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U. Schlotzer-Schrehardt, P. Sommer, C. Reynaud, F. Pasutto, C. Rummelt, F. E. Kruse, M. Zenkel; The Role of Lysyl Oxidase-Like 1 (LOXL1) in the Pathophysiology of Pseudoexfoliation Syndrome. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5121.
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Common single nucleotide polymorphisms (SNPs) in the lysyl oxidase-like 1 (LOXL1) gene, coding for a key enzyme in elastic fiber homeostasis, have been recently identified as powerful genetic risk factors for pseudoexfoliation (PEX) syndrome and glaucoma. To determine the role of LOXL1 in the pathophysiology of PEX, we investigated the expression and localization of LOXL1 in ocular and extraocular tissues of PEX and control patients.
Fifteen eyes with PEX syndrome/glaucoma of various disease stages and 15 age-matched control eyes, either obtained at autopsy or surgical enucleation, as well as extraocular tissues from 8 organ donors with and without PEX were used. Semiquantitative immunohistochemical analysis was performed on the light and electron microscopic level using well-characterized antibodies against LOXL1 pro-peptide and active enzyme, LOX, and various elastic fiber components. The findings were correlated with the patients’ individual genotypes.
Cellular expression of LOX and LOXL1 protein was detected in virtually all ocular tissues of both PEX and control patients. The risk allele of SNP rs1048661, but not of rs3825942, was associated with lower levels of LOXL1 in ocular tissues. Whereas LOX was equally expressed in PEX and control tissues, cellular expression of LOXL1 was either markedly increased in early stages or decreased in advanced stages of PEX as compared to controls. Moreover, LOXL1 was found to be a major component of PEX material in all intra- and extraocular locations, labelling both microfibrils and mature PEX fibrils in close association to cellular surfaces. Immunopositivity for the inactive pro-enzyme was more pronounced than that for the active enzyme and could be completely abolished by pre-adsorption of antibodies with LOXL1 peptide. LOXL1 staining of PEX fibrils co-localized with fibrillin-1, tropoelastin, LTBP-1/2, fibulin-2/3/5, emilin, clusterin, and vitronectin in double labelling experiments.
These data suggest that the genetic alterations in the LOXL1 gene could not only affect the expression, but also the activity of LOXL1 through modifications of substrate targeting or impaired cleavage of the pro-enzyme, which, in cooperation with additional pathophysiologic factors, may lead to abnormal aggregation of elastic fiber components into the characteristic PEX material.
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