Published online before print October 30, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080535

Accepted for publication August 28, 2008.

Article

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

Ursula Schlötzer-Schrehardt^*@, Francesca Pasutto, Pascal Sommer, Ian Hornstra, Friedrich E. Kruse^*, Gottfried O.H. Naumann^*, André Reis, and Matthias Zenkel^*

From the Department of Ophthalmology* and the Institute of Human Genetics, University of Erlangen-Nürnberg, Erlangen, Germany; the Institut de Biologie et de Chimie des Proteines, Universite Claude Bernard Lyon, Lyon, France; and the Division of Dermatology, Washington University School of Medicine, Saint Louis, Missouri

^@ To whom correspondence should be addressed. E-mail: ursula.schloetzer-schrehardt{at}uk-erlangen.de.

	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 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.