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

Francesca Pasutto, Matthias Zenkel, Ursula Hoja, Daniel Berner, Steffen Uebe, Fulvia Ferrazzi, Johannes Schödel, Panah Liravi, Mineo Ozaki, Daniela Paoli, Paolo Frezzotti, Takanori Mizoguchi, Satoko Nakano, Toshiaki Kubota, Shinichi Manabe, Erika Salvi, Paolo Manunta, Daniele Cusi, Christian Gieger, Heinz-Erich Wichmann, Tin Aung, Chiea Chuen Khor, Friedrich E. Kruse, André Reis and Ursula Schlötzer-Schrehardt ()
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Francesca Pasutto: Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Matthias Zenkel: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Ursula Hoja: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Daniel Berner: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Steffen Uebe: Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Fulvia Ferrazzi: Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Johannes Schödel: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Panah Liravi: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Mineo Ozaki: Ozaki Eye Hospital
Daniela Paoli: Ospedale Monfalcone, Centro Glaucomi, Via Galvani 1, 34074 Monfalcone, Italy
Paolo Frezzotti: Ophthalmology Unit, Surgery and Neuroscience, University of Siena
Takanori Mizoguchi: Mizoguchi Eye Clinic
Satoko Nakano: Oita University, Faculty of Medicine
Toshiaki Kubota: Oita University, Faculty of Medicine
Shinichi Manabe: Hayashi Eye Hospital
Erika Salvi: University of Milano
Paolo Manunta: University Vita-Salute San Raffaele
Daniele Cusi: Institute of Biomedical Technologies, National Research Centre (ITB-CNR)
Christian Gieger: Institute of Epidemiology, Helmholtz Center Munich
Heinz-Erich Wichmann: Institute of Epidemiology, Helmholtz Center Munich
Tin Aung: Singapore Eye Research Institute, Singapore National Eye Center
Friedrich E. Kruse: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
André Reis: Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Ursula Schlötzer-Schrehardt: Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15466

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