Abstract
Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.
Highlights
Lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date
We show that increased transcriptional activity at the risk sequence is associated with reduced binding of retinoid X receptor alpha (RXRa) and with enhanced alternative splicing coupled with nonsense-mediated decay (NMD), which altogether reduces the levels of lysyl oxidase-like 1 (LOXL1) mRNA in cells and tissues of risk allele carriers, underlining a functional link between LOXL1 genetic variation and regulation of LOXL1 expression
Because mRNA expression of lysyl oxidases is known to be regulated by retinoic acid[38], we further focused on the nuclear retinoic acid receptor RXRa, which mediates retinoic acid-induced gene activation
Summary
Lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. We find that the rs11638944:C4G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRa (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression. We show that increased transcriptional activity at the risk sequence is associated with reduced binding of retinoid X receptor alpha (RXRa) and with enhanced alternative splicing coupled with nonsense-mediated decay (NMD), which altogether reduces the levels of LOXL1 mRNA in cells and tissues of risk allele carriers, underlining a functional link between LOXL1 genetic variation and regulation of LOXL1 expression
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