Mutations in KERA, encoding keratocan, cause cornea plana

Pellegata, Natalia S.; Dieguez-Lucena, Jose L.; Joensuu, Tarja; Lau, Stephanie; Montgomery, Kate; Krahe, Ralf; Kivelä, Tero; Kucherlapati, Raju; Forsius, Henrik; Chapelle, Albert de la

doi:10.1038/75664

Cited by 146 publications

(116 citation statements)

References 23 publications

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“…Dysgenesis of the anterior segment: keratoglobus-like protrusion, thin corneal stroma, thin Descemet's membrane, reduced number of endothelial cells; Fuch's endothelial dystrophy and posterior polymorphous corneal dystrophy (Biswas et al 2001;Hopfer et al 2005) Lumican / fibromodulin / PRELP / opticin High myopia (Wang et al 2006;Majava et al 2007) Lumican Corneal opacity, larger collagen fibril diameter, disorganized collagen arrangement (Chakravarti et al 1998) Keratocan Thinner stroma, larger collagen fibril diameter, less organized fibrils; cornea plana (Pellegata et al 2000;Liu et al 2003) N-acetylglucosamine-6-Osulfotransferase…”

Section: Constituents Of Corneal Stromal Ecmmentioning

confidence: 99%

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Parapuram

Hodge

2014

J. Cell Commun. Signal.

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Several studies have established the role of activated corneal keratocytes in the fibrosis of the cornea. However, the role of keratocytes in maintaining the structural integrity of a normal cornea is less appreciated. We focus on the probable functions of integrins in the eye and of the importance of integrin-mediated keratocyte interactions with stromal matrix in the maintenance of corneal integrity. We point out that further understanding of how keratocytes interact with their matrix could establish a novel direction in preventing corneal pathology including loss of structural integrity as in keratoconus or as in fibrosis of the corneal stroma.Keywords Cornea . Keratocytes . Corneal stroma . Extracellular matrix . Integrins . KeratoconusThe simple cellular organization of the cornea is belied by its fascinating specialization for transparency. The cornea has three main tissue layers, the outer epithelium, the stroma in the middle and the inner endothelial layer. The stromal connective tissue, the layer mainly responsible for the corneal configuration, constituting nearly 80 % of the thickness of the cornea, is extremely resilient, capable of resisting intraocular pressure and protecting the posterior structures of the eye. The stromal tissue consists of lamellae of orthogonally arranged collagen fibrils surrounded by proteoglycans; in between the lamellae of collagen are found the keratocytes. The nearorderly arrangement of collagen lamellae, the narrow diameter of the collagen fibrils, regular interfibrillar space, associated proteoglycans and the expression of crystalline proteins in the keratocytes (Birk 2001;Kao and Liu 2002;Jester et al. 2007; Hassell and Birk 2010) are some of the main factors responsible for corneal transparency. Consequently, the factors affecting corneal transparency such as fibrotic changes due to disease or injury are problems primarily associated with the stroma. Thus it is important to achieve further understanding of the mechanisms by which the stroma acquires and maintains its structural integrity and its transparency.

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Section: Constituents Of Corneal Stromal Ecmmentioning

confidence: 99%

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

Parapuram

Hodge

2014

J. Cell Commun. Signal.

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“…Mutations in KERA are directly associated with inherited cornea plana, which manifests clinically as reduced visual acuity due to a flattened convex corneal curvature and corneal parenchymal opacity. 52 The zebrafish homologue zKera is widely expressed in the brain and ocular tissue at larval stages and limited to the cornea in the adult suggestive of an important role in the maintenance of corneal transparency and structure. 53 The surface of the human eye is covered by corneal epithelial cells, which regenerate from a small population of limbal epithelial stem cells (LESCs) found in limbal epithelial crypts at the peripheral cornea.…”

Section: Corneal Dystrophiesmentioning

confidence: 99%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

153

162

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Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.

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“…These include decorin, lumican, keratocan, and osteoglycin (also known as mimecan). The importance of LRR proteoglycans in corneal stroma development is exemplified in mice lacking lumican, for example, that develop corneal opacity (25), and in people who have mutations in kera, the gene encoding keratocan, who have cornea plana (26), in which the forward convex curvature is flattened leading to a decrease in refraction. Studies, therefore, to determine the structure of corneal fibrils and to identify, in three dimensions, the binding of FACIT collagens, LRR proteoglycans, and other macromolecules, are directly relevant to understanding the assembly of the corneal stroma in health and disease.…”

mentioning

confidence: 99%

Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization

Holmes

Gilpin

Baldock

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

215

142

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The ability of the cornea to transmit light while being mechanically resilient is directly attributable to the formation of an extracellular matrix containing orthogonal sheets of collagen fibrils. The detailed structure of the fibrils and how this structure underpins the mechanical properties and organization of the cornea is understood poorly. In this study, we used automated electron tomography to study the three-dimensional organization of molecules in corneal collagen fibrils. The reconstructions show that the collagen molecules in the 36-nm diameter collagen fibrils are organized into microfibrils (Ϸ4-nm diameter) that are tilted by Ϸ15°to the fibril long axis in a right-handed helix. An unexpected finding was that the microfibrils exhibit a constant-tilt angle independent of radial position within the fibril. This feature suggests that microfibrils in concentric layers are not always parallel to each other and cannot retain the same neighbors between layers. Analysis of the lateral structure shows that the microfibrils exhibit regions of order and disorder within the 67-nm axial repeat of collagen fibrils. Furthermore, the microfibrils are ordered at three specific regions of the axial repeat of collagen fibrils that correspond to the N-and C-telopeptides and the d-band of the gap zone. The reconstructions also show macromolecules binding to the fibril surface at sites that correspond precisely to where the microfibrils are most orderly.automated electron tomography ͉ microfibril ͉ filaments T he cornea is a highly specialized tissue that combines optical transparency with mechanical resilience. These properties are directly attributable to the formation of an extracellular matrix containing narrow-diameter (Ϸ36 nm) and heterotypic collagen fibrils that are spaced and organized uniformly into sheets of parallel fibrils. Each sheet is arranged orthogonal to its neighbor and to the path of light through the cornea. We reasoned that an understanding of the morphogenesis of the corneal stroma requires detailed knowledge of the structure of individual collagen fibrils.Corneal fibrils are D-periodic (axial periodicity of collagen fibrils, where D Ϸ67 nm), uniformly narrow (Ϸ30-35 nm in diameter), and indeterminate in length, particularly in older animals. The D-periodicity of the fibril arises from side-to-side associations of triple-helical collagen molecules that are Ϸ300 nm in length (i.e., the molecular length ϭ 4.4 ϫ D) and are staggered by D. The D-stagger of collagen molecules produces alternating regions of protein density in the fibril, which explains the characteristic gap and overlap appearance of fibrils negatively contrasted for transmission electron microscopy. Previous attempts to study the high-resolution structure of collagen fibrils have used primarily x-ray fiber diffraction of rat tail tendon (e.g., ref. 1 and references therein) and lamprey notochord (2) in which the fibrils are aligned and composed mostly of one genetic type of collagen. This method has yielded information about the triple...

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Mutations in KERA, encoding keratocan, cause cornea plana

Cited by 146 publications

References 23 publications

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

The integrin needle in the stromal haystack: emerging role in corneal physiology and pathology

The zebrafish eye—a paradigm for investigating human ocular genetics

Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization

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