therapeutic options for glaucoma.
... It is intriguing that elastin degradation is also the hallmark of Marfan's syndrome, a connective tissue disease caused by a mutation in fibrillin1, a protein essential for the formation of the elastic fibers 83 . About 2% of Marfan's patients exhibit glaucoma 84,85 . Moreover, elastin degradation and fragmentation led to the release of elastin peptides, which colocalized with areas of microcalcification in the aorta of Marfan's patients 86 . ...
The ability to ablate a gene in a given tissue by generating a conditional knockout (cKO) is crucial for determining its function in the targeted tissue. Such tissue-specific ablation is even more critical when the gene’s conventional knockout (KO) is lethal, which precludes studying the consequences of its deletion in other tissues. Therefore, here we describe a successful strategy that generated a Matrix Gla floxed mouse ( Mgp.floxed ) by the CRISPR/Cas9 system, that subsequently allowed the generation of cKOs by local viral delivery of the Cre-recombinase enzyme. MGP is a well-established inhibitor of calcification gene, highly expressed in arteries’ smooth muscle cells and chondrocytes. MGP is also one of the most abundant genes in the trabecular meshwork, the eye tissue responsible for maintenance of intraocular pressure (IOP) and development of Glaucoma. Our strategy entailed one-step injection of two gRNAs, Cas9 protein and a long-single-stranded-circular DNA donor vector (lsscDNA, 6.7 kb) containing two loxP sites in cis and 900–700 bp 5′/3′ homology arms. Ocular intracameral injection of Mgp.floxed mice with a Cre-adenovirus, led to an Mgp. TMcKO mouse which developed elevated IOP. Our study discovered a new role for the Mgp gene as a keeper of physiological IOP in the eye.
... Affected individuals are, in general, male, white race, myopic between the second and fifth decades of life. SDP is caused by the dispersion of the pigment caused by mechanical contact between the posterior pigmented layer of the iris and the anterior surface of the zonule fibers, as a result of excessive posterior bulging of the peripheral portion of the iris [1][2][3]. The pigment granules are released in the aqueous humor and are deposited in all the structures of the anterior chamber, including the trabecular meshwork [4]. ...
... However, given the severity of the other diagnostic symptoms of Knobloch syndrome, variants in COL18A1 are unlikely to cause a large proportion of PDS/PG cases. Two case reports have associated Marfan syndrome (OMIM number 154700) with PDS/PG and suggested that FBN1 variants, while not causative for PDS, may contribute to conversion to glaucoma [74,75]. Although glaucoma generally has been associated with Marfan syndrome [76], there currently exists insufficient evidence to associate PDS/PG directly with Marfan syndrome or variants in FBN1. ...
We explore the ideas and advances surrounding the genetic basis of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). As PG is the leading cause of nontraumatic blindness in young adults and current tailored interventions have proven ineffective, a better understanding of the underlying causes of PDS, PG, and their relationship is essential. Despite PDS being a subclinical disease, a large proportion of patients progress to PG with associated vision loss. Decades of research have supported a genetic component both for PDS and conversion to PG. We review the body of evidence supporting a genetic basis in humans and animal models and reevaluate classical mechanisms of PDS/PG considering this new evidence.
... There are, however, several genetic variants within the collagen genes that are significantly associated with glaucomatous endophenotypes such as maximum vertical cup-disc ratio, increased optic disc cup area and altered central corneal thickness [29][30][31][32]. Other mutations within fibrillin 1, latent-transforming growth factor beta-binding protein 2 and versican genes have been associated with glaucoma in humans [33][34][35][36][37]. These proteins constitute large ECM fibrils that have roles in cell adhesion within the matrix. ...
Introduction:
Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm's Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment.
... There are mutations in multiple genes encoding elastic microfiber components that are associated with glaucoma . Fibrillin-1 mutations cause Marfan syndrome and ocular abnormalities include pigmentary glaucoma, ectopia lentis, myopia and glaucoma (Kuchtey et al., 2013;Micheal et al., 2012;Zhao et al., 2012). Fibrillin-1 mutations also cause Weill-Marchesani syndrome, which is another connective tissue disorder that includes severe myopia and glaucoma (Faivre et al., 2003a(Faivre et al., , 2003b. ...
... Mutations in collagen genes in mice display phenotypes consistent with glaucoma. A targeted mutation in collagen type I, which renders the molecule resistant to proteolytic cleavage by MMPs-1 and -2, was found to increase IOP in mice suggesting an association between IOP regulation and collagen turnover (Aihara Kuchtey et al., 2013;Michael, 2012;Zhao et al., 2012;Faivre et al., 2003a, 2003b Primary congenital glaucoma; Primary open-angle glaucoma; secondary glaucoma; pseudoexfoliation glaucoma Ali et al., 2009;Narooia-Nejad, 2009;Desir et al., 2010;Jelodari-Mamaghani et al., 2013;Krumbiegel et al., 2009. ...
