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M. Zenkel, F. Pasutto, J. Lampel, F. E. Kruse, U. Schlötzer-Schrehardt; Genotype-Correlated Expression of Lysyl Oxidase-Like 1 (LOXL1) in Patients With Pseudoexfoliation Syndrome/Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5869. doi: https://doi.org/.
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Recently, two non-synonymous single nucleotide polymorphisms (SNPs) in exon 1 of the lysyl oxidase-like 1 (LOXL1) gene were identified, which together conferred a population attributable risk of 99% for pseudoexfoliation (PEX) syndrome/glaucoma. To determine the role of LOXL1 in the pathophysiology of PEX syndrome/ glaucoma, we investigated its expression in anterior segment tissues from PEX and control patients in correlation with the individual SNP genotypes.
Anterior segment tissues from eyes with PEX syndrome with and without glaucoma, and normal and glaucomatous control eyes (n=16 for each group) were analyzed for the expression of LOXL1 using quantitative real-time PCR and Western blotting. PEX patients were classified as early or late stage according to slitlamp findings of PEX material deposits on lens and pupillary margin. The two non-synonymous SNPs, rs1048661 and rs3825942 were genotyped by direct sequencing and correlated to LOXL1 expression levels.
LOXL1 mRNA and protein expression was detected in cornea, trabecular meshwork, iris, lens, and ciliary body of all eyes examined. Genotyping of the two SNPs revealed that all patients of the PEX group and 10/16 (63%) of the control group carried the high risk haplotype (GG). In both PEX and control eyes, the expression of LOXL1 was significantly reduced by 31% per risk G-allele of rs1048661 (p<0.0001). In contrast, rs3825942 alleles or the haplotype formed by both SNPs did not affect LOXL1 levels in any group. In the PEX group, LOXL1 expression was significantly increased in early stages of PEX syndrome (p<0.05), but significantly reduced by 22% (p<0.01) in patients with advanced stages of the disease irrespective of the presence of glaucoma.
In view of the frequent occurrence of the high risk haplotype in the unaffected control group and the differential regulation of LOXL1 in early and late stages of the PEX process, our data suggest that additional genetic or environmental comodulating factors of unidentified nature influence the abnormal matrix metabolism and the phenotypic manifestation of PEX syndrome.
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