[Hereditary ectopia lentis: diagnosis and surgical treatment]. / Nasledstvenno obuslovlennye varianty ektopii khrustalika: diagnostika i khirurgicheskoe lechenie.

This review describes hereditary diseases in which ectopia lentis may be present as one of the symptoms, considers the basic diagnostic concepts of lens disposition, and analyzes the options in surgical treatment of ectopia lentis and optical correction of aphakia.

[Ocular manifestations of Marfan syndrome]. / Glaznye proyavleniya sindroma Marfana.

Marfan syndrome is an orphan disease that is caused by a mutation in the FBN1 gene located on chromosome 15 (15q21.1) and is usually inherited in an autosomal dominant manner. The article reviews the results of studies concerning the potential ocular manifestations of Marfan syndrome.

Matrix Metalloproteinase-2 Activated by Ultraviolet-B Degrades Human Ciliary Zonules In Vitro.

The ciliary zonules, also known as the zonules of Zinn, help to control the thickness of the lens during focusing. The ciliary zonules are composed of oxytalan fibers, which are synthesized by human nonpigmented ciliary epithelial cells (HNPCEC). The ciliary zonules are exposed to ultraviolet (UV), especially UV-A and UV-B, throughout life. We previously demonstrated that UV-B, but not UV-A, degrades fibrillin-1- and fibrillin-2-positive oxytalan fibers. However, the mechanism by which UV-B degrades oxytalan fibers remains unknown. In this study, we investigate the involvement of matrix metalloproteinase-2 (MMP-2) in the UV-B-induced degradation of fibrillin-1- and fibrillin-2-positive oxytalan fibers in cultured HNPCECs. Enzyme-linked immunosorbent assay revealed that UV-B irradiation at levels of 100 and 150 mJ/cm2 significantly increased the level of active MMP-2. Notably, MMP-2 inhibitors completely suppressed the degradation of fibrillin-1- and fibrillin-2-positive oxytalan fibers. In addition, we show that UV-B activates MMP-2 via stress-responsive kinase p38. Taken together, the results suggest that UV-B activates a production of active type of MMP-2 via the p38 pathway, and subsequently, an active-type MMP-2 degrades the fibrillin-1- and fibrillin-2-positive oxytalan fibers in cultured HNPCECs.

The mgΔlpn mouse model for Marfan syndrome recapitulates the ocular phenotypes of the disease.

PURPOSE: Fibrillin-1 and -2 are major components of tissue microfibrils that compose the ciliary zonule and cornea. While mutations in human fibrillin-1 lead to ectopia lentis, a major manifestation of Marfan syndrome (MFS), in mice fibrillin-2 can compensate for reduced/lack of fibrillin-1 and maintain the integrity of ocular structures. Here we examine the consequences of a heterozygous dominant-negative mutation in the Fbn1 gene in the ocular system of the mgΔlpn mouse model for MFS. METHODS: Eyes from mgΔlpn and wild-type mice at 3 and 6 months of age were analyzed by histology. The ciliary zonule was analyzed by scanning electron microscopy (SEM) and immunofluorescence. RESULTS: Mutant mice presented a significantly larger distance of the ciliary body to the lens at 3 and 6 months of age when compared to wild-type, and ectopia lentis. Immunofluorescence and SEM corroborated those findings in MFS mice, revealing a disorganized mesh of microfibrils on the floor of the ciliary body. Moreover, mutant mice also had a larger volume of the anterior chamber, possibly due to excess aqueous humor. Finally, losartan treatment had limited efficacy in improving ocular phenotypes. CONCLUSIONS: In contrast with null or hypomorphic mutations, expression of a dominant-negative form of fibrillin-1 leads to disruption of microfibrils in the zonule of mice. This in turn causes lens dislocation and enlargement of the anterior chamber. Therefore, heterozygous mgΔlpn mice recapitulate the major ocular phenotypes of MFS and can be instrumental in understanding the development of the disease.

Late spontaneous bilateral intraocular lens subluxation accompanied with intraocular pressure elevation in a patient with acromegaly.

A 53-year-old male with newly diagnosed acromegaly came to our clinic with the chief complaint of diplopia. He had the past ocular history of uneventful phacoemulsification cataract surgery with intraocular lens (IOL) implantation in the right eye 17 years ago and left eye 15 years ago. Postoperative examination showed remarkable improvement in visual acuity. Two years ago, he developed elevated intraocular pressure (IOP) in both eyes, which was well-controlled with the use of travoprost 0.004%/timolol 0.5%. At the clinic, slit-lamp examination revealed inferiorly subluxated IOL bilaterally. The patient received IOL repositioning with pars plana vitrectomy and scleral fixation in the left eye smoothly. We hypothesize that excess growth hormone is associated with dysregulation of fibrillin, resulting in zonular weakness, which causes late bilateral IOL subluxation. Elevated IOP may also be related to acromegaly. To the best of our knowledge, this is the first report to describe the association between IOL subluxation and acromegaly.

Targeted deletion of fibrillin-1 in the mouse eye results in ectopia lentis and other ocular phenotypes associated with Marfan syndrome.

Fibrillin is an evolutionarily ancient protein that lends elasticity and resiliency to a variety of tissues. In humans, mutations in fibrillin-1 cause Marfan and related syndromes, conditions in which the eye is often severely affected. To gain insights into the ocular sequelae of Marfan syndrome, we targeted Fbn1 in mouse lens or non-pigmented ciliary epithelium (NPCE). Conditional knockout of Fbn1 in NPCE, but not lens, profoundly affected the ciliary zonule, the system of fibrillin-rich fibers that centers the lens in the eye. The tensile strength of the fibrillin-depleted zonule was reduced substantially, due to a shift toward production of smaller caliber fibers. By 3 months, zonular fibers invariably ruptured and mice developed ectopia lentis, a hallmark of Marfan syndrome. At later stages, untethered lenses lost their polarity and developed cataracts, and the length and volume of mutant eyes increased. This model thus captures key aspects of Marfan-related syndromes, providing insights into the role of fibrillin-1 in eye development and disease.

The Effect of Ultraviolet B on Fibrillin-1 and Fibrillin-2 in Human Non-pigmented Ciliary Epithelial Cells In Vitro.

The ciliary zonules link the lens to the ciliary body in the eye, controlling the thickness of the lens for focusing through their characteristic elasticity. The ciliary zonules are composed of oxytalan fibers. Physiological or pathological damage to the ciliary zonules, including exposure to ultraviolet (UV)-A and UV-B components, can lead to lens dislocation. However, no studies have shown whether UV affects the ciliary zonule. Here, we assessed the effects of UV light on human nonpigmented ciliary epithelial cells (HNPCECs). HNPCECs were cultured for 4 weeks, and expression of fibrillin-1 and fibrillin-2 was confirmed. In control cultures (0 mJ/cm2), some fibrillin-1-positive fibers were merged with fibrillin-2. After UV-A irradiation, the appearance of both fibrillin-1- and fibrillin-2-positive fibers was unchanged. However, after UV-B irradiation, fibrillin-1-positive fibers became thin at an irradiation level of 100 mJ/cm2, and the fiber structure became amorphous at 150 mJ/cm2. Fibrillin-2-positive fibers lost their continuity and disappeared after being exposed to 150 mJ/cm2 UV-B. UV-B irradiation did not affect cell viability, possibly because of the sensitivity of fibrillin-1 and fibrillin-2 to UV-B. Thus, dislocation of the lens with age may be attributable to cumulative exposure to UV-B.

Human eye development is characterized by coordinated expression of fibrillin isoforms.

PURPOSE: Mutations in human fibrillin-1 and -2, which are major constituents of tissue microfibrils, can affect multiple ocular components, including the ciliary zonule, lens, drainage apparatus, cornea, and retina. However, the expression pattern of the three human fibrillins and an integral microfibrillar component, MAGP1, during human eye development is not known. METHODS: We analyzed sections from human eyes at gestational weeks (GWs) 6, 8, and 11 and at 1 and 3 years of age with antibodies specific for each human fibrillin isoform or MAGP1, using immunofluorescence microscopy. RESULTS: During embryonic development, each fibrillin isoform was detected in vascular structures bridging the ciliary body and the developing lens, hyaloid vasculature, and retina. In addition, they were present in the developing corneal basement membranes and lens capsule. MAGP1 codistributed with the fibrillin isoforms. In contrast, the juvenile zonule was composed of fibrillin-1 microfibrils containing MAGP1, but fibrillin-2 was absent and fibrillin-3 was only sparsely detected. CONCLUSIONS: Fibrillin-1, -2, and, unique to humans, fibrillin-3 are found in various ocular structures during human embryonic eye development, whereas fibrillin-1 dominates the postnatal zonule. We speculate that vasculature spanning the ciliary body and lens, which elaborates fibrillin-2 and -3, may provide an initial scaffold for fibrillin assembly and zonule formation.

Microfibril-associated glycoprotein-1 controls human ciliary zonule development in vitro.

The ciliary zonule in the eye, also known as Zinn's zonule, is composed of oxytalan fibers, which are bundles of microfibrils consisting mainly of fibrillin-1. However, it is still unclear which of the microfibril-associated molecules present in the ciliary zonule controls oxytalan fibers. Microfibril-associated glycoprotein-1 (MAGP-1) is the only microfibril-associated molecule identified in the human ciliary zonule. In the present study, we used siRNA against MAGP-1 in cultures of human non-pigmented ciliary epithelial cells to examine the extracellular deposition and appearance of fibrillin-1 employing Western blotting and immunofluorescence. MAGP-1 suppression led to a reduction of fibrillin-1 deposition. Immunofluorescence also confirmed that RNAi-mediated down-regulation of MAGP-1 led to suppression of fiber development. These results suggest that MAGP-1 plays a crucial role in the extracellular deposition of fibrillin-1 during formation of the human ciliary zonule.

Matrix metalloproteinase-2 degrades fibrillin-1 and fibrillin-2 of oxytalan fibers in the human eye and periodontal ligaments in vitro.

Oxytalan fibers are distributed in the eye and periodontal ligaments (PDL). The ciliary zonule, known as Zinn's zonule, in the eye is composed of oxytalan fibers, which are bundles of microfibrils consisting mainly of fibrillin-1 and fibrillin-2. As turnover of oxytalan fibers is slow during life, their degradation mechanism remains unclarified. This study was performed to examine degradation pattern of fibrillin-1 and fibrillin-2 by experimental MMP activation. We cultured human non-pigmented ciliary epithelial cells (HNPCEC) and PDL fibroblasts for 7 days, then treated them with concanavalin A to activate matrix metalloproteinase (MMP)-2, and examined the degradation of fibrillin-1 and fibrillin-2 for 72 hr using immunofluorescence. At 7 days of HNPCEC culture, fibrillin-1-positive fibers were observed, some of which merged with fibrillin-2. After MMP-2 activation, fibrillin-1-positive fibers became thin and disappeared by 72 hr, while fibrillin-2-positive fibers disappeared almost completely within 24 hr. At 7 days of PDL fibroblast culture, fibrillin-1-positive fibers were mostly merged with fibrillin-2. After MMP-2 activation, fibrillin-1-positive fibers became thin by 24 hr and had almost disappeared by 48 hr, while fibrillin-2-positive fibers decreased constantly after 24 hr. A MMP-2 inhibitor completely suppressed these degradations. These results suggest that the patterns of fibrillin-1 and fibrillin-2 degradation differ between the eye and the PDL, possibly reflecting the sensitivity of fibrillin-1 and fibrillin-2 of each type of oxytalan fiber against MMP-2.

Ocular phenotype of Fbn2-null mice.

PURPOSE: Fibrillin-2 (Fbn2) is the dominant fibrillin isoform expressed during development of the mouse eye. To test its role in morphogenesis, we examined the ocular phenotype of Fbn2(-/-) mice. METHODS: Ocular morphology was assessed by confocal microscopy using antibodies against microfibril components. RESULTS: Fbn2(-/-) mice had a high incidence of anterior segment dysgenesis. The iris was the most commonly affected tissue. Complete iridal coloboma was present in 37% of eyes. Dyscoria, corectopia and pseudopolycoria were also common (43% combined incidence). In wild-type (WT) mice, fibrillin-2-rich microfibrils are prominent in the pupillary membrane (PM) during development. In Fbn2-null mice, the absence of Fbn2 was partially compensated for by increased expression of fibrillin-1, although the resulting PM microfibrils were disorganized, compared with WTs. In colobomatous adult Fbn2(-/-) eyes, the PM failed to regress normally, especially beneath the notched region of the iris. Segments of the ciliary body were hypoplastic, and zonular fibers, although relatively plentiful, were unevenly distributed around the lens equator. In regions where the zonular fibers were particularly disturbed, the synchronous differentiation of the underlying lens fiber cells was affected. CONCLUSIONS: Fbn2 has an indispensable role in ocular morphogenesis in mice. The high incidence of iris coloboma in Fbn2-null animals implies a previously unsuspected role in optic fissure closure. The observation that fiber cell differentiation was disturbed in Fbn2(-/-) mice raises the possibility that the attachment of zonular fibers to the lens surface may help specify the equatorial margin of the lens epithelium.