Molecular pathology of pseudoexfoliation syndrome/glaucoma – New insights from LOXL1 gene associations☆
TL;DR: The available data suggest that LOXL1 is differentially regulated dependent on the phase of progression of the fibrotic process, and while increased levels of LO XL1 participate in the formation of abnormal PEX fiber aggregates in the initial phase of fibrogenesis, inadequate tissue levels may promote elastotic processes in advanced stages of the disease.
About: This article is published in Experimental Eye Research.The article was published on 2009-04-30. It has received 111 citations till now. The article focuses on the topics: Pseudoexfoliation syndrome.
Citations
More filters
TL;DR: Increased LOX activity may be at least partially responsible for TGFβ-mediated IOP elevation and increased aqueous humor outflow resistance, suggesting complex regulation of these important extracellular matrix cross-linking enzymes.
Abstract: Glaucoma is a leading cause of irreversible visual impairment and blindness in the world, with primary open-angle glaucoma (POAG) being the major form.1,2 Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma,3,4 and this ocular hypertension is due to increased aqueous humor outflow resistance in the trabecular meshwork (TM) and is associated with increased deposition of extracellular matrix (ECM) material within the TM. The profibrotic cytokine TGFβ2 has been implicated in the pathogenesis of POAG.5 Levels of TGFβ2 are elevated in the aqueous humor6–8 and TM (Tovar-Vidalez T et al., manuscript submitted) of POAG patients. TM cells express TGFβ receptors, and TGFβ2 has direct effects on the TM.9 TGFβ2 has been shown to increase aqueous outflow resistance and to elevate IOP in perfusion cultured human and porcine eyes10–12 and in rodent eyes.13 TGFβ1 is elevated in the aqueous humor of patients with exfoliation glaucoma,14 suggesting that this TGFβ isoform is associated with the accumulation of exfoliation material, including ECM proteins, in the anterior segments of patients with this syndrome.
TGFβ2 regulates ECM metabolism in TM cells and tissues. This cytokine increases expression of a variety of ECM proteins, including fibronectin, collagen, elastin, and proteoglycans, as well as PAI-1 and TIMP-1, inhibitors that suppress proteolytic degradation of the ECM.15 In addition, TGFβ2 increases expression of the ECM cross-linking enzyme transglutaminase (TGM)-2 in TM cells.16 The combination of increased ECM synthesis, increased cross-linking, and decreased degradation causes increased ECM deposition in the TM, which may be responsible for the TGFβ2-mediated increased resistance to aqueous humor outflow. Similar changes occur in the TM of POAG patients, with increased levels of fibronectin,17 collagen,18 PAI-1,19 and TGM2.20
In addition to TGM2, there is a second important class of ECM cross-linking enzymes. The lysyl oxidase (LOX) family contains five genes (LOX and LOXL1 to -4) encoding enzymes that covalently cross-link elastin and collagens via generation of aldehydes on lysine residues.21,22 This cross-linking reaction provides additional mechanical strength to the ECM and makes it more resistant to degradation. LOX enzymes play a role in a variety of fibrotic diseases.21–25 Single-nucleotide polymorphisms (SNPs) in LOXL1 are associated with a significantly increased risk of exfoliation glaucoma,26,27 further suggesting potential roles for LOXs in glaucoma pathogenesis. The purpose of the present study was to determine (1) whether the LOX and LOXL genes and proteins are expressed in human TM cells, (2) whether TGFβ induces LOX gene expression and activity in the TM, and (3) which TGFβ signaling pathway(s) regulate LOX expression in the TM.
175 citations
TL;DR: This review examines the current status of genetic investigations of POAG, ACG, XFG, including the less common forms of glaucoma primary congenital glAUcoma (PCG), the developmentalglaucomas, and pigment dispersion glau coma.
123 citations
Cites background from "Molecular pathology of pseudoexfoli..."
...XFS is a systemic disorder of extracellular matrix characterized by the accumulation of abnormal fibrillarymaterial inmultiple ocular tissues including the lens surface as well as tissues throughout the body (Ritch and SchlotzerSchrehardt, 2001)....
[...]
...These data indicate that coding changes in LOXL1 are not functionally involved in XFG/S....
[...]
...Distinct from other members of the lysyl oxidase family, LOXL1intiateselastogenesis by binding to tropoelastin, a monomer of elastin, and fibulin-5 (Schlotzer-Schrehardt, 2009)....
[...]
...Variants of CNTNAP2 (Contactin associated protein-like 2) have been found in associationwith XFS/XFG in two Germanpopulations (Krumbiegel et al., 2010)....
[...]
...LOXL1 is specifically involved in elastogenesis and is a major component of exfoliative material obtained from ocular tissues in patients with XFG/S (Schlotzer-Schrehardt, 2009)....
[...]
TL;DR: A rare protective allele at LOXL1 is identified through deep resequencing of XFS cases and controls and a potential role for naturally occurring rare LO XL1 variants in disease biology is highlighted.
Abstract: Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide Variants in two genes, LOXL1 and CACNA1A, have previously been 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 across populations, and to identify new variants associated with XFS We identified a rare protective allele at LOXL1 (pPhe407, odds ratio (OR) = 25, P = 29 × 10-14) through deep resequencing of XFS cases and controls from nine countries 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) We identified association signals at 13q12 (POMP), 11q233 (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
104 citations
TL;DR: The marked decrease in stiffness, implying an increased deformability of the ONH in PEX eyes, may reflect an inherent tissue weakness rendering these eyes more vulnerable to glaucomatous damage.
Abstract: PURPOSE Pseudoexfoliation (PEX) syndrome is a systemic disorder of the elastic fiber system that can lead to PEX glaucoma Elastotic alterations in the lamina cribrosa (LC) of PEX eyes suggested biomechanical implications predisposing to pressure-induced optic nerve damage In this pilot study, the stiffness of LC and peripapillary sclera (ppSC) in eyes with and without PEX syndrome were analyzed by atomic force microscopy (AFM) nanoindentation METHODS Unfixed cryosections (5-μm thick) were prepared from the optic nerve heads (ONH) of three donor eyes with PEX syndrome and three age-matched control eyes AFM force mapping was performed in selected regions of the central, midperipheral, and peripheral LC and the ppSC using a spherical cantilever tip To determine the local Young's modulus of elasticity (YME) as a measure of tissue stiffness, force curves were acquired and analyzed using the spherical Hertz model RESULTS For the LC, the median YME values calculated from single stiffness maps averaged 172 (±27) kPa in normal eyes and 101 (±14) kPa in PEX eyes, indicating a significant PEX-related decrease in stiffness by over 40% (P < 001) The corresponding YME values for the ppSC, which revealed a 9-fold higher tissue stiffness than in the LC, averaged 1583 (±598) kPa for control and 858 (±169) kPa for PEX samples CONCLUSIONS AFM was proven suitable for determining the stiffness of ONH tissues, encouraging further large-scale analyses The marked decrease in stiffness, implying an increased deformability of the ONH in PEX eyes, may reflect an inherent tissue weakness rendering these eyes more vulnerable to glaucomatous damage
95 citations
Journal Article•
TL;DR: Surprisingly, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG and is found with a strong association with the opposite allele in the South African population.
Abstract: PURPOSE To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa. METHODS Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher's exact test. RESULTS A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2 x 10(-13) and 1.7 x 10(-5), respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects. CONCLUSIONS This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG.
94 citations
Cites background from "Molecular pathology of pseudoexfoli..."
...It has been postulated that genetic variations in LOXL1 in this region may contribute to the formation of the pathological fibrillar aggregates accumulating in tissues of patients with XFG [40]....
[...]
References
More filters
Book•
15 Nov 1999
TL;DR: Providing the most comprehensive and convenient way to reference all of the latest developments in Opthamology, this CD-Rom allows users to search all six volumes with a single query.
Abstract: SECTION 1 Genetics SECTION II Immunology SECTIONIII Microbiology SECTION IV Pharmacology SECTION V Toxicology SECTION V1 Epidemiology SECTION VII Lasers in Ophthalmology SECTION VIII Conjunctiva, Cornea, And Sclera SECTION IX Uvietis SECTION X Lens SECTION XI Retina and Vitreous SECTION XII Glaucoma SECTION XIII Lids and Orbit SECTION XIV Ophthalmic Pathology SECTION XV Neuroophthalmology SECTION XVI Pediatric Opthalmology SECTION XVII The eye and systemic disease SECTION XVIII Ocular Oncology SECTION XX Optics SECTION XXI Low Vision SECTION XXII Psychologic, Social, Legal And Economic Aspects
987 citations
TL;DR: Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association with glaucoma, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS).
Abstract: Glaucoma is a leading cause of irreversible blindness A genome-wide search yielded multiple single-nucleotide polymorphisms (SNPs) in the 15q241 region associated with glaucoma Further investigation revealed that the association is confined to exfoliation glaucoma (XFG) Two nonsynonymous SNPs in exon 1 of the gene LOXL1 explain the association, and the data suggest that they confer risk of XFG mainly through exfoliation syndrome (XFS) About 25% of the general population is homozygous for the highest-risk haplotype, and their risk of suffering from XFG is more than 100 times that of individuals carrying only low-risk haplotypes The population-attributable risk is more than 99% The product of LOXL1 catalyzes the formation of elastin fibers found to be a major component of the lesions in XFG
654 citations
"Molecular pathology of pseudoexfoli..." refers background in this paper
...This concept of an elastotic process was recently substantiated by the groundbreaking finding of the lysyl oxidase-like 1 (LOXL1) gene as a major genetic risk factor for PEX syndrome and PEX glaucoma (Thorleifsson et al., 2007)....
[...]
...LOXL1 polymorphisms are highly associated with both PEX syndrome and PEX glaucoma and appear to confer risk of glaucoma mainly through PEX (Thorleifsson et al., 2007)....
[...]
...Performing a genome-wide association study, Thorleifsson et al. (2007) detected three common sequence variants or single nucleotide polymorphisms (SNPs) in the LOXL1 gene on chromosome 15q24....
[...]
TL;DR: It is shown that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation.
Abstract: Elastic fibers are components of the extracellular matrix and confer resilience1. Once laid down, they are thought to remain stable2, except in the uterine tract where cycles of active remodeling occur3. Loss of elastic fibers underlies connective tissue aging and important diseases including emphysema4,5,6,7. Failure to maintain elastic fibers is explained by a theory of antielastase-elastase imbalance8, but little is known about the role of renewal. Here we show that mice lacking the protein lysyl oxidase–like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. Thus elastin polymer deposition is a crucial aspect of elastic fiber maintenance and is dependent on LOXL1, which serves both as a cross-linking enzyme and an element of the scaffold to ensure spatially defined deposition of elastin.
629 citations
TL;DR: Lysyl oxidase is a copper-dependent amine oxidase that plays a critical role in the biogenesis of connective tissue matrices by crosslinking the extracellular matrix proteins, collagen and elastin.
547 citations
"Molecular pathology of pseudoexfoli..." refers background in this paper
...matrix molecules including elastin and fibrillin (Smith-Mungo and Kagan, 1998)....
[...]
...Other environmental conditions associated with fibrotic processes, such as oxidative stress and hypoxia, have been reported to regulate both LOXL1 expression and activity and synthesis of matrix molecules including elastin and fibrillin (Smith-Mungo and Kagan, 1998)....
[...]
TL;DR: In this paper, the authors provide an update on most recent developments regarding ocular and systemic manifestations and complications, clinical diagnosis and management, and molecular pathophysiology of pseudoexfoliation (PEX) syndrome, and discuss future tasks and challenges in this field.
516 citations