DOCSLIB.ORG

An Investigation Into LOXL1 Variants in Black South African Individuals with Exfoliation Syndrome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
An Investigation Into LOXL1 Variants in Black South African Individuals with Exfoliation Syndrome OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD An Investigation Into LOXL1 Variants in Black South African Individuals With Exfoliation Syndrome Robyn M. Rautenbach, MBChB, DipOphth(SA); Soraya Bardien, PhD; Justin Harvey, MCom(Mathematical Statistics); Ari Ziskind, MBChB, FCSOphth(SA), MSc, BSc Objective: To investigate the association between 2 ly- ing majority of cases with XFS (PϽ.00001; odds ra- syl oxidase–like 1 (LOXL1) polymorphisms, rs1048661 tio,17.10; 95% confidence interval, 4.91-59.56), con- (R141L) and rs3825942 (G153D), and exfoliation syn- trary to all previous articles in which the GG genotype was drome (XFS) in black South African individuals. strongly associated with the disease phenotype. Methods: A total of 43 black patients with XFS and 47 Conclusion: The LOXL1 SNPs R141L and G153D are ethnically matched controls were recruited for genetic significantly associated with XFS in this black South Afri- analysis. Samples were analyzed for presence of the can population. The AA genotype of G153D confers XFS LOXL1–R141L and G153D variants using restriction frag- risk in this population, as opposed to the GG genotype ment length polymorphism analysis. A case-control as- described in all other populations, suggesting that un- sociation study was performed. identified genetic or environmental factors indepen- dent of these LOXL1 SNPs may influence phenotypic ex- Results: The R141L and G153D single-nucleotide poly- pression of the syndrome. morphisms (SNPs) were both significantly associated with XFS (P=.00582 and PϽ.00001, respectively). Consis- Clinical Relevance: Elucidation of the role of genetic tent with findings in white populations but not in Asian factors, including the LOXL1 gene, in XFS will facilitate cohorts, the GG genotype of the R141L SNP was present identification of individuals predisposed to developing in significantly more XFS cases than controls (P=.00582). this condition. However, in this black South African study population, the AA genotype of G153D was present in an overwhelm- Arch Ophthalmol. 2011;129(2):206-210 XFOLIATION SYNDROME angle glaucoma, accounting for approxi- (XFS) is a generalized dis- mately 25% of cases worldwide.5 order of the extracellular The prevalence of XFS increases with matrix characterized by the age, and a number of studies have re- pathological deposition and ported geographical clustering of this con- Eaccumulation of fibrillar material through- dition based on race and ethnicity.6 Fa- out the eye. The origin of this fibrillar ma- milial aggregation studies have suggested terial is unknown but believed to be de- a significant genetic contribution to XFS.7 rived from abnormal basement membranes Despite these findings, a simple inherit- Author Affiliations: Division of of aging epithelial cells in ocular struc- ance model is not evident, suggesting that 1 Ophthalmology, Stellenbosch tures. In addition to its occurrence within XFS is the result of a complex inherit- University and Tygerberg the eye, exfoliative fibrillopathy has been ance pattern with multiple contributing ge- Hospital (Drs Rautenbach and reported in the skin, blood vessels, and vis- netic and/or environmental factors. Ziskind); and Division of ceral organs, suggesting that XFS may in A landmark genome-wide association Molecular Biology and Human fact be an ocular manifestation of a sys- study by Thorleifsson et al8 identified 3 Genetics, Faculty of Health temic disorder.2-4 common single-nucleotide polymor- Sciences (Dr Bardien) and This condition is associated with an ar- phisms (SNPs) in the lysyl oxidase–like Centre for Statistical Consultation, Department of ray of ocular manifestations, most fre- 1(LOXL1) gene on chromosome 15q24.1 Statistics and Actuarial Science, quently a severe and progressive form of that were strongly associated with XFS and Stellenbosch University chronic open-angle glaucoma. Exfolia- exfoliation glaucoma in Scandinavian (Dr Harvey), Cape Town, tion syndrome is acknowledged as the populations. The LOXL family of pro- South Africa. most common identifiable cause of open- teins play a vital role in the homeostasis (REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 2), FEB 2011 WWW.ARCHOPHTHALMOL.COM 206 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 of elastic tissues, acting as cross-linking enzymes and to detect a clinically significant association between the pres- thereby ensuring spatially defined deposition of elastin ence or absence of a specific polymorphism and XFS. Data was fibrils.9,10 The identification of the LOXL1 protein in pseu- analyzed using SAS version 9.1 (SAS Institute Inc, Cary, North doexfoliation deposits verifies its involvement in abnor- Carolina). Descriptive statistics were computed for patient age, mal fibrinogenesis in pseudoexfoliative tissues.11,12 and comparison between the mean ages of cases and controls was performed by t test for 2 groups. Furthermore, the pri- Two of these SNPs, rs1048661 (R141L) and rs3825942 mary outcome variables were analyzed by contingency tables. (G153D), are located within exon 1 of LOXL1 and cause Associations between the cases and controls and the different amino acid missense changes in the protein. This exon allele, genotype, and haplotype frequencies was examined using codes for the N-terminal portion of the protein, which Pearson ␹2 test. Odds ratios and relative risk estimates were also may have a role in directing the LOXL1 protein to sites produced to examine further interactions between the disease of elastogenesis. The third LOXL1 SNP, rs2165241, is lo- and specific alleles and genotypes. Confidence intervals (CIs) cated in the first intron of the gene and is presumed not for these estimates were also produced. A PϽ.05 represented to have any biological consequence. All 3 of these SNPs statistical significance in hypothesis testing and 95% confi- were in significant linkage disequilibrium in the studied dence intervals were used to describe the estimation of un- population.8 These genetic findings have been repli- known parameters. Hardy-Weinberg equilibrium of the allele and genotype fre- cated to a large extent, with some important variations, 13-17 quencies of cases and control subjects was examined, both sepa- in numerous studies throughout North America, Aus- rately and in combination, using ␹2 and Fisher exact tests. tralia,18 Europe,19 and Asia.20-26 This study investigates the association of these LOXL1 gene polymorphisms with XFS among black South Af- RESULTS ricans, a geographical cluster with a high prevalence of XFS and exfoliation glaucoma.27,28 Of the 43 patients with XFS, 15 had exfoliation glau- coma. Of the 47 controls; 13 had primary open-angle glau- METHODS coma but no evidence of exfoliation. The cases and con- trols were age-matched with a mean (SD) age of 72.37 (9.57) in XFS cases and 71.81(7.56) in controls without PATIENT POPULATION XFS, with no significant difference found between the means of these 2 groups (P=.75621). An ethnically matched cohort of 43 elderly black patients with exfoliation syndrome and 47 control individuals were identi- The G allele of SNP rs1048661 (R141L) was detected fied from the outpatient ophthalmology service at the East Lon- in a statistically higher frequency in patients with XFS don Hospital Complex (Eastern Cape, South Africa) for this than controls (P=.00106). The relative risk of having no study. The study was approved by the Stellenbosch University disease given the presence of the G allele vs the T allele Committee for Human Research (N08/08/208), and all pa- for this SNP was 0.49 (95% CI. 0.42-0.57). The A allele tients and controls were recruited after informed consent. All of SNP rs3825942 (G153D) was strongly associated with cases and controls underwent an anterior segment evaluation exfoliation syndrome (PϽ.00001) in this sample, with after pupillary dilatation to confirm the presence or absence of patients being 9.94 times more likely to have an A allele the characteristic fibrillar material diagnostic of XFS. Venous than a G allele (odds ratio,9.94; 95% CI, 4.75-20.79) blood samples were collected from all study participants. (Table 1). The genotype frequencies for the rs1048661 (R141L) GENOTYPING SNP and the rs3825942 (G153D) SNP confirmed statis- tically significant differences between the XFS cases and DNA was extracted from the peripheral venous blood samples controls. The GG genotype of R141L was present in sig- according to established methods. Polymerase chain reaction primers were designed to amplify the region containing the nificantly more XFS cases than controls (P=.00582), with LOXL1 R141L and G153D variants (forward: 5Ј-GCA GGT GTA a relative risk of having no disease (GG vs GT/TT) CAG CTT GCT CA-3Ј and reverse: 5Ј-GGC CGG TAG TAC of0.46 (95% CI, 0.37-0.59). In this study population, we ACG AAA CC-3Ј), which produced a product of 474 base pairs. found that the AA genotype of G153D was present in an Restriction fragment–length polymorphism analysis was used overwhelming majority of cases with XFS (PϽ.00001), to genotype the 2 SNPs. The Smal (fermentas) and Eco24I (fer- with an odds ratio (AA vs GG) of 17.10 (95% CI, 4.91- mentas) restriction endonuclease enzymes were used for R141L 59.56) (Table 1). and G153D, respectively. Following digestion, the polymer- The haplotypes composed of the 2 LOXL1 SNPs ase chain reaction products were resolved on 12% polyacryl- rs1048661 and rs3825942 were determined, with the fre- amide gels and the bands visualized using silver staining. The quencies of the 2-SNP haplotypes differing significantly genotyping method was verified by sequencing randomly se- between the patients with XFS and the controls lected samples using the BigDye Terminator Sequence Ready Ͻ Reaction kit version 3.1 (Applied Biosystems, Foster City, Cali- (P .00001). The GA haplotype was associated with the fornia) and analyzed on a 3130xl Genetic Analyzer (Applied highest risk of XFS in which a patient is 9.94 times more Biosystems).
Load more

Recommended publications
  • High Resolution Profile of Body Wide Pathological Changes Induced by Abnormal Elastin Metabolism in Loxl1 Knockout Mice
    bioRxiv preprint doi: https://doi.org/10.1101/353169; this version posted June 21, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. High resolution profile of body wide pathological changes induced by abnormal elastin metabolism in Loxl1 knockout mice Bingbing Wu1,2,3,#, Yu Li1,2,3,#, Chengrui An2,3, Deming Jiang1,2,3, Lin Gong1,2,3, Yanshan Liu1,2,3, Yixiao Liu1,2,3,Jun Li2,3, HongWei Ouyang2,3,4*, XiaoHui Zou1,2,3,* 1 Clinical Research Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, PR China 2Zhejiang Provincial Key Laboratory of Tissue Engineering and Regenerative Medicine, Hangzhou, Zhejiang 310058, PR China 3Dr.Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regeneration Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, PR China 4Zhejiang University-University of Edinburgh Institute, Hangzhou, 310058, PR China #Co-first author *Corresponding author Correspondence and requests for materials should be addressed to X.H.Z. (Email: [email protected]) Corresponding address: Clinical Research Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qing Chun Road, Hangzhou, Zhejiang, P.R. China, 310003, Fax/Phone: +086-0571-88208262 bioRxiv preprint doi: https://doi.org/10.1101/353169; this version posted June 21, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract： Abnormal ECM caused serious body wide diseases and elastin is one of the important ECM components.
    [Show full text]
  • The Function and Mechanisms of Action of LOXL2 in Cancer (Review)
    1200 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 36: 1200-1204, 2015 The function and mechanisms of action of LOXL2 in cancer (Review) LINGHONG WU and YING ZHU Department of Infectious Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China Received May 31, 2015; Accepted August 26, 2015 DOI: 10.3892/ijmm.2015.2337 Abstract. The lysyl oxidase (LOX) family is comprised of five copper‑dependent amine oxidase, and its main role is to members, and some members have recently emerged as impor- catalyze the covalent cross‑link of collagen and elastin in tant regulators of tumor progression. Among these, at present, the extracellular matrix (ECM). This occurs through the LOX‑like (LOXL)2 is the prototypical LOX and the most oxidative deamination of peptidyl lysine residues in ECM comprehensively studied member. A growing body of evidence components (1,2). Each member of the LOX family has a has implicated LOXL2 in the promotion of cancer cell inva- highly conserved carboxyl (C)‑terminal domain that contains a sion, metastasis and angiogenesis, as well as in the malignant copper‑binding motif, lysine tyrosylquinone (LTQ) residues and transformation of solid tumors. Moreover, a high expression of a cytokine receptor‑like (CRL) domain, which is essential for LOXL2 is associated with a poor prognosis. These data have catalytic activity (3). The amino‑terminal regions are different piqued the interest of a number of researchers and research and are thought to be important in protein‑protein interactions. groups, who have identified LOXL2 as a strong target candidate The prodomains in LOX and LOXL1 enable their secretion in the development of inhibitors for use as functional and effi- as inactive proenzymes, which are then activated extracel- cacious tumor therapeutics.
    [Show full text]
  • LOXL1 Confers Antiapoptosis and Promotes Gliomagenesis Through Stabilizing BAG2
    Cell Death & Differentiation (2020) 27:3021–3036 https://doi.org/10.1038/s41418-020-0558-4 ARTICLE LOXL1 confers antiapoptosis and promotes gliomagenesis through stabilizing BAG2 1,2 3 4 3 4 3 1 1 Hua Yu ● Jun Ding ● Hongwen Zhu ● Yao Jing ● Hu Zhou ● Hengli Tian ● Ke Tang ● Gang Wang ● Xiongjun Wang1,2 Received: 10 January 2020 / Revised: 30 April 2020 / Accepted: 5 May 2020 / Published online: 18 May 2020 © The Author(s) 2020. This article is published with open access Abstract The lysyl oxidase (LOX) family is closely related to the progression of glioma. To ensure the clinical significance of LOX family in glioma, The Cancer Genome Atlas (TCGA) database was mined and the analysis indicated that higher LOXL1 expression was correlated with more malignant glioma progression. The functions of LOXL1 in promoting glioma cell survival and inhibiting apoptosis were studied by gain- and loss-of-function experiments in cells and animals. LOXL1 was found to exhibit antiapoptotic activity by interacting with multiple antiapoptosis modulators, especially BAG family molecular chaperone regulator 2 (BAG2). LOXL1-D515 interacted with BAG2-K186 through a hydrogen bond, and its lysyl 1234567890();,: 1234567890();,: oxidase activity prevented BAG2 degradation by competing with K186 ubiquitylation. Then, we discovered that LOXL1 expression was specifically upregulated through the VEGFR-Src-CEBPA axis. Clinically, the patients with higher LOXL1 levels in their blood had much more abundant BAG2 protein levels in glioma tissues. Conclusively, LOXL1 functions as an important mediator that increases the antiapoptotic capacity of tumor cells, and approaches targeting LOXL1 represent a potential strategy for treating glioma.
    [Show full text]
  • LOXL1 Is Regulated by Integrin 11 and Promotes Non-Small Cell Lung
    cancers Article LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity 1, 1, 2,3 1 1,4,5, Cédric Zeltz y, Elena Pasko y , Thomas R. Cox , Roya Navab and Ming-Sound Tsao * 1 Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; [email protected] (C.Z.); [email protected] (E.P.); [email protected] (R.N.) 2 The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia; [email protected] 3 St Vincent’s Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia 4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada 5 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada * Correspondence: [email protected] These authors contributed equally to this work. y Received: 15 April 2019; Accepted: 17 May 2019; Published: 22 May 2019 Abstract: Integrin α11, a stromal collagen receptor, promotes tumor growth and metastasis of non-small cell lung cancer (NSCLC) and is associated with the regulation of collagen stiffness in the tumor stroma. We have previously reported that lysyl oxidase like-1 (LOXL1), a matrix cross-linking enzyme, is down-regulated in integrin α11-deficient mice. In the present study, we investigated the relationship between LOXL1 and integrin α11, and the role of LOXL1 in NSCLC tumorigenicity. Our results show that the expression of LOXL1 and integrin α11 was correlated in three lung adenocarcinoma patient datasets and that integrin α11 indeed regulated LOXL1 expression in stromal cells.
    [Show full text]
  • LOXL1 Gene Polymorphism Candidates for Exfoliation Glaucoma
    Molecular Vision 2021; 27:262-269 <http://www.molvis.org/molvis/v27/262> © 2021 Molecular Vision Received 8 August 2020 | Accepted 6 May 2021 | Published 8 May 2021 LOXL1 gene polymorphism candidates for exfoliation glaucoma are also associated with a risk for primary open-angle glaucoma in a Caucasian population from central Russia Natalya Eliseeva,1 Irina Ponomarenko,1 Evgeny Reshetnikov,1 Volodymyr Dvornyk,2 Mikhail Churnosov1 1Department of Medical Biological Disciplines, Belgorod State University, Belgorod, Russia; 2Department of Life Sciences, College of Science and General Studies, Alfaisal University, Riyadh, Saudi Arabia Purpose: This study was aimed to replicate the previously reported associations of the three LOXL1 gene polymorphisms with exfoliation glaucoma (XFG) and to analyze these genetic variants for their possible contribution to primary open- angle glaucoma (POAG) in Caucasians from central Russia. Methods: In total, 932 participants were recruited for the study, including 328 patients with XFG, 208 patients with POAG, and 396 controls. The participants were of Russian ethnicity (self-reported) and born in Central Russia. They were genotyped at three single nucleotide polymorphisms (SNPs) of the LOXL1 gene (rs2165241, rs4886776, and rs893818). The association was analyzed using logistic regression. −6 Results: Allele C of rs2165241 was associated with a decreased risk of XFG (odds ratio [OR] =0.27–0.45, pperm ≤5*10 ) and POAG (OR=0.35–0.47, рperm≤0.001), and allele A of rs4886776 and rs893818 were associated with a lower risk of XFG (OR=0.53–0.57, рperm≤0.001). Haplotype TGG of loci rs2165241-rs4886776-rs893818 was associated with an elevated risk of XFG (OR=2.23, рperm=0.001) and POAG (OR=2.01, рperm=0.001), haplotype CGG was also associated with a decreased risk of XFG (OR=0.45, рperm=0.001) and POAG (OR=0.35, рperm=0.001).
    [Show full text]
  • Association of Single Nucleotide Polymorphisms Located in LOXL1 with Exfoliation Glaucoma in Southwestern Sweden
    G C A T T A C G G C A T genes Article Association of Single Nucleotide Polymorphisms Located in LOXL1 with Exfoliation Glaucoma in Southwestern Sweden Marcelo Ayala 1,2,3,*, Madeleine Zetterberg 1,4, Ingmar Skoog 5,6 and Anna Zettergren 6 1 Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; [email protected] 2 Eye Department, Region Västra Götaland, Skaraborg Hospital/Skövde, 54142 Skövde, Sweden 3 Department of Clinical Neuroscience, Karolinska Institute, 17165 Stockholm, Sweden 4 Department of Ophthalmology, Region Västra Götaland, Sahlgrenska University Hospital, 43130 Mölndal, Sweden 5 Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, 40530 Gothenburg, Sweden; [email protected] 6 Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) University of Gothenburg, 40530 Gothenburg, Sweden; [email protected] * Correspondence: [email protected]; Tel.: +46-500-431-000 Abstract: Introduction: Glaucoma is an optic neuropathy that leads to visual field defects. Genetic mechanisms seem to be involved in glaucoma development. Lysyl Oxidase Like 1 (LOXL1) has been described in previous studies as a predictor factor for exfoliation glaucoma. The present article studied the association between three single nucleotide polymorphisms (SNPs) in the LOXL1 gene and the presence of exfoliation glaucoma in Southwestern Sweden. Methods: Case-control study for genetic association. In total, 136 patients and 1011 controls were included in the study. Patients with exfoliation glaucoma were recruited at the Eye Department of Sahlgrenska University Citation: Ayala, M.; Zetterberg, M.; Hospital and Skaraborgs Hospital, Sweden.
    [Show full text]
  • De Novo Variants in an Extracellular Matrix Protein Coding Gene, fibulin-5 (FBLN5) Are Associated with Pseudoexfoliation
    European Journal of Human Genetics (2019) 27:1858–1866 https://doi.org/10.1038/s41431-019-0482-6 ARTICLE De novo variants in an extracellular matrix protein coding gene, fibulin-5 (FBLN5) are associated with pseudoexfoliation 1,2 1,2 1,2 3 Biswajit Padhy ● Ramani Shyam Kapuganti ● Bushra Hayat ● Pranjya Paramita Mohanty ● Debasmita Pankaj Alone 1,2 Received: 28 August 2018 / Revised: 5 July 2019 / Accepted: 16 July 2019 / Published online: 29 July 2019 © The Author(s), under exclusive licence to European Society of Human Genetics 2019 Abstract Fibulin-5 (FBLN5), an extracellular scaffold protein, plays a crucial role in the activation of Lysyl oxidase like-1 (LOXL1), a tropoelastin crosslinking enzyme, and subsequent deposition of elastin in the extracellular matrix. Following study identifies polymorphisms within FBLN5 gene as risk factors and its aberrant expression in the pathogenesis of an ocular disorder, pseudoexfoliation (PEX). Exons and exon–intron boundaries within FBLN5 gene were scanned through fluorescence-based capillary electrophoresis for polymorphisms as risk factors for PEX pathogenesis in recruited study subjects with Indian ethnicity. mRNA and protein expression of FBLN5 was checked in lens capsule of study subjects 1234567890();,: 1234567890();,: through qRT-PCR and western blotting, respectively. In vitro functional analysis of risk variants was done through luciferase reporter assays. Thirty study subjects from control and PEX affected groups were scanned for potential risk variants. Putative polymorphisms identified by scanning were further evaluated for genetic association in a larger sample size comprising of 338 control and 375 PEX affected subjects. Two noncoding polymorphisms, hg38 chr14: g.91947643G>A (rs7149187:G>A) and hg38 chr14:g.91870431T>C (rs929608:T>C) within FBLN5 gene are found to be significantly associated with PEX as risk factors with a p-value of 0.005 and 0.004, respectively.
    [Show full text]
  • Exfoliation Syndrome Associated with LOXL1 Gene Polymorphisms in A
    A RQUIVOS B RASILEIROS DE LETTERS Exfoliation syndrome associated with LOXL1 gene polymorphisms in a Black patient from Latin America: a case report Síndrome de esfoliação associada a polimorfismos do gene LOXL1 em paciente negro da América Latina: relato de caso Guilherme Eiichi da Silva Takitani1, Alexandre Gomes Bortoloti de Azevedo1, Fabiana Louise Motta1, Sérgio Henrique Teixeira1, Juliana Maria Ferraz Sallum1, Roberto Murad Vessani1 1. Department of Ophthalmology, Universidade Federal de São Paulo, São Paulo, SP, Brazil. ABSTRACT | A 89-year-old Black female with a 6-year do cristalino. A gonioscopia mostrou uma linha de Sampaolesi de history of advanced open-angle glaucoma was referred to the ângulo aberto e depósitos esbranquiçados. O exame de fundo de Glaucoma Service of the Ophthalmology Department - Federal olho revelou disco óptico com escavação total em ambos os olhos University of São Paulo (UNIFESP). Best-corrected visual com atrofia peripapilar. A análise genética para polimorfismos de acuity was 20/400 in the right eye and 20/60 in the left eye. nucleotídeo único do gene semelhante à lysyl oxidase-like 1 ligado Pseudoexfoliation material was observed at the iris border, à síndrome de esfoliação identificou dois desses polimorfismos angle, and the anterior lens surface. Anterior biomicroscopy de nucleotídeo único, rs1048661 e rs216524. revealed exfoliation material forming an evident peripheral Descritores: Síndrome de exfoliação; Grupo com ancestrais do zone and a central disc separated by a clear intermediate continente africano; Síndrome de exfoliação; Gene LOXL-1; Brasil zone on the anterior lens surface OU. Gonioscopy showed an open-angle Sampaolesis’s line and whitish material deposits OU.
    [Show full text]
  • LOXL2 Inhibitors and Breast Cancer Progression
    antioxidants Review LOXL2 Inhibitors and Breast Cancer Progression Sandra Ferreira 1 , Nuno Saraiva 1 , Patrícia Rijo 1,2 and Ana S. Fernandes 1,* 1 CBIOS, Universidade Lusófona’s Research Center for Biosciences & Health Technologies, Campo Grande 376, 1749-024 Lisbon, Portugal; [email protected] (S.F.); [email protected] (N.S.); [email protected] (P.R.) 2 Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal * Correspondence: [email protected]; Tel.: +351-217-515-500 (ext. 627) Abstract: LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression.
    [Show full text]
  • Genetic Association Study of Exfoliation Syndrome Identifies A
    Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci Tin Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, Takanori Mizoguchi, Robert Igo, Aravind Haripriya, Susan Williams, Yury Astakhov, et al. To cite this version: Tin Aung, Mineo Ozaki, Mei Chin Lee, Ursula Schlötzer-Schrehardt, Gudmar Thorleifsson, et al.. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nature Genetics, Nature Publishing Group, 2017, 49 (7), pp.993-1004. 10.1038/ng.3875. pasteur-02003892 HAL Id: pasteur-02003892 https://hal-pasteur.archives-ouvertes.fr/pasteur-02003892 Submitted on 3 Apr 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Archived at the Flinders Academic Commons: http://dspace.flinders.edu.au/dspace/ ‘This is the peer reviewed version of the following article: Aung, T., Ozaki, M., Lee, M. C., Schlotzer-Schrehardt, U., Thorleifsson, G., Mizoguchi, T., . Khor, C. C. (2017). Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet, advance online publication. doi:10.1038/ng.3875 which has been published in final form at http://dx.doi.org/10.1038/ng.3875 © 2017 Nature America, Inc., part of Springer Nature.
    [Show full text]
  • Differential Lysyl Oxidase Like 1 Expression in Pseudoexfoliation Glaucoma Is Orchestrated Via DNA Methylation
    Contents lists available at ScienceDirect Experimental Eye Research journal homepage: www.elsevier.com/locate/yexer Differential Lysyl oxidase like 1 expression in pseudoexfoliation glaucoma is orchestrated via DNA methylation Alison G. Greene a, Sarah B. Eivers a, Fiona McDonnell a,1, Edward W.J. Dervan b, Colm J. O’Brien a,b, Deborah M. Wallace a,* a Clinical Research Centre, School of Medicine, University College Dublin, Ireland b Department of Ophthalmology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland ARTICLE INFO ABSTRACT Keywords: Pseudoexfoliation syndrome (PXF) is the most common cause of secondary open angle glaucoma worldwide. LOXL1 Single nucleotide polymorphisms (SNPs) in the gene Lysyl oxidase like 1 (LOXL1) are strongly associated with Pseudoexfoliation glaucoma the development of pseudoexfoliation glaucoma (PXFG). However, these SNPs are also present in 50–80% of the Methylation general population, suggestive of other factors being involved in the pathogenesis of PXFG. In this study, we Epigenetics aimed to investigate the infuence of epigenetic regulation, specifcally DNA methylation, on LOXL1 expression in PXFG using human tenons fbroblasts (HTFs), aqueous humour and serum samples from donors with and without PXFG. LOXL1 expression in HTFs was measured by qPCR and Western Blotting and LOXL1 concentration in aqueous humour was determined by ELISA. Global DNA methylation levels were quantifed using an ELISA for 5-methylcytosine. MeDIP assays assessed the methylation status of the LOXL1 promoter region. Expression of methylation-associated enzymes (DNMT1, DNMT3a and MeCP2) were determined by qPCR and inhibited by 0.3 μM 5-azacytidine (5-aza). Results showed that LOXL1 expression was signifcantly decreased in PXFG HTFs compared with Control HTFs at gene (Fold change 0.37 0.05, P < 0.01) level and showed a decrease, when ± measured at the protein level (Fold change 0.65 0.42, P 0.22), however this was not found to be signifcant.
    [Show full text]
  • Lysyl Oxidases Regulate Fibrillar Collagen Remodelling in Idiopathic Pulmonary Fibrosis (Doi: 10.1242/Dmm.030114) Gavin Tjin, Eric S
    © 2017. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2017) 10, 1545 doi:10.1242/dmm.033191 CORRECTION Correction: Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis (doi: 10.1242/dmm.030114) Gavin Tjin, Eric S. White, Alen Faiz, Delphine Sicard, Daniel J. Tschumperlin, Annabelle Mahar, Eleanor P. W. Kable and Janette K. Burgess An error was published in Dis. Model. Mech. (2017). 10, 1301-1312 (doi: 10.1242/dmm.030114). A reference was incorrectly cited in the Results section (subsection ‘Inhibition of LO activity reduced TGF-β-induced collagen remodelling in collagen I hydrogels’). The corrected sentence and reference are below. ‘To confirm the role of LO enzymes in fibrillar collagen remodelling, 3D in vitro cell culture experiments using inhibitors of LO activity were performed. β-APN is a non-selective inhibitor of LO activity, whereas Compound A is a specific inhibitor of LOXL2 activity, referred to as PXS-S2A in a recent publication by Chang et al. (2017).’ Chang, J., Lucas, M. C., Leonte, L. E., Garcia-Montolio, M., Singh, L. B., Findlay, A. D., Deodhar, M., Foot, J. S., Jarolimek, W., Timpson, P. et al. (2017). Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer. Oncotarget 8, 26066-26078. http://doi.org/10. 18632/oncotarget.15257. The authors apologise to readers for this error. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
    [Show full text]