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Journal Article•

Lysyl oxidase-like protein 1 (LOXL1) gene polymorphisms and exfoliation glaucoma in a Central European population

Georg Mossböck1, Wilfried Renner, Christoph Faschinger, Otto Schmut, Andreas Wedrich, Martin Weger •
University of Graz1
09 May 2008-Molecular Vision (Emory University)-Vol. 14, pp 857-861
TL;DR: The data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend the knowledge to a Central European population.
Abstract: PURPOSE Exfoliation syndrome (XFS) is characterized by an accumulation of abnormal extracellular material in the anterior part of the eye that frequently leads to increased intraocular pressure and glaucomatous optic neuropathy. Recently, two non-synonymous polymorphisms (rs1048661 G>T and rs3825942 G>A) of lysyl oxidase-like protein 1 (LOXL1), a monoamine oxidase that catalyzes the polymerization of tropoelastin to elastin, were found to be associated with increased risk for XFS and exfoliation glaucoma (XFG). The aim of the present study was to investigate the role of these LOXL1 variants in a Central European cohort of Caucasian patients with XFG. METHODS The present case-control study comprised of 167 unrelated patients with XFG and 170 control subjects. Genotyping of the LOXL1 rs1048661 and rs3825942 polymorphisms was done using polymerase chain reaction. RESULTS The frequency of allele G of rs1048661 as well as rs3825942 was significantly higher in patients than in controls (rs1048661: 0.841 in patients versus 0.669; p<0.001; rs3825942: 0.994 in patients versus 0.817; p<0.001). Odds ratios of 52.1 (95% confidence interval [CI]: 13.85-195.6) and 14.67 (95% CI: 3.81-56.2), respectively, were calculated for the two high-risk haplotypes GG and TG compared to the haplotype GA. CONCLUSIONS Our data confirm the previously reported association between LOXL1 polymorphisms and XFG and extend our knowledge to a Central European population.

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Citations
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Journal Article•DOI•
The lens capsule.

[...]

Brian P. Danysh1, Melinda K. Duncan1•
University of Delaware1
02 Feb 2009-Experimental Eye Research
TL;DR: This review covers the development and structure of the lens capsule, lens diseases associated with mutations in extracellular matrix genes and the role of the capsule in lens function including those proposed for visual accommodation, selective permeability to infectious agents, and cell signaling.
Abstract: The lens capsule is a modified basement membrane that completely surrounds the ocular lens It is known that this extracellular matrix is important for both the structure and biomechanics of the lens in addition to providing informational cues to maintain lens cell phenotype This review covers the development and structure of the lens capsule, lens diseases associated with mutations in extracellular matrix genes and the role of the capsule in lens function including those proposed for visual accommodation, selective permeability to infectious agents, and cell signaling

232 citations

Journal Article•DOI•
Genotype-Correlated Expression of Lysyl Oxidase-Like 1 in Ocular Tissues of Patients with Pseudoexfoliation Syndrome/Glaucoma and Normal Patients

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Ursula Schlötzer-Schrehardt1, Francesca Pasutto1, Pascal Sommer2, Ian Hornstra3, Friedrich E. Kruse1, Gottfried O. H. Naumann1, André Reis1, Matthias Zenkel1 •
University of Erlangen-Nuremberg1, Claude Bernard University Lyon 12, Washington University in St. Louis3
01 Dec 2008-American Journal of Pathology
TL;DR: Findings provide evidence for LOXL1 involvement in the initial stages of abnormal fibrogenesis in PEX tissues and suggest Alterations ofLOXL1 activation, processing, and/or substrate specificity may contribute to the abnormal aggregation of elastic fiber components into characteristic PEX fibrils.
Abstract: Pseudoexfoliation (PEX) syndrome is a generalized disease of the extracellular matrix and the most common identifiable cause of open-angle glaucoma. Two single nucleotide polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene (rs1048661 and rs3825942) have been recently identified as strong genetic risk factors for both PEX syndrome and PEX glaucoma. Here we investigated the expression and localization of LOXL1, LOXL2, and lysyl oxidase (LOX) in tissues of PEX syndrome/glaucoma patients and controls in correlation with their individual single nucleotide polymorphism genotypes and stages of disease. LOXL1 ocular expression was reduced by approximately 20% per risk allele of rs1048661, whereas risk alleles of rs3825942, which were highly overrepresented in PEX cases, did not affect LOXL1 expression levels. Irrespective of the individual genotype, LOXL1 expression was significantly increased in early PEX stages but was decreased in advanced stages both with and without glaucoma compared with controls, whereas LOX and LOXL2 showed no differences between groups. LOXL1 was also found to be a major component of fibrillar PEX aggregates in both intra- and extraocular locations and to co-localize with various elastic fiber components. These findings provide evidence for LOXL1 involvement in the initial stages of abnormal fibrogenesis in PEX tissues. Alterations of LOXL1 activation, processing, and/or substrate specificity may contribute to the abnormal aggregation of elastic fiber components into characteristic PEX fibrils.

119 citations

Journal Article•DOI•
Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population

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Masakazu Nakano1, Yoko Ikeda, Takazumi Taniguchi, Tomohito Yagi, Masahiro Fuwa, Natsue Omi, Yuichi Tokuda, Masami Tanaka, Kengo Yoshii, Masaaki Kageyama, Shigeta Naruse, Akira Matsuda, Kazuhiko Mori, Shigeru Kinoshita, Kei Tashiro •
Kyoto Prefectural University of Medicine1
04 Aug 2009-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: It turned out that 3 genetic loci probably associated with POAG have been identified, and these findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.
Abstract: Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.

113 citations

Journal Article•DOI•
Molecular pathology of pseudoexfoliation syndrome/glaucoma – New insights from LOXL1 gene associations☆

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Ursula Schlötzer-Schrehardt1•
University of Erlangen-Nuremberg1
30 Apr 2009-Experimental Eye Research
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.
Abstract: Pseudoexfoliation (PEX) syndrome is a generalized disease of the extracellular matrix and a major cause of severe open-angle glaucoma. Single nucleotide polymorphisms (SNPs) in exon 1 of the lysyl oxidase-like 1 (LOXL1) gene have been recently identified as strong genetic risk factors for both PEX syndrome and PEX glaucoma. LOXL1 is a pivotal cross-linking enzyme in extracellular matrix metabolism and seems to be specifically required for elastic fiber formation and stabilization. This review outlines our current understanding of the role of LOXL1 in the pathophysiology of PEX syndrome and PEX glaucoma. The available data suggest that LOXL1 is differentially regulated dependent on the phase of progression of the fibrotic process. While increased levels of LOXL1 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. Although the functional significance of LOXL1 in the specific PEX-associated matrix process still has to be determined, elucidation of the underlying molecular pathogenesis has been evolving, and might eventually open new approaches for specific treatment strategies in the future.

111 citations

Cites background from "Lysyl oxidase-like protein 1 (LOXL1..."

  • ...Following this discovery, several replication studies in populations from the United States (Fingert et al., 2007; Aragon-Martin et al., 2008; Challa et al., 2008; Fan et al., 2008; Yang et al., 2008), Australia (Hewitt et al., 2008), Europe (Mossböck et al., 2008; Pasutto et al., 2008), Japan (Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008), and India (Ramprasad et al., 2008) confirmed genetic susceptibility of LOXL1 polymorphisms to PEX syndrome/glaucoma and verified the LOXL1 gene as a major genetic risk factor for this condition worldwide....

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  • ...…et al., 2007; Aragon-Martin et al., 2008; Challa et al., 2008; Fan et al., 2008; Yang et al., 2008), Australia (Hewitt et al., 2008), Europe (Mossböck et al., 2008; Pasutto et al., 2008), Japan (Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008), and India…...

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Journal Article•DOI•
Major review: Exfoliation syndrome; advances in disease genetics, molecular biology, and epidemiology

[...]

Inas F. Aboobakar1, William M. Johnson1, W. Daniel Stamer1, Michael A. Hauser1, R. Rand Allingham1 •
Duke University1
01 Jan 2017-Experimental Eye Research
TL;DR: Current knowledge of XFS pathogenesis is summarized, gaps in knowledge are identified, and areas for future research are discussed.
Abstract: Exfoliation syndrome (XFS) is a common age-related disorder that leads to deposition of extracellular fibrillar material throughout the body. The most recognized disease manifestation is exfoliation glaucoma (XFG), which is a common cause of blindness worldwide. Recent developments in XFS genetics, cell biology and epidemiology have greatly improved our understanding of the etiology of this complex inherited disease. This review summarizes current knowledge of XFS pathogenesis, identifies gaps in knowledge, and discusses areas for future research.

96 citations

Cites background from "Lysyl oxidase-like protein 1 (LOXL1..."

  • ..., 2008a), Central European (Mossbock et al., 2008), Chinese (Gong et al....

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  • ...The association of LOXL1 coding variants (Arg141Leu and Gly153Asp) with XFG risk has been replicated in all studied populations around the world, including Australian Caucasian (Hewitt et al., 2008), U.S. Caucasian (Aragon-Martin et al., 2008; Challa et al., 2008; Fingert et al., 2007; Yang et al., 2008; Fan et al., 2008a), Central European (Mossbock et al., 2008), Chinese (Gong et al., 2008; Chen et al., 2009; Lee et al., 2009), Finnish (Lemmela et al., 2009), German (Wolf et al., 2010a; Pasutto et al., 2008), Greek (Anastasopoulos et al., 2014), Indian (Ramprasad et al., 2008), Italian (Pasutto et al., 2008), Japanese (Ozaki et al., 2008; Fuse et al., 2008; Hayashi et al., 2008; Mabuchi et al., 2008; Mori et al., 2008; Tanito et al., 2008), Korean (Sagong et al., 2011; Park do et al., 2013), Mexican (Jaimes et al., 2012), Polish (Malukiewicz et al., 2011), Saudi Arabian (Abu-Amero et al., 2010), South African (Williams et al., 2010; Rautenbach et al., 2011), Spanish (Alvarez et al., 2015; de Juan-Marcos et al., 2016), Turkish (Tuncay et al., 2016; Yilmaz et al., 2016), and the Uygur population (Mayinu and Chen, 2011; Ma et al., 2014)....

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  • ...…U.S. Caucasian (Aragon-Martin et al., 2008; Challa et al., 2008; Fingert et al., 2007; Yang et al., 2008; Fan et al., 2008a), Central European (Mossbock et al., 2008), Chinese (Gong et al., 2008; Chen et al., 2009; Lee et al., 2009), Finnish (Lemmela et al., 2009), German (Wolf et al., 2010a;…...

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References
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Journal Article•DOI•
Haploview: analysis and visualization of LD and haplotype maps

[...]

Jeffrey C. Barrett1, Ben Fry1, Julian Maller1, Mark J. Daly1•
Massachusetts Institute of Technology1
15 Jan 2005-Bioinformatics
TL;DR: Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface.
Abstract: Summary: Research over the last few years has revealed significant haplotype structure in the human genome. The characterization of these patterns, particularly in the context of medical genetic association studies, is becoming a routine research activity. Haploview is a software package that provides computation of linkage disequilibrium statistics and population haplotype patterns from primary genotype data in a visually appealing and interactive interface. Availability: http://www.broad.mit.edu/mpg/haploview/ Contact: jcbarret@broad.mit.edu

13,862 citations

Journal Article•DOI•
Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

[...]

Gudmar Thorleifsson1, Kristinn P. Magnusson1, Patrick Sulem1, G. Bragi Walters1, Daniel F. Gudbjartsson1, Hreinn Stefansson1, Thorlakur Jonsson1, Adalbjorg Jonasdottir1, Aslaug Jonasdottir1, Gerdur Stefansdottir1, Gisli Masson1, Gudmundur A. Hardarson1, H. Petursson1, Arsaell Arnarsson2, Mehdi Motallebipour3, Ola Wallerman3, Claes Wadelius3, Jeffrey R. Gulcher1, Unnur Thorsteinsdottir1, Augustine Kong1, Fridbert Jonasson2, Kari Stefansson1 •
deCODE genetics1, University of Iceland2, Uppsala University3
07 Sep 2007-Science
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

"Lysyl oxidase-like protein 1 (LOXL1..." refers background or result in this paper

  • ...Most importantly, a recent genome-wide association study from Icelandic and Swedish patients with XFS and XFG found two common non-synonymous single nucleotide polymorphisms in exon 1 of the lysyl oxidase-like protein 1 gene (LOXL1; OMIM 153456) conferring increased risk for the development of XFS and XFG (rs1048661 and rs3825942) [10]....

    [...]

  • ...Beside the original study from Thorleifsson and coworkers [10] that included an Icelandic and a Swedish cohort, four studies from the United States, one study from Australia, one study from Japan, and one from India investigating LOXL1 polymorphisms in XFS and XFG have been performed [10,15-21]....

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Journal Article•DOI•
Elastic fiber homeostasis requires lysyl oxidase-like 1 protein.

[...]

Xiao-Qing Liu1, Yun Zhao1, Jiangang Gao, Basil S. Pawlyk1, Barry Starcher2, Jeffrey A. Spencer3, Hiromi Yanagisawa, J. Zuo, Tiansen Li1 •
Harvard University1, University of Texas Health Science Center at Tyler2, University of Texas Southwestern Medical Center3
25 Jan 2004-Nature Genetics
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

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...Mice lacking LOXL1 display tropoelastin accumulation in multiple tissues, which leads to pelvic organ prolapse, emphysematous changes, and vascular abnormalities [13]....

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  • ...This deamination leads to the polymerization of tropoelastin to elastin, which is the first step of elastogenesis [12,13]....

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Journal Article•DOI•
Pseudoexfoliation syndrome, ocular manifestation of a systemic disorder?

[...]

Ursula Schlötzer-Schrehardt1, Mahmut R. Koca, Gottfried O. H. Naumann, Hildegard Volkholz•
University of Erlangen-Nuremberg1
01 Dec 1992-Archives of Ophthalmology
TL;DR: Findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.
Abstract: The pseudoexfoliation syndrome has recently been suggested to represent the local manifestation of a more widespread disorder. In this study, a case of classic bilateral pseudoexfoliation syndrome with systemic distribution of pseudoexfoliation material involving a variety of organ systems is described. Using transmission electron microscopy, typical pseudoexfoliation fibers were identified in autopsy tissue specimens of skin, heart, lungs, liver, kidney, and cerebral meninges in addition to the classic intraocular locations. The pseudoexfoliation material was mainly localized to connective-tissue portions or septa traversing the various organs. The pseudoexfoliation fibers were consistently associated with connective-tissue components, particularly fibroblasts and collagen and elastic fibers; myocardial tissue specimens; and heart-muscle cells. These findings provide evidence for the systemic nature of the pseudoexfoliation syndrome, which apparently involves an aberrant connective-tissue metabolism throughout the body.

400 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...Mainstay of the pathogenesis of exfoliation syndrome is the accumulation of pathognomonic fibrils in the anterior segment of the eye as well as in extraocular locations [1]....

    [...]

  • ...Exfoliation syndrome (XFS; OMIM 177650) is characterized by an accumulation of abnormal extracellular fibrillar material not only in different structures of the eye but also in various extraocular tissues [1]....

    [...]

Journal Article•DOI•
Why is glaucoma associated with exfoliation syndrome

[...]

Robert Ritch1, Ursula Schlötzer-Schrehardt, Anastasios G. P. Konstas•
New York Eye and Ear Infirmary1
01 May 2003-Progress in Retinal and Eye Research
TL;DR: Exfoliation syndrome is an age-related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar material in tissues throughout the anterior segment and also in connective tissue portions of various visceral organs.
Abstract: Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar material in tissues throughout the anterior segment and also in connective tissue portions of various visceral organs. Mature exfoliation fibrils are composed of 8-10 nm microfibrils resembling elastic microfibrils. The exact chemical composition of exfoliation material (XFM) remains unknown. It appears to consist of a complex glycoprotein/ proteoglycan structure composed of a protein core surrounded by abundant glycoconjugates. The protein components include both non-collagenous basement membrane components and epitopes of the elastic fiber system, particularly components of elastic microfibrils. Overall, XFS is the most common identifiable cause of glaucoma, accounting for the majority of cases in some countries, and causing both open-angle glaucoma and angle-closure glaucoma. Iridolenticular friction leads to loss of XFM from the anterior lens surface and disruption of the iris pigment epithelium, resulting in pigment deposition in the trabecular meshwork, which also produces XFM locally. The primary cause of chronic pressure elevation appears to be the active involvement of trabecular cells and Schlemm's canal cells in particular, in the generalized pathologic matrix process with subsequent degenerative changes of Schlemm's canal and adjacent tissues. Narrow angles and angle-closure are common in XFS. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness or dialysis. Enlargement of the lens due to cataract formation and relative pupillary constriction are additional factors.

218 citations

"Lysyl oxidase-like protein 1 (LOXL1..." refers background in this paper

  • ...These fibrils are partly composed of components of the elastic fiber system like elastin, tropoelastin, amyloid P, and latent TGF-β binding proteins [2,4]....

    [...]

  • ...Secondary open-angle glaucoma due to XFS (exfoliation glaucoma, XFG) develops as a consequence of deposition of exfoliation material and of liberated iris pigment in the trabecular meshwork leading to elevated intraocular pressure and consecutively glaucomatous optic neuropathy [4]....

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Related Papers (5)
Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

[...]

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[...]

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Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people.

[...]

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Alex W. Hewitt, Alex W. Hewitt, Shiwani Sharma, Kathryn P. Burdon, Jie Jin Wang, Paul N. Baird, David P. Dimasi, David A. Mackey, David A. Mackey, Paul Mitchell, Jamie E Craig