Role of Transforming Growth Factor-β1 and its Latent Form Binding Protein in Pseudoexfoliation Syndrome

Schlötzer‐Schrehardt, Ursula; Zenkel, Matthias; Küchle, Michael; Sakai, Lynn Y.; Naumann, Gottfried O.H.

doi:10.1006/exer.2001.1084

Cited by 214 publications

(179 citation statements)

References 51 publications

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“…XFS is characterized by excessive production and progressive accumulation of an abnormal fibrillar material, termed exfoliation material, containing ECM components such as elastin, fibrillin-1, and fibronectin localized to the surface of various cell types including lens epithelial cells 1,38,39 . LOXL1 has been reported to modulate ECM biogenesis by cross-linking elastin and collagen in connective tissues [40][41][42] .…”

Section: Resultsmentioning

confidence: 99%

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

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Section: Resultsmentioning

confidence: 99%

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

et al. 2017

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“…Since the initial discovery in 1994 by Tripathi et al, 84 that the aqueous humor of glaucoma patients contains elevated levels of TGFb2, evidence has accumulated supporting elevated TGFb2 in the aqueous humor, [85][86][87][88][89][90][91] and additionally, the ability of TGFb2 to increase IOP, as recently reviewed by Fuchshofer and Tamm. 92 Perfusion of human anterior segments with TGFb2 results in decreased facility of outflow of AH and accumulation of matrix material in the TM.…”

Section: Microfibril Defects and Chronic Over-activation Of Tgfb Signmentioning

confidence: 96%

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

Kuchtey

2014

Journal of Ocular Pharmacology and Therapeutics

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Microfibrils are macromolecular aggregates located in the extracellular matrix of both elastic and nonelastic tissues that have essential functions in formation of elastic fibers and control of signaling through the transforming growth factor beta (TGFb) family of cytokines. Elevation of systemic TGFb and chronic activation of TGFb signal transduction are associated with diseases caused by mutations in microfibril-associated genes, including FBN1. A role for microfibrils in glaucoma is suggested by identification of risk alleles in LOXL1 for exfoliation glaucoma and mutations in LTBP2 for primary congenital glaucoma, both of which are microfibrilassociated genes.

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“…TGFb is present in the aqueous humour of the eye and exists largely in a latent, inactive form [55,56]. Under normal conditions TGFb activity is tightly regulated by proteins in the ocular humours such as a2-macroglobulin, which have a high affinity for free active TGFb [57], however following trauma to the lens, e.g.…”

Section: Tgfb: the Orchestrator Of Fibrosismentioning

confidence: 99%

The lens as a model for fibrotic disease

Eldred

Dawes

Wormstone

2011

Phil. Trans. R. Soc. B

102

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Fibrosis affects multiple organs and is associated with hyperproliferation, cell transdifferentiation, matrix modification and contraction. It is therefore essential to discover the key drivers of fibrotic events, which in turn will facilitate the development of appropriate therapeutic strategies. The lens is an elegant experimental model to study the processes that give rise to fibrosis. The molecular and cellular organization of the lens is well defined and consequently modifications associated with fibrosis can be clearly assessed. Moreover, the avascular and non-innervated properties of the lens allow effective in vitro studies to be employed that complement in vivo systems and relate to clinical data. Using the lens as a model for fibrosis has direct relevance to millions affected by lens disorders, but also serves as a valuable experimental tool to understand fibrosis per se.

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Role of Transforming Growth Factor-β1 and its Latent Form Binding Protein in Pseudoexfoliation Syndrome

Cited by 214 publications

References 51 publications

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

The Microfibril Hypothesis of Glaucoma: Implications for Treatment of Elevated Intraocular Pressure

The lens as a model for fibrotic disease

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