Structural Collagen Alterations in Macular Corneal Dystrophy Occur Mainly in the Posterior Stroma

Palka, Barbara P.; Sotozono, Chie; Tanioka, Hidetoshi; Akama, Tomoya O.; Yagi, Naoto; Boote, Craig; Young, Robert D.; Meek, Keith Michael Andrew; Kinoshita, Shigeru; Quantock, Andrew J.

doi:10.3109/02713681003760150

Cited by 16 publications

(10 citation statements)

References 56 publications

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“…Intra‐ and extracellular accumulation of glycosaminoglycans in the stroma, Descemet's membrane, and endothelium is seen on histopathology. Collagen fibril spacing is reduced and large‐diameter collagen fibrils are seen, with the deep stroma being more severely affected . The corneal sensitivity was not evaluated in the described patients and photophobia was not described, although one patient was reported to show recurrent epiphora.…”

Section: Discussionmentioning

confidence: 99%

Phenotype of macular corneal dystrophy in Labrador Retrievers: A multicenter study

Busse

Kafarnik

Linn-Pearl

et al. 2019

Veterinary Ophthalmology

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Objective To describe the phenotype of canine macular corneal dystrophy (MCD) including the clinical presentation, multimodal ocular imaging, histopathology, and ultrastructural analysis in ten Labrador Retrievers. Procedure Multicentered data collection. Results Labrador Retrievers affected by MCD were presented between the age of 4.5 and 6 years of age with a history of cloudy eyes and/or visual impairment. Findings on ophthalmic examination included a diffuse haze of the corneal stroma and multiple, well‐demarcated, off‐white to yellow‐brown, punctate corneal opacities heterogeneous in size. Corneal vascularization developed in most dogs as the disease progressed. Disease progression was associated with increased density of the corneal haze as well as increased number and size of the focal opacities and dogs developed significant visual impairment. Spectral domain‐optical coherence tomography revealed multifocal hyper‐reflective regions within the stroma. In vivo confocal microscopy revealed marked alterations in reflectivity throughout the entire stroma. Normal keratocytes could not be identified in affected areas. Histopathology showed stromal collagen fibers separated by acidophilic granular material on hematoxylin and eosin stain. The material stained with periodic acid‐Schiff and colloidal iron stain but not with Masson trichrome stain, confirming the accumulation of glycosaminoglycans. On electron microscopic ultrastructural examination, keratocytes presented with vacuolated rough endoplasmic reticulum and multiple electron dense cytoplasmic inclusions. In areas keratocytes appeared ruptured, with cell organelles and proteinaceous material grouped together between collagen fibers. Conclusion MCD in Labrador Retrievers has similarities with the human counterpart of the condition and is an important differential diagnosis in dogs with corneal disease.

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Section: Discussionmentioning

confidence: 99%

Phenotype of macular corneal dystrophy in Labrador Retrievers: A multicenter study

Busse

Kafarnik

Linn-Pearl

et al. 2019

Veterinary Ophthalmology

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“… 9 This is thought to arise from a reduction in water-binding potential in the extrafibrillar space, alluded to above, augmented by a lack of mutual repulsion between charged KS side chains on KS-PGs, whose protein cores are bound to collagen fibrils. Indeed, this concept finds some support in depth-profiled studies of collagen fibril spacing in human MCD corneas, which show that the compaction of collagen fibrils is more prevalent in the posterior corneal stroma, 9 , 44 a region of the tissue in mammalian corneas in which KS-GAGs are most abundant. 45 – 47 Reduction in center-to-center distance between collagen fibrils was observed in x-ray diffraction studies of Chst5 -null corneal tissue, 14 further demonstrating a role for KS-PGs in maintenance of interfibrillar spacing.…”

Section: Discussionmentioning

confidence: 91%

Keratan Sulfate Phenotype in the β-1,3-N-Acetylglucosaminyltransferase-7–Null Mouse Cornea

Littlechild

Young

Caterson

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeSynthesis of keratan sulfate (KS) relies on coordinated action of multiple enzymes, including the N-acetylglucosamine–transferring enzyme, β-1,3-N-acetylglucosaminyltransferase-7 (β3GnT7). A mouse model deficient in β3GnT7 was developed to explore structural changes in KS and the extracellular matrix (ECM; i.e., the corneal stroma), elucidate the KS biosynthesis mechanism, and understand its role in corneal organization.MethodsA knockout vector for the β3GnT7-encoding gene, B3gnt7, was created to develop heterozygous- (htz) and homozygous-null (null) knockouts. Epithelial, stromal, and whole cornea thicknesses were measured from each group. Proteoglycans were stained with cupromeronic blue for visualization by electron microscopy, and Western blot analyses were conducted on the KS core protein, lumican. Corneal sections were labelled fluorescently for KS and chondroitin sulfate/dermatan sulfate (CS/DS) using monoclonal antibodies 1B4 or 2B6, respectively.ResultsWild-type (WT) and htz corneas were of similar stromal thickness, whereas null specimens measured relatively thin. Electron micrographs revealed that WT and htz samples contained comparable levels of KS- and CS/DS-PGs. Null corneas, however, lacked detectable KS and featured uncharacteristically elongated electron dense PG filaments, which were susceptible to chondroitinase ABC digestion. Western blotting revealed lumican in the null corneas was substituted with low-molecular-weight KS, relative to WT or htz tissue. KS was not immunohistochemically detectable in the null cornea, whereas CS/DS content appeared increased.ConclusionsAddition of N-acetylglucosamine via β3GnT7 to KS glycosaminoglycans is necessary for their biosynthesis. Without β3GnT7, murine corneal stromas lack KS and appear to compensate for this loss with upregulation of chondroitinase ABC-sensitive PGs.

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“…For example, posterior stromal regions were found to be more severely affected by the disruption of fibril structure and organisation in decorin/biglycan compound mutant mice, suggesting a synergy of regulatory roles for proteoglycans, in this case decorin and biglycan, in matrix assembly (Zhang et al, 2009). As mentioned earlier, the deep stroma is also the most affected corneal region in macular corneal dystrophy, and this is where pockets of abnormally large diameter collagen fibrils are found (Palka et al, 2010). A subsequent study of the peripheral cornea in mice further showed that fibromodulin may cooperate with lumican in fibril regulation during postnatal corneal development (Chen et al, 2010).…”

Section: Electron Microscopymentioning

confidence: 92%

“…Recent SAXS studies of this disease have indicated that the major reduction in collagen fibril spacing occurs in the deeper stromal layers (Palka et al, 2010), which is possibly reflective of the proposed greater importance of keratan sulphate proteoglycans in the posterior stroma of the corneas of larger animals based on its preferential synthesis owing to a restricted oxygen supply (Scott and Haigh, 1988). WAXS experiments have also been conducted on post-operative macular dystrophy corneas and have consistently documented an unusual signal, corresponding to a periodic structure of 0.46 nm, which is not seen in x-ray patterns obtained from normal human corneas (Quantock et al, 1992; 1993a; 1997a).…”

Section: X-ray Scatteringmentioning

confidence: 99%

From nano to macro: Studying the hierarchical structure of the corneal extracellular matrix

Quantock

Winkler

Parfitt

et al. 2015

Experimental Eye Research

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In this review, we discuss current methods for studying ocular extracellular matrix (ECM) assembly from the ‘nano’ to the ‘macro’ levels of hierarchical organization. Since collagen is the major structural protein in the eye, providing mechanical strength and controlling ocular shape, the methods presented focus on understanding the molecular assembly of collagen at the nanometer level using x-ray scattering through to the millimeter to centimeter level using nonlinear optical (NLO) imaging of second harmonic generated (SHG) signals. Three-dimensional analysis of ECM structure is also discussed, including electron tomography, serial block face scanning electron microscopy (SBF-SEM) and digital image reconstruction. Techniques to detect non-collagenous structural components of the ECM are also presented, and these include immunoelectron microscopy and staining with cationic dyes. Together, these various approaches are providing new insights into the structural blueprint of the ocular ECM, and in particular that of the cornea, which impacts upon our current understanding of the control of corneal shape, pathogenic mechanisms underlying ectatic disorders of the cornea and the potential for corneal tissue engineering.

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Structural Collagen Alterations in Macular Corneal Dystrophy Occur Mainly in the Posterior Stroma

Cited by 16 publications

References 56 publications

Phenotype of macular corneal dystrophy in Labrador Retrievers: A multicenter study

Phenotype of macular corneal dystrophy in Labrador Retrievers: A multicenter study

Keratan Sulfate Phenotype in the β-1,3-N-Acetylglucosaminyltransferase-7–Null Mouse Cornea

From nano to macro: Studying the hierarchical structure of the corneal extracellular matrix

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