Congenital Stromal Dystrophy of the Cornea Caused by a Mutation in the Decorin Gene

Bredrup, Cecilie; Knappskog, Per M.; Majewski, Jacek; Rødahl, Eyvind; Boman, Helge

doi:10.1167/iovs.04-0804

Cited by 135 publications

(113 citation statements)

References 22 publications

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“…The SLRP family consists of 17 member proteins that are largely characterized by the presence of N-terminal cysteine-rich clusters (33), and the exact role of SLRPs in vivo is poorly understood. It has been reported that they may regulate cell proliferation and differentiation in certain developmental contexts (33), and genetic mutations in decorin (DCN) and LUM have been implicated in inherited ocular disorders such as congenital stromal dystrophy and high myopia in the cornea (35,36). Our study suggests that SLRPs are novel regulators for smooth muscle differentiation.…”

Section: Discussionmentioning

confidence: 56%

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Huang

Cotton²,

Wang³

et al. 2013

Journal of Biological Chemistry

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Hedgehog (Hh) signaling is involved in multiple aspects of embryonic gut development, including mesenchymal growth and smooth muscle differentiation. The Gli family transcription factors is thought to collectively mediate Hh signaling in mammals. However, the function of different Gli proteins in gut development remains uncharacterized. Here, we genetically dissect the contribution of Gli transcriptional activation and de-repression in intestinal growth and patterning. We find that removal of the Gli3 repressor is dispensable for intestinal development and does not play a major role in Hh-controlled gut development. However, Gli2 activation is able to fully rescue the Smoothened (Smo)-null intestinal phenotype, suggesting that the Gli2 transcription factor is the main effector for Hh signaling in the intestine. To understand further the molecular mechanism underlying Hh/Gli function in the developing gut, we identify a subset of small leucine-rich glycoproteins (SLRPs) that may function downstream of Hh signaling in the mesenchyme. We show that osteoglycin, a SLRP, inhibits Hh-induced differentiation toward the smooth muscle lineage in C3H10T1/2 pluripotent mesenchymal cells. Taken together, our study reveals, for the first time, the distinct roles of Gli proteins in intestine development and suggests SLRPs as novel regulators of smooth muscle cell differentiation

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Section: Discussionmentioning

confidence: 56%

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Huang

Cotton²,

Wang³

et al. 2013

Journal of Biological Chemistry

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“…SLRPs are involved in corneal stromal development, wound healing, and repair/remodeling and have been linked to several ocular abnormalities such as myopia 25 and cornea plana, 26 as well as CSCD. 4,5 Notably, decorin-null mice have clear corneas probably because of a functional compensation from upregulated biglycan. However, the double-mutant mice lacking both Dcn and Bgn genes show a severe stromal phenotype, which document decorin's central role in regulating fibrillogenesis in the corneal stroma.…”

Section: Discussionmentioning

confidence: 99%

“…Patients develop early-onset corneal opacities and a disrupted stromal structure, indicating a novel role for decorin in regulating fibril organization. 4,6 Decorin is the prototype SLRP and contains a protein core and a single chondroitin/dermatan sulfate side chain covalently attached to Ser7 near the N-terminus. 7 The protein core has a central domain of tandem leucine-rich repeats (LRRs) flanked by conserved Cys-rich domains.…”

mentioning

confidence: 99%

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Chen

Sun

Meng

et al. 2011

The American Journal of Pathology

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Autosomal-dominant congenital stromal corneal dystrophy (CSCD) is a human genetic disease characterized by corneal opacities beginning shortly after birth. It is linked to a frameshift mutation in decorin, resulting in a C-terminal truncation lacking 33 amino acids that includes the "ear" repeat, a feature specific for small leucine-rich proteoglycans. Our goals are to elucidate the roles of the mutant decorin in CSCD pathophysiology and to decipher the mechanism whereby mutant decorin affects matrix assembly. A novel animal model that recapitulates human CSCD was generated. This transgenic mouse model targets expression of truncated decorin to keratocytes, thereby mimicking the human frameshift mutation. Mutant mice expressed both wild-type and mutant decorin. Corneal opacities were found throughout, with increased severity toward the posterior stroma. The architecture of the lamellae was disrupted with relatively normal lamellae separated by regions of abnormal fibril organization. Within abnormal zones, the interfibrillar spacing and the fibril diameters were increased. Truncated decorin negatively affected the expression of endogenous decorin, biglycan, lumican, and keratocan and positively affected fibromodulin. Our results provide a mechanistic explanation for the generation of corneal opacities in CSCD.Thus, truncated decorin acts in a dominant-negative manner to interfere dually with matrix assembly and binding to receptor tyrosine kinases, thereby causing abnormal expression of endogenous small leucinerich proteoglycans leading to structural abnormalities within the cornea and vision loss.

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“…Thinner stroma, decreased interfibrillar spacing, disorganized collagen arrangement; macular corneal dystrophy (Midura et al 1990;Hayashida et al 2006) Decorin Mild changes in collagen ultrastructure; congenital stromal dystrophy (Bredrup et al 2005;Zhang et al 2009 (Chaurasia et al 2013) Tenascin-C Upon corneal injury: delayed stromal wound healing, impaired keratocyte migration, fewer myofibroblasts, less invasion of macrophages, reduced expression of TGF-β (Matsuda et al 1999;Sumioka et al 2013) Proteoglycans are found associated with collagen fibrils in the corneal stroma; they have a core protein with one or more glycosaminoglycan (GAG) side chains covalently attached. Corneal proteoglycans mainly belong to the small leucine-rich type proteoglycan (SLRP) gene family and include decorin, biglycan, lumican, keratocan, mimecan and fibromodulin.…”

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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Congenital Stromal Dystrophy of the Cornea Caused by a Mutation in the Decorin Gene

Cited by 135 publications

References 22 publications

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

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

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