Identification of <em>LRP5 </em>mutations in families with familial exudative vitreoretinopathy

Liu Yuqing, Zhu Xiong, Li Shujin, Yang Yeming, Yang Mu, Zhao Peiquan, Zhu Xianjun

doi:10.16288/j.yczz.16-339

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Hereditas(Beijing) >

2017 , Vol. 39 >Issue 3: 241 - 249

DOI: https://doi.org/10.16288/j.yczz.16-339

Research Articles

Identification of LRP5 mutations in families with familial exudative vitreoretinopathy

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1. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu 610072, China;
2. Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China;
3. Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu 610212 China;
4. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610042, China

Received date: 2016-10-16

Revised date: 2017-01-18

Online published: 2017-02-23

Supported by

Supported by the National Natural Science Foundation of China (Nos; 81470668, 81271007) and Sichuan Science and Technology Department project (Nos; 2014JQ0023, 2016TD0009)

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Abstract

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease characterized by defects in the development of periphery retinal vessels. However, the clinical phenotypes of FEVR vary widely from asymptomatic to complete blindness. We analyzed patients from three Chinese families and one sporadic patient with FEVR to investigate the clinical features and disease-causing mutations. Ocular phenotypes included increased ramification of the peripheral retinal vessels, a peripheral avascular zone, inferotemporal dragging of the optic disc and macula, and retinal folds. Peripheral blood DNA samples were obtained from patients with FEVR and their family members. Primers were designed to amplify the coding exons and adjacent intronic regions of the FEVR-causing genes FZD4, LRP5, NDP and TSPAN12. By polymerase chain reactions, each amplicon was subjected to direct Sanger sequencing analysis. Potential pathogenic changes of the sequence variants were analyzed by the orthologous protein sequence alignment and computational prediction software. We identified five LRP5 mutations: three novel heterozygous mutations-p.M181R, p.R399S and p.G503R and two known mutations that were never reported in FEVR patients: p.R494Q and p.G876S. All five mutations involved highly conserved residues and were predicted to be damaging by SIFT and PolyPhen-2. None was present in 500 normal individuals. To assess the pathogenesis of these mutations, wild-type and all five mutant LRP5 proteins were assayed for the ability to activate the Norrin/β-catenin pathway by established luciferase reporter assays, and all mutants failed to activate the pathway. This study extends the genetic database of the FEVR disease in China and provides a basis for molecular diagnosis of the disease.

Key words： familial exudative vitreoretinopathy (FEVR); low density lipoprotein receptor related protein-5 (LRP5); gene mutation

Cite this article

Liu Yuqing, Zhu Xiong, Li Shujin, Yang Yeming, Yang Mu, Zhao Peiquan, Zhu Xianjun . Identification of LRP5 mutations in families with familial exudative vitreoretinopathy[J]. Hereditas(Beijing), 2017 , 39(3) : 241 -249 . DOI: 10.16288/j.yczz.16-339

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