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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.

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☆

[...]

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.

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....

    [...]

  • ...…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…...

    [...]

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.

96 citations

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

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

    [...]

  • ...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)....

    [...]

  • ...…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•
Genetic association of LOXL1 gene variants and exfoliation glaucoma in a Utah cohort.

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Xian Yang1, Norman A. Zabriskie, V. S. Hau, Haoyu Chen, Zongzhong Tong, Daniel Gibbs, Parisa Farhi, Bradley J. Katz, Ling Luo, Erik G. Pearson, Jason Goldsmith, Xiang Ma, Yukki Kaminoh, Yuhong Chen, Baifeng Yu, Jiexi Zeng, Kang Zhang, Zhenglin Yang •
University of Utah1
15 Feb 2008-Cell Cycle
TL;DR: The findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XFG.
Abstract: Exfoliation glaucoma (XFG) is the commonest identifiable cause of secondary open-angle glaucoma worldwide, characterized by the deposition of fibrillar proteins in the anterior segment of the eye. We investigated LOXL1 gene variants previously identified to confer susceptibility to exfoliation glaucoma (XFG) in a Utah Caucasian cohort. After a standard eye examination protocol we genotyped SNPs rs2165241 and rs3825942 in 62 XFG or XFS patients and 170 normal controls. Genotype frequency distribution, odds ratios (ORs), and population attributable risks were calculated for the risk alleles. The SNP rs2165241 was significantly associated with XFG and XFS (p=4.13x10-9 for an additive model, ORhet=4.42 (2.30-8.50), ORhom=34.19 (4.48-261.00); T allele: 83.1% in cases versus 52.4% in controls). Significant association was also found for rs3825942: (p=1.89x10-6). Our findings confirm genetic association of LOXL1 with XFG and XFS and implicate a potential role of cross linking of elastin in the pathogenesis of XF...

56 citations

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

  • ...The prevalence of allele G of rs1048661 and rs3825942 found in the present study were remarkably similar to four of these studies [14-16] while in three studies, slightly lower prevalences have been reported (Table 3) [18-20]....

    [...]

  • ...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]....

    [...]

Journal Article•DOI•
Exfoliation syndrome: Clinical and genetic features

[...]

Andrew C. Orr, Johane M. Robitaille, Paul A. Price, John R. Hamilton, Denis M. Falvey, Alex G. De Saint-Sardos, Sylvia Pasternak, Duane L. Guernsey 
01 Sep 2001-Ophthalmic Genetics
TL;DR: Although a multifactorial mode of inheritance cannot be excluded, exfoliation syndrome appears to be inherited as an autosomal dominant trait whose late onset and incomplete penetrance poses a significant but not insuperable obstacle to pedigree construction.
Abstract: We have ascertained a large number of individuals and families with exfoliation syndrome in order to clarify the disorder’s mode of inheritance. Patients with exfoliation syndrome and their relatives were recruited from the practices of a group of ophthalmologists in Maritime Canada. The degree to which the subjects were affected was graded according to a standardized 1–4-point clinical scheme. Pedigrees were constructed from information supplied by family members and from genealogical sources. A total of 782 patients and relatives participated, of whom 467 were definitely affected. The mean age of affected males and females did not differ significantly, but females appeared to be more severely affected at ascertainment than males. More than half of the affected subjects had definite exfoliation in only one eye. Approximately 30 multiplex families were discovered, including one containing 23 affected members among a total of 137 examined individuals that constitutes the largest exfoliative pedigree thus f...

50 citations

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

  • ...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]....

    [...]

  • ...The exact cause for the production of the exfoliation material is still elusive, but there is ample evidence that genetic factors may contribute to the pathogenesis of XFS....

    [...]

  • ...Therefore, XFS has been suggested to be a generalized elastic fibrillopathy....

    [...]

  • ...Furthermore, increased rates of loss of heterozygosity have been found in specimens of the anterior segment in individuals with XFS, suggesting genetic factors play a role in the pathogenesis of the disease [9]....

    [...]

  • ...at XFS among relatives of patients with XFS [5-8]....

    [...]

Journal Article•DOI•
Population Differences in Elastin Maturation in Optic Nerve Head Tissue and Astrocytes

[...]

Zsolt Urban1, Zsolt Urban2, Olga A. Agapova, Vishwanathan Hucthagowder2, Ping Yang2, Barry C. Starcher3, M. Rosario Hernandez •
Washington University in St. Louis1, University of Texas at Austin2, Northwestern University3
01 Jul 2007-Investigative Ophthalmology & Visual Science
TL;DR: ELN and LOXL2 are suggested as candidate susceptibility genes for population-specific genetic risk of primary open-angle glaucoma (POAG) through reduced number of cross-linking domains in elastin and decreased lysyl oxidase-like 2 expression.
Abstract: PURPOSE. Glaucomatous optic neuropathy is characterized by remodeling of the extracellular matrix with disorganization of elastic fibers in the optic nerve head (ONH). There are significant differences in prevalence of glaucomatous optic neuropathy between African Americans (AAs) and Caucasian Americans (CAs). The goal of this study was to evaluate differences in elastin synthesis and maturation in ONH tissue and cells of AA and CA donors with no eye disease, to provide a basis for underlying racial differences in susceptibility to elevated intraocular pressure. METHODS. The amount of mature elastin in ONHs from each group of donors was evaluated by desmosine radioimmunoassay. The distribution of elastic fibers in ONH tissue was investigated by immunofluorescent staining. Elastin and lysyl oxidase mRNA levels and alternative splicing of elastin in ONH astrocytes were investigated by quantitative PCR. Tropoelastin protein expression was assessed by immunoblot analysis. RESULTS. ONHs from AA donors had significantly reduced levels of desmosine compared with those of CAs. In contrast, elastin mRNA and tropoelastin synthesis were elevated in ONH astrocytes from AA individuals. The inclusion of exon 23 in elastin mRNA and lysyl oxidase-like 2 mRNA levels was significantly reduced in astrocytes from AA compared with CA donors. CONCLUSIONS. A reduced number of cross-linking domains in elastin and decreased lysyl oxidase-like 2 expression leads to decreased amount of mature elastin in ONHs from healthy AA individuals compared with CA donors. These results suggest ELN and LOXL2 as candidate susceptibility genes for population-specific genetic risk of primary open-angle glaucoma (POAG). (Invest Ophthalmol Vis Sci. 2007;48:3209‐3215)

40 citations

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

  • ...The prevalence of allele G of rs1048661 and rs3825942 found in the present study were remarkably similar to four of these studies [14-16] while in three studies, slightly lower prevalences have been reported (Table 3) [18-20]....

    [...]

  • ...Interestingly, regarding primary openangle glaucoma, elastin and lysyl oxidase-like protein 2 has been suggested as candidate susceptibility genes [14]....

    [...]

Journal Article•DOI•
Early diagnosis of exfoliation syndrome in the offspring of affected patients.

[...]

Cristiano Oliveira1, Ursula Schlötzer-Schrehardt2, Geraldo Magela Vieira1, Jeffrey M. Liebmann3, Jeffrey M. Liebmann4, Robert Ritch5, Robert Ritch1 •
New York Eye and Ear Infirmary1, University of Erlangen-Nuremberg2, New York University3, Manhattan Eye, Ear and Throat Hospital4, New York Medical College5
01 Aug 2006-Acta Ophthalmologica Scandinavica
TL;DR: Evidence of early deposition of exfoliation material can be found in the conjunctiva of the middle-aged offspring of patients with XFS, substantiating the existence of a hereditary predisposition to this disease.
Abstract: . Purpose: To determine whether conjunctival biopsy in the offspring of patients with exfoliation syndrome (XFS) can provide early diagnosis of the disease. Methods: Patients with XFS with or without glaucoma were invited to ask their sons and daughters over the age of 40 years to participate in the study. After a complete eye examination, those without clinically evident XFS underwent conjunctival biopsy. The specimens were examined by transmission electron microscopy. Results: A total of 17 sons and daughters (seven men, 10 women) of 17 patients were enrolled. Their mean age was 50.3 ± 8 years. Twelve specimens were negative and five presented precursor material evidence of typical exfoliation material. Conclusion: Evidence of early deposition of exfoliation material can be found in the conjunctiva of the middle-aged offspring of patients with XFS, substantiating the existence of a hereditary predisposition to this disease.

17 citations

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

  • ...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]....

    [...]

  • ...The exact cause for the production of the exfoliation material is still elusive, but there is ample evidence that genetic factors may contribute to the pathogenesis of XFS....

    [...]

  • ...Therefore, XFS has been suggested to be a generalized elastic fibrillopathy....

    [...]

  • ...Furthermore, increased rates of loss of heterozygosity have been found in specimens of the anterior segment in individuals with XFS, suggesting genetic factors play a role in the pathogenesis of the disease [9]....

    [...]

  • ...at XFS among relatives of patients with XFS [5-8]....

    [...]

Journal Article•
Loss of heterozygosity in patients with pseudoexfoliation syndrome.

[...]

Renata Zalewska1, Witold Pepinski, Danuta Smolenska-Janica, Zofia Mariak, Ewa Proniewska-Skretek, Małgorzata Skawrońska, Jerzy Janica •
Medical University of Białystok1
17 Jun 2003-Molecular Vision
TL;DR: It is possible, that genetic factors may be involved in the etiology and pathogenesis of PEX, and loss of heterozygosity in a microsatellite marker locus indicates that the neighboring gene may be inactivated.
Abstract: Purpose The purpose of the study was to evaluate the possible occurrence of loss of heterozygosity (LOH) in the anterior capsule, lens nucleus, iris, and trabeculum samples taken from patients with pseudoexfoliation syndrome (PEX). Loss of heterozygosity in a microsatellite marker locus indicates that the neighboring gene may be inactivated. Previous attempts to find a gene defect that might be responsible for pseudoexfoliation glaucoma have been unsuccessful. Methods Specimens of the anterior capsule, the lens nucleus, the iris, the trabeculum, and reference blood samples were collected from 19 PEX patients. Fluorescent multiplex PCR was used to amplify the microsatellite markers located on chromosomes 2, 4, 7, 12, 18, 19, and 21. Results LOH was found in 58% of the iris specimens and 50% of the anterior capsule specimens collected from PEX patients. The highest incidence of LOH was observed at the marker D7S820. Conclusions It is possible, that genetic factors may be involved in the etiology and pathogenesis of PEX.

16 citations

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

  • ...Furthermore, increased rates of loss of heterozygosity have been found in specimens of the anterior segment in individuals with XFS, suggesting genetic factors play a role in the pathogenesis of the disease [9]....

    [...]

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

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07 Sep 2007-Science
Gudmar Thorleifsson, Kristinn P. Magnusson, Patrick Sulem, G. Bragi Walters, Daniel F. Gudbjartsson, Hreinn Stefansson, Thorlakur Jonsson, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Gerdur Stefansdottir, Gisli Masson, Gudmundur A. Hardarson, H. Petursson, Arsaell Arnarsson, Mehdi Motallebipour, Ola Wallerman, Claes Wadelius, Jeffrey R. Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Fridbert Jonasson, Kari Stefansson 
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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