Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1

F Pasutto, M Zenkel, U Hoja, D Berner, S Uebe, F Ferrazzi, J Schödel, P Liravi, M Ozaki, D Paoli, P Frezzotti, T Mizoguchi, S Nakano, T Kubota, S Manabe, Erika Salvi, P Manunta, D Cusi, C Gieger, HE WichmannT Aung, CC Khor, FE Kruse, A Reis, U Schlötzer-Schrehardt

Research output: Contribution to journalArticlepeer-review

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. © The Author(s) 2017.
Original languageEnglish
Article number15466
JournalNature Communications
Volume8
Issue number2
DOIs
Publication statusPublished - 2017

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