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Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
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Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
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Journal Article
Pseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
2017
Overview
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.
LOXL1
is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto
et al
., find intronic
LOXL1
risk variants influence transcription factor binding and alternative splicing of
LOXL1
in affected tissues reducing levels of
LOXL1
mRNA.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 38
/ 38/88
/ 45
/ 45/43
/ Aged
/ Alleles
/ Amino Acid Oxidoreductases - genetics
/ Disease
/ Exfoliation Syndrome - diagnosis
/ Exfoliation Syndrome - genetics
/ Female
/ Genetic Predisposition to Disease
/ Genome-Wide Association Study
/ Genomes
/ Genotype
/ Germany
/ Glaucoma
/ Humanities and Social Sciences
/ Humans
/ Introns
/ Italy
/ Japan
/ Male
/ Polymorphism, Single Nucleotide
/ Proteins
/ Retinoid X Receptor alpha - genetics
/ Science
