Glycosaminoglycans in Eye Diseases A Macular Corneal Dystrophy

Macular corneal dystrophy is a rare dystrophy that is characterized by abnormal deposits in the corneal stroma, keratocytes, Descemet's membrane, and a c e g k q

Figure 1 Schematic diagram of the eye in horizontal section indicating each ocular component. a, corneal epithelium; b, keratocyte; c, corneal endothelium; d, aqueous humor; e, conjunctiva; f, sclera; g, trabecular meshwork; h, iris; i, lens; j, ciliary zonule and body; k, vitreous; l, retina; m, interphotoreceptor matrix; n, retinal pigment epithelium; o, Bruch's membrane; p, choroid; q, optic nerve head; r, lamina cribrosa; s, extrao-cular muscles and tissues. The candidate glycosaminoglycans involved in the ocular components of each eye disease described in this chapter are as follows: macular corneal dystrophy (b, c: KS, CS/DS, HA), glaucoma (d: HA; g: CS/DS, HS, HA; q, r: CS, HS, HA), cataract (i: CS/DS, HS, HA), diabetic retinopathy (k: HA; l: HS), retinal detach-ment/proliferative vitreoretinopathy (k, l, m, n: CS/DS, HS, HA), myopia (f, p: CS), thyroid eye disease (s: CS, HA), pseudoexfoliation syndrome (c, d, g, h, i, j: KS, CS/DS, HA). KS, keratan sulfate; CS/DS, chondroitin sulfate/dermatan sulfate; HS, heparan sulfate; HA, hyaluronan.

Figure 1 Schematic diagram of the eye in horizontal section indicating each ocular component. a, corneal epithelium; b, keratocyte; c, corneal endothelium; d, aqueous humor; e, conjunctiva; f, sclera; g, trabecular meshwork; h, iris; i, lens; j, ciliary zonule and body; k, vitreous; l, retina; m, interphotoreceptor matrix; n, retinal pigment epithelium; o, Bruch's membrane; p, choroid; q, optic nerve head; r, lamina cribrosa; s, extrao-cular muscles and tissues. The candidate glycosaminoglycans involved in the ocular components of each eye disease described in this chapter are as follows: macular corneal dystrophy (b, c: KS, CS/DS, HA), glaucoma (d: HA; g: CS/DS, HS, HA; q, r: CS, HS, HA), cataract (i: CS/DS, HS, HA), diabetic retinopathy (k: HA; l: HS), retinal detach-ment/proliferative vitreoretinopathy (k, l, m, n: CS/DS, HS, HA), myopia (f, p: CS), thyroid eye disease (s: CS, HA), pseudoexfoliation syndrome (c, d, g, h, i, j: KS, CS/DS, HA). KS, keratan sulfate; CS/DS, chondroitin sulfate/dermatan sulfate; HS, heparan sulfate; HA, hyaluronan.

endothelium, which is accompanied by progressive clouding. Corneal cells and organ cultures from patients with macular corneal dystrophy show diminished synthesis of keratan sulfate proteoglycans (1,2). Nakazawa et al. indicated that the associated error in the synthesis of corneal keratan sulfate in macular corneal dystrophy is caused by failure of specific sulfotransferases involved in sulfation (3).

Macular corneal dystrophy can be classified into three immunophenotypes, types I, IA, and II, according to the serum level of sulfated keratan sulfate and immunoreactivity of the corneal tissue. In macular corneal dystrophy type I, the keratan sulfate level is low in both the serum and corneal tissue. In macular

Table 1 Glycosaminoglycans Associated with Eye Diseases KS Macular corneal dystrophy, pseudoexfoliation syndrome

CS/DS Macular corneal dystrophy, glaucoma, cataract, retinal detachment/proliferative vitreoretinopathy, myopia, thyroid eye disease, pseudoexfoliation syndrome HS Glaucoma, cataract, diabetic retinopathy, retinal detachment/proliferative vitreoretinopathy

HA Macular corneal dystrophy, glaucoma, cataract, diabetic retinopathy, retinal detachment/proliferative vitreoretinopathy, thyroid eye disease, pseudoexfoliation syndrome

KS, keratan sulfate; CS/DS, chondroitin sulfate/dermatan sulfate; HS, heparan sulfate; HA, hyaluronan.

corneal dystrophy type IA, the serum keratan sulfate level is low, but keratan sulfate accumulated within the keratocytes reacts with 5D4, a monoclonal antibody that recognizes a sulfated epitope on the keratan sulfate chain. In macular corneal dystrophy type II, the serum keratan sulfate level is often normal, but accumulated corneal keratan sulfate reacts with the 5D4 antibody. As an example, a quantitative analysis revealed that the antigenic keratan sulfate content of the cornea of a macular corneal dystrophy type I patient was at least 800 times lower than that in normal control subjects (4). The key molecules involved in the disease are modification enzymes of keratan sulfate. For example, the activity of GlcNAc6ST was found to be decreased in a cornea with macular corneal dystrophy (5), and recent studies have identified mutations in a carbohydrate sulfotransferase gene encoding corneal N-acetylglucosamine 6-O-sulfotransferase on chromosome 16q22 as one of the causes of macular corneal dystrophy (6-9).

The keratan and chondroitin/dermatan sulfate levels in normal human corneas and corneas affected by macular corneal dystrophies types I and II were compared (10). The results revealed that the keratan sulfate chain size was reduced and chain sulfation was absent in type I, and that sulfation of both GlcNAc and Gal was significantly reduced in type II. The chondroitin/dermatan sulfate chain sizes were also decreased in all diseased corneas, and the contents of 4- and 6-sulfated disaccharides were proportionally increased. The keratan sulfate chain concentrations were reduced in both types I and II, whereas the chondroitin/der-matan sulfate chain concentrations were increased in both types. Hyaluronan, which is not normally present in healthy adult corneas, was also detected in both disease subtypes.

Macular corneal dystrophy types I and II have also been characterized histo-chemically. In normal corneas, high levels of sulfated keratan sulfate were detected in the stroma, Bowman's layer, and Descemet's membrane with low levels in the keratocytes, epithelium, and endothelium. Furthermore, in normal corneas, negligible levels of labeling for N-acetyllactosamine (unsulfated keratan sulfate) were detected. In macular corneal dystrophy type I corneas, sulfated keratan sulfate was not detected anywhere, but a specific distribution of N-acetyllactosamine (unsulfated keratan sulfate) was evident with heavily labeled deposits in the stroma, keratocytes, endothelium, and disrupted posterior region of Descemet's membrane (11). In macular corneal dystrophy type II corneas, the midstroma contained 30% less sulfur than normal corneas (12).

B. Glaucoma

Glaucoma is a type of optic neuropathy associated with characteristic optic disk damage, which may result in certain visual field loss patterns, at least partly in response to suboptimal intraocular pressure. There are three representative ocular lesions containing glycosaminoglycans, namely the aqueous humor, trabecular meshwork, and optic nerve head/lamina cribrosa, which are involved in glaucoma.

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