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Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive disorder that is most often seen in Japan. This bilateral dystrophy usually presents in the first decade of life and is associated with a decrease of visual acuity. Typically, a mulberry-like opacity is present with protuberant subepithelial mounds that grow with age. Corneal neovascularisation (NV) also accompanies advanced cases.1 Corneal transplantation is the major therapeutic option for GDLD, but because NV can significantly increase the risk of graft rejection, a better understanding of the mechanism(s) for the corneal NV would be valuable.
Case report
A 39 year old Japanese man with GDLD was studied. His right eye had band-shaped corneal opacities in the interpalpebral area with a number of gelatinous prominences, and vascular invasions from the superior limbus into the clear cornea (Fig 1A). Because the visual acuity of the right eye had decreased to 20/800, penetrating keratoplasty was performed, and the diagnosis of GDLD was confirmed by characteristic histopathological findings of amyloid deposits beneath the corneal epithelium and mutation of the M1S1 gene.2
(A) Slit lamp photographs of the right cornea of a 39 year old man with gelatinous drop-like dystrophy (GDLD), demonstrating subepithelial raised lesions with a mulberry-like appearance and band-shaped opacities occupying the inferior cornea. There is also neovascular infiltration from the superior limbus of the cornea, some of the vessels are indicated by arrows. (B) Light microscopic photograph of a corneal button section surgically excised from the 39 year old man. Histological section of this cornea shows eosinophilic amorphous material in the subepithelial region, and the overlying epithelium was degenerated. Note the prominent inflammatory infiltrate (haematoxylin and eosin, original magnification ×200). (C) Immunostaining of GDLD cornea with vitronectin showing immunopositivity in the infiltrating leucocytes and basal epithelial cell layer. Diffuse staining for vitronectin is also found in the deposits. Anti-vitronectin also appears to stain the superficial layer of corneal epithelial cells, although we cannot totally rule out the possibility that this might represent an edge artefact (haematoxylin counterstain, original magnification ×200).
It was recently reported that vitronectin, a multifunctional extracellular matrix adhesion molecule, is often a component of the abnormal extracellular deposits in various age related human diseases such as age related macular degeneration and amyloidosis. This suggested that similar pathways may be involved in the aetiologies of other age related diseases.3 Because the disease state of GDLD deteriorates with age, we hypothesised that similar vitronectin related pathways may also be associated with GDLD, and examined whether vitronectin was expressed in the GDLD cornea by immunohistochemistry.
An antibody directed against vitronectin (Santa Cruz Biotechnology, Santa Cruz, CA, USA) exhibited intense reactivity with the infiltrating leucocytes and corneal epithelium around the deposits. Substantial levels of vitronectin protein were also present in the deposits (Fig 1B, C).
Because the production of new extracellular matrix proteins has a crucial role in supporting cell proliferations that are necessary for new blood vessel growth,4 and because vitronectin receptors, such as integrin αvβ3 and αvβ5, are involved in angiogenesis,4 we further hypothesised that the accumulated vitronectin in the GDLD cornea may also have a role in the accompanying corneal NV.
We therefore examined the angiogenic potential of vitronectin using an in vivo corneal assay.5 Five μl hydron pellets (Interferon Sciences, New Brunswick, NJ, USA) containing 1 μg of mouse vitronectin (Invitrogen, Carlsbad, CA, USA) were implanted into the cornea of anaesthetised male Sprague-Dawley (S-D) rats and, after 7 days, the animals were killed, and the corneal vessels were photographed. Vitronectin elicited a strong angiogenic response, but administration of phosphate buffered saline (PBS) alone did not (Fig 2).
Representative photographs showing the effect of vitronectin on in vivo angiogenesis in rat cornea. Hydron pellets were formulated and implanted into rat corneas. After 7 days, vessels in the region of the pellet implant were photographed. Pellets contained PBS (A) or vitronectin (B). Six rats were used to assess the effect of vitronectin and neovascularisation was observed in all six replicates.
Comment
These results provide the first evidence for the expression of vitronectin in the cornea with GDLD, and for the in vivo inducement of angiogenesis by vitronectin. The results indicate that vitronectin may have a role in corneal NV in patients with GDLD. Therefore, further studies exploring mechanisms of corneal NV mediated by vitronectin-integrin system, and how mutation of M1S1 leads to accumulation of vitronectin with more samples, may eventually offer a novel insight in understanding the aetiology of corneal NV associated with GDLD.
Acknowledgments
This work was supported in part by grants from Sumitomo Life Social Welfare Services Foundation (SY), Japan National Society for the Prevention of Blindness (AY), and Japan Eye Bank Association (AY).
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