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.
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, E. Salvi, P. Manunta, D. Cusi, C. Gieger, H. Wichmann, T. Aung, C.C. Khor, F.E. Kruse, A. Reis, U. Schlötzer Schrehardt. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8(2017 May 23), pp. 15466.1-15466.16. [10.1038/ncomms15466]
Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
E. Salvi;
2017
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.File | Dimensione | Formato | |
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