Developmental abnormalities in the cornea of a mouse model for Marfan syndrome

Feneck, Eleanor M.; Souza, Rodrigo Barbosa de; Lewis, Philip N.; Hayes, Sally; Pereira, Lygia V.; Meek, Keith Michael Andrew

doi:10.1016/j.exer.2020.108001

Cited by 16 publications

(10 citation statements)

References 30 publications

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“…Extreme thinning of the cornea was observed at 1 month of age in Zfp469 BCS/BCS mice, and BCS cases have been reported in humans soon after birth (Ramappa et al, 2014) suggesting that this disorder is initiated during development. This has also been observed in a mouse model for Marfan syndrome, another connective tissue disorder, which shows reduced CCT in Fbn1 +/− mice from E16.5 onwards (Feneck et al, 2020). The corneal stroma is established during early development, with collagen deposition by presumptive corneal stromal cells observed at E13 in the mouse (Feneck et al, 2019).…”

Section: Discussionsupporting

confidence: 61%

A Mouse Model of Brittle Cornea Syndrome caused by mutation in Zfp469

Stanton

Findlay

Drake

et al. 2021

Preprint

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Brittle Cornea Syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene, Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the type I:type V collagen ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of type I collagen offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus where the cornea thins progressively.Summary statementA mouse model of Brittle Cornea Syndrome was created to elucidate molecular mechanisms underlying pathology of this rare connective tissue disorder in which extremely thin corneas rupture, causing irreversible blindness.

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Section: Discussionsupporting

confidence: 61%

A Mouse Model of Brittle Cornea Syndrome caused by mutation in Zfp469

Stanton

Findlay

Drake

et al. 2021

Preprint

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“… 22 In FBN 1 +/ − mouse corneas, significantly reduced amounts of fibrillin-1-containing microfibrils have been detected, as well as microfibril disorganization compared to controls, both at the adult and late embryonic stage. 22 , 23 The lens capsule in human MFS patients has similarly showed both quantitative and qualitative changes, with irregular and fragmented bundles evident upon histologic analysis. 24 In adult FBN 1 +/ − mouse corneas, the interfibrillar spacing of collagen fibrils has been shown to be increased, despite the reduced corneal thickness, which indicates a lower number of collagen lamellae in the adult FBN 1 +/ − corneas compared to wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Scheimpflug-Based Analysis of the Reflectivity of the Cornea in Marfan Syndrome

Tack

Kreps

Zaeytijd

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose We sought to investigate corneal reflectivity in Marfan syndrome (MFS) on the basis of Scheimpflug light intensity distribution. Methods In a retrospective case-control analysis, the left eyes of 40 MFS patients and 40 age- and refraction-matched healthy controls were investigated. Patients with MFS meeting the Ghent II diagnostic criteria and with genetic confirmation of disease were included. Exclusion criteria were the following: coexisting corneal, conjunctival, or scleral pathology; use of medication known to affect corneal transparency; history of ocular surgery; and insufficient data. Scheimpflug tomography images were exported to analyze corneal transparency in different corneal layers and regions. Each corneal image was automatically segmented, after which the corresponding pixel intensities in the defined regions of interest were statistically modeled using a Weibull probability density function from which parameters α (transparency) and β (homogeneity) were derived. Results The cornea in MFS showed significantly higher light reflectivity (overall cornea, α = 71 ± 17 arbitrary units (a.u.)) than in the control group (overall cornea, α = 59 ± 15 a.u.) ( t test, P = 0.003). The α parameter was significantly higher in MFS eyes in all examined layers and regions ( P < 0.05), whereas the β parameter showed no statistical difference between MFS and controls ( P > 0.05). The difference in α did not correlate with ocular biometric properties (corneal thickness and curvature) or ectopia lentis ( P > 0.05). Conclusions The cornea in MFS shows significantly higher reflectivity than healthy controls with similar levels of homogeneity. Translational Relevance The proposed methodology detects corneal reflectivity changes in MFS not available from regular slit-lamp examination.

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“…Another disease that has been shown to cause secondary changes to GAG and PG expression is Marfan syndrome. Marfan syndrome is a disease that affects the ECM of connective tissues due to mutations in the gene that encodes fibrillin-1, necessary for the formation of elastic fibers ( Feneck et al, 2020 ). Patients suffer many ocular manifestations, including thinned and flattened corneas.…”

Section: Involvement Of Proteoglycans and Glycosaminoglycans In Cornementioning

confidence: 99%

“…Decorin expression has been shown to be significantly decreased in the corneas of a mouse model of Marfan syndrome and fibroblasts from a patient with Marfan syndrome ( Superti-Furga et al, 1992 ; Feneck et al, 2020 ). The Meek group speculate the decrease in decorin expression could be a consequence of the increased levels of TGF-β expression found in the corneas of individuals with Marfan disease ( Feneck et al, 2020 ). However, whether the loss of decorin could further contribute to the pathogenesis of Marfan syndrome remains to be established.…”

Section: Involvement Of Proteoglycans and Glycosaminoglycans In Cornementioning

confidence: 99%

Distribution and Function of Glycosaminoglycans and Proteoglycans in the Development, Homeostasis and Pathology of the Ocular Surface

Puri

Coulson-Thomas

Gesteira

et al. 2020

Front. Cell Dev. Biol.

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The ocular surface, which forms the interface between the eye and the external environment, includes the cornea, corneoscleral limbus, the conjunctiva and the accessory glands that produce the tear film. Glycosaminoglycans (GAGs) and proteoglycans (PGs) have been shown to play important roles in the development, hemostasis and pathology of the ocular surface. Herein we review the current literature related to the distribution and function of GAGs and PGs within the ocular surface, with focus on the cornea. The unique organization of ECM components within the cornea is essential for the maintenance of corneal transparency and function. Many studies have described the importance of GAGs within the epithelial and stromal compartment, while very few studies have analyzed the ECM of the endothelial layer. Importantly, GAGs have been shown to be essential for maintaining corneal homeostasis, epithelial cell differentiation and wound healing, and, more recently, a role has been suggested for the ECM in regulating limbal stem cells, corneal innervation, corneal inflammation, corneal angiogenesis and lymphangiogenesis. Reports have also associated genetic defects of the ECM to corneal pathologies. Thus, we also highlight the role of different GAGs and PGs in ocular surface homeostasis, as well as in pathology.

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Developmental abnormalities in the cornea of a mouse model for Marfan syndrome

Cited by 16 publications

References 30 publications

A Mouse Model of Brittle Cornea Syndrome caused by mutation in Zfp469

A Mouse Model of Brittle Cornea Syndrome caused by mutation in Zfp469

Scheimpflug-Based Analysis of the Reflectivity of the Cornea in Marfan Syndrome

Distribution and Function of Glycosaminoglycans and Proteoglycans in the Development, Homeostasis and Pathology of the Ocular Surface

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