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

Journal article


Publication Details

Author(s): 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
Journal: Nature Communications
Publication year: 2017
Volume: 8
Pages range: 15466
ISSN: 2041-1723


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.



FAU Authors / FAU Editors

Berner, Daniel
Augenklinik
Ferrazzi, Fulvia Dr.
Humangenetisches Institut
Hoja, Ursula Dr.
Sonderforschungsbereich 796 (mit integriertem Graduiertenkolleg) Steuerungsmechanismen mikrobieller Effektoren in Wirtszellen
Kruse, Friedrich Prof. Dr.
Lehrstuhl für Augenheilkunde
Schlötzer-Schrehardt, Ursula apl. Prof. Dr.
Medizinische Fakultät
Uebe, Steffen Dr. rer. nat.
Humangenetisches Institut
Zenkel, Matthias Dr. rer. nat.
Augenklinik


External institutions with authors

CNR-ITB
Genome Institute of Singapore
Hayashi Eye Hospital
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU)
Mizoguchi Eye Hospital
Monfalcone Hospital
Oita University / 大分大学
Ozaki Eye Hospital
Singapore National Eye Centre (SNEC)
Università degli studi di Milano
Università degli Studi di Siena (UNISI) / University of Siena
Università Vita-Salute San Raffaele (UniSR)


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: 

Last updated on 2018-08-10 at 08:26