Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

APLP2 regulates refractive error and myopia development in mice and humans

Tkatchenko, Andrei V., Tkatchenko, Tatiana V., Guggenheim, Jeremy Andrew, Verhoeven, Virginie J. M., Hysi, Pirro G., Wojciechowski, Robert, Singh, Pawan Kumar, Kumar, Ashok, Thinakaran, Gopal and Williams, Cathy 2015. APLP2 regulates refractive error and myopia development in mice and humans. PLoS Genetics 11 (8) , e1005432. 10.1371/journal.pgen.1005432

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (3MB) | Preview

Abstract

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Optometry and Vision Sciences
Subjects: R Medicine > RE Ophthalmology
Publisher: Public Library of Science
ISSN: 1553-7404
Funders: MRC, Wellcome Trust and others
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 7 July 2015
Last Modified: 11 Mar 2019 13:28
URI: http://orca.cf.ac.uk/id/eprint/78721

Citation Data

Cited 24 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics