Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome.

Variants in LOXL1 are significantly associated with exfoliation syndrome (XFS), however the impact of the associated variants on disease development is not yet understood. Initially the associated missense changes, R141L and G153D, were considered to be pathogenic alleles. Flipping of the risk allele in certain populations for both missense variants provided strong evidence that these missense changes are not biologically significant and suggest that other LOXL1 variant(s), in linkage disequilibrium with these missense variants, predispose to exfoliation syndrome by affecting gene expression or protein function. Several lines of evidence support dysregulation of LOXL1 gene expression as a contributing factor to disease development. First, in the German population the R141L (rs1048661) risk allele reduced LOXL1 expression by 20%. Second, haplotype analysis identified a risk haplotype that includes including R141L, G153D, as well as a LOXL1 promoter region variant previously shown to reduce gene expression (rs16958477). Third, the LOXL1 risk haplotype influences gene expression induced by disease-associated factors TGF-B1, oxidative stress, UV light and hypoxia. Finally, a LOXL1 null mouse has some features of XFS suggesting that decreased enzyme activity contributes to predisposition to the disease. Collectively, these results suggest that dysregulation of LOXL1 expression is a contributing factor to exfoliation disease development.