Pathophysiological Mechanisms of Autosomal Dominant Congenital Stromal Corneal Dystrophy

Abstract

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.

Interclass small leucine-rich repeat proteoglycan interactions regulate collagen fibrillogenesis and corneal stromal assembly

“…In vivo corneal haze was analyzed with the Heidelberg Retinal Tomography HRT Rostock Cornea Module (HRT-III; Heidelberg Engineering Inc., Heidelberg, Germany)(Chen et al, 2011). Briefly, four P30 mice from each group of wild-type, Bgn −/0 , Lum −/− , and Bgn −/0 /Lum −/− were anesthetized and restrained on an adapted stage.…”

“…In addition, the expression of lumican has been shown to drive the expression of keratocan (Carlson et al, 2005). Altered expression of both class I and class II SLRPs also was observed in a mutant decorin transgenic mouse model (Chen et al, 2011). Regulatory interactions across classes have been demonstrated by an increased severity of the tendon fibril structural phenotype in the absence of both biglycan and fibromodulin compared to either one alone (Ameye et al, 2002).…”

Decorin as a multivalent therapeutic agent against cancer

“…In decorin, this is found in the penultimate LRR, LRR XI. Interestingly, truncation or mutations arising in the ear repeat of decorin cause congenital stromal corneal dystrophy [20,98]. Mechanistically, mouse models of decorin lacking this ear repeat trigger intracellular accumulation of decorin within the endoplasmic reticulum, thereby causing ER stress, and compromising proper corneal collagen deposition and assembly [99].…”

Regulation of corneal stroma extracellular matrix assembly

“…Presumably, the loss of the cys residue prevents disulfide bond formations in this critical region, resulting in altered conformation rather than a truncation, and a plausible explanation for the milder functional consequences. A novel animal model that recapitulates human CSCD was generated in our lab, where mice expressed both wild-type and mutant decorin (Chen et al, 2011). Several phenotypic features were described, including: early onset corneal opacities throughout, increased severity toward the posterior stroma, and disrupted lamellae architecture with relatively normal lamellae separated by regions of abnormal fibril organization.…”