Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
Pasutto F, Zenkel M, Hoja U, Berner D, Uebe S, Ferrazzi F, Schoedel J, Liravi P, Ozaki M, Paoli D, Frezzotti P, Mizoguchi T, Nakano S, Kubota T, Manabe S, Salvi E, Manunta P, Cusi D, Gieger C, Wichmann HE, Aung T, Khor CC, Kruse F, Reis A, Schlötzer-Schrehardt U (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 8
Pages Range: 15466
DOI: 10.1038/ncomms15466
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 RXR? (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.
Authors with CRIS profile
Matthias Zenkel
Department of Ophthalmology
Ursula Hoja
Daniel Berner Department of Ophthalmology Steffen Uebe Institute of Human Genetics Fulvia Ferrazzi Institute of Human Genetics Friedrich Kruse Lehrstuhl für Augenheilkunde André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Ursula Schlötzer-Schrehardt Medizinische Fakultät
Daniel Berner Department of Ophthalmology Steffen Uebe Institute of Human Genetics Fulvia Ferrazzi Institute of Human Genetics Friedrich Kruse Lehrstuhl für Augenheilkunde André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Ursula Schlötzer-Schrehardt Medizinische Fakultät
Additional Organisation(s)
Involved external institutions
Mizoguchi Eye Hospital
Japan (JP)
Oita University / 大分大学
Japan (JP)
Hayashi Eye Hospital
Japan (JP)
Università degli studi di Milano
Italy (IT)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Singapore National Eye Centre (SNEC)
Singapore (SG)
Genome Institute of Singapore
Singapore (SG)
Ozaki Eye Hospital
Japan (JP)
Università degli Studi di Siena (UNISI) / University of Siena
Italy (IT)
Università Vita-Salute San Raffaele (UniSR)
Italy (IT)
CNR-ITB
Italy (IT)
Monfalcone Hospital
Italy (IT)
Japan (JP)
Oita University / 大分大学
Japan (JP)
Hayashi Eye Hospital
Japan (JP)
Università degli studi di Milano
Italy (IT)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Singapore National Eye Centre (SNEC)
Singapore (SG)
Genome Institute of Singapore
Singapore (SG)
Ozaki Eye Hospital
Japan (JP)
Università degli Studi di Siena (UNISI) / University of Siena
Italy (IT)
Università Vita-Salute San Raffaele (UniSR)
Italy (IT)
CNR-ITB
Italy (IT)
Monfalcone Hospital
Italy (IT)
How to cite
APA:
Pasutto, F., Zenkel, M., Hoja, U., Berner, D., Uebe, S., Ferrazzi, F.,... Schlötzer-Schrehardt, U. (2017). Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1. Nature Communications, 8, 15466. https://dx.doi.org/10.1038/ncomms15466
MLA:
Pasutto, Francesca, et al. "Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1." Nature Communications 8 (2017): 15466.
BibTeX: Download