title: Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy.
abstract: BACKGROUND
  Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe inherited retinal disorder characterized by incomplete retinal vascular development and neovascularization. At least five genes have been reported to be associated with FEVR, including NDP, LRP5, FZD4, TSPAN12, and ZNF408. Recently reported data showed that mutations in the KIF11 gene can also lead to FEVR conditions. Previous studies suggested that known mutations only explain approximately 40-60% of FEVR cases in different populations.
  
  
  OBJECTIVE
  To investigate the causative genetic mutations in four Indian families with FEVR.
  
  
  METHODS
  Whole exome sequencing was carried out to analyze the genomic DNA samples from the four FEVR proband patients and Sanger sequencing was utilized to verify all identified polymorphisms. A luciferase assay was used to test the mutant protein activity.
  
  
  RESULTS
  We identified four novel LRP5 missense mutations in these FEVR families: c.C1042T (p.R348W), c.G1141A (p.D381N), c.C1870T (p.R624W), and c.A4550G (p.Y1517C). The luciferase assay demonstrated that all four of these LRP5 mutations led to significant reduction of enzymatic activity with response to NORRIN, suggesting that they are pathogenic.
  
  
  CONCLUSIONS
  Our findings expand the mutational spectrum of FEVR in the Indian population and provide some guidelines in clinical diagnosis.
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .
authors.forename: Yeming
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Shujin
authors.initials: S
authors.lastname: Li
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Tai
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .
authors.forename: Lulin
authors.initials: L
authors.lastname: Huang
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Yanan
authors.initials: Y
authors.lastname: Di
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Chao
authors.initials: C
authors.lastname: Qu
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .
authors.forename: Guolin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 5 Retina-Vitreous Services, Aravind Eye Hospital , Madurai, Tamil Nadu, India .
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Kim
authors.affiliation: 6 Department of Genetics, Aravind Medical Research Foundation, Aravind Eye Hospital , Madurai, Tamil Nadu, India .
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
authors.affiliation: 1 Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu, China .|2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: 2 Sichuan Provincial Key Laboratory for Human Disease Gene Study, School of Medicine, Hospital of the University of Electronic Science and Technology of China , and Sichuan Provincial People's Hospital, Chengdu, China .|3 Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital , Chengdu, Sichuan, China .|4 Key Laboratory for NeuroInformation of Ministry of Education and Medical Information Center, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan, China .|7 Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital , Chengdu, Sichuan, China .
authors.forename: Xianjun
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D015785:Eye Diseases, Hereditary; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007194:India; D007231:Infant, Newborn; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism
chemical_list: C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5