Expression and Regulation of LOXL1 and Elastin-related Genes in Eyes With Exfoliation Syndrome

Wiggs, Janey L.; Pasquale, Louis R.

doi:10.1097/ijg.0000000000000124

Cited by 22 publications

(14 citation statements)

References 9 publications

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“…This sequencing effort confirmed previously reported strong allele reversals at key LOXL1 common variants and also at recently reported non-coding variants (Supplementary Tables 3, 4 and 5) 13,21,23 .…”

Section: Resultssupporting

confidence: 71%

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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: Resultssupporting

confidence: 71%

“…Despite the overwhelming strength of the genetic association seen at polymorphisms mapping to LOXL1, the results are inconsistent due to risk alleles being 'flipped' in certain populations 12,13 . Such stark allele reversals imply that the genetic architecture underlying XFS disease biology is complex and worthy of further study.…”

Section: Introductionmentioning

confidence: 95%

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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“…One report indicates that LOXL1 and LOXL4 expression are anti-tumorigenic and inhibit RAS and ERK1/2 signaling in bladder cancer 125 , while LOXL1 was suggested to enhance lung metastasis in low pH hypoxic tumor microenvironments 126 . A role for caffeine-stimulated LOXL1 expression in inhibiting tumor metastasis has also been suggested 127 .…”

Section: Bodymentioning

confidence: 99%

Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

Trackman

2016

Expert Opinion on Therapeutic Targets

109

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Introduction The lysyl oxidase family of enzymes is classically known as being required for connective tissue maturation by oxidizing lysine residues in elastin and lysine and hydroxylysine residues in collagen precursors. The resulting aldehydes then participate in cross-link formation, which is required for normal connective tissue integrity. These enzymes have biological functions that extend beyond this fundamental biosynthetic role, with contributions to angiogenesis, cell proliferation, and cell differentiation. Dysregulation of lysyl oxidases occurs in multiple pathologies including fibrosis, primary and metastatic cancers, and complications of diabetes in a variety of tissues. Areas covered This review summarizes the major findings of novel roles for lysyl oxidases in pathologies, and highlights some of the potential therapeutic approaches that are in development and which stem from these new findings. Expert opinion Fundamental questions remain regarding the mechanisms of novel biological functions of this family of proteins, and regarding functions that are independent of their catalytic enzyme activity. However, progress is underway in the development of isoform-specific pharmacologic inhibitors, potential therapeutic antibodies and gaining an increased understanding of both tumor suppressor and metastasis promotion activities. Ultimately, this is likely to lead to novel therapeutic agents.

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“…10 Initially, LOXL1 missense alleles were associated with disease in populations worldwide, 106 however subsequent studies showed that the missense alleles are not likely to impact the amine oxidase activity of the enzyme. 107 It is likely that dysregulation of LOXL1 is associated with disease development 108 and LOXL1 variants influencing gene expression could influence disease risk. A LOXL1 null mouse has some, but not all, features of XFS.…”

Section: Extracellular Matrix Cell Junctions and Cell Adhesionmentioning

confidence: 99%

Glaucoma Genes and Mechanisms

Wiggs

2015

Progress in Molecular Biology and Translational Science

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Genetic studies have yielded important genes contributing to both early-onset and adult-onset forms of glaucoma. The proteins encoded by the current collection of glaucoma genes participate in a broad range of cellular processes and biological systems. Approximately half the glaucoma-related genes function in the extracellular matrix, however proteins involved in cytokine signaling, lipid metabolism, membrane biology, regulation of cell division, autophagy, and ocular development also contribute to the disease pathogenesis. While the function of these proteins in health and disease are not completely understood, recent studies are providing insight into underlying disease mechanisms, a critical step toward the development of gene-based therapies. In this review, genes known to cause early-onset glaucoma or contribute to adult-onset glaucoma are organized according to the cell processes or biological systems that are impacted by the function of the disease-related protein product.

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Expression and Regulation of LOXL1 and Elastin-related Genes in Eyes With Exfoliation Syndrome

Cited by 22 publications

References 9 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

Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

Glaucoma Genes and Mechanisms

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