title: Novel mutations in the TSPAN12 gene in Chinese patients with familial exudative vitreoretinopathy.
abstract: OBJECTIVE
  Familial exudative vitreoretinopathy (FEVR) is a group of inherited blinding eye diseases characterized by defects in the development of the retinal vessels. Recent studies have identified genetic variants in tetraspanin 12 (TSPAN12) as a cause of FEVR. The purpose of this study was to identify novel TSPAN12 mutations in Chinese patients with FEVR and to describe the associated phenotypes.
  
  
  METHODS
  Mutation screening was performed by directly sequencing PCR products of genomic DNA with primers designed to amplify the seven coding exons and adjacent intronic regions of the FEVR-causing gene TSPAN12. Clinical phenotypes of the patients with TSPAN12 mutations were documented. Wild-type and mutant TSPAN12 proteins were assayed for the Norrin-β-catenin signaling pathway with luciferase reporter assays.
  
  
  RESULTS
  Three novel heterozygous mutations in TSPAN12 were identified: c.566G>A (p.C189Y), c.177delC (p.Y59fsX67), and c.C254T (p.T85M). All three mutations involved highly conserved residues and were not present in 200 normal individuals. 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. The probands showed relatively severe retinopathy, whereas the other family members were often asymptomatic. In SuperTopFlash (STF) cell line transfection studies, C189Y, Y59fsX67, and T85M mutants failed to induce luciferase reporter activity in response to Norrin.
  
  
  CONCLUSIONS
  We found three novel TSPAN12 mutations in Chinese patients with autosomal dominant FEVR, and suggest that TSPAN12 mutations cause FEVR. The phenotypes associated with the TSPAN12 mutations showed extensive variation in disease severity among members of the same family, which implied the complexity of FEVR mutations and phenotypes.
authors.affiliation: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China ; Chengdu Institute of Biology, Chinese Academy of Sciences and Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China.
authors.forename: Lulin
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fei
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China ; Chengdu Institute of Biology, Chinese Academy of Sciences and Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; Chengdu Institute of Biology, Chinese Academy of Sciences and Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China.
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Tai
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Ma
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gong
authors.affiliation: Medicine Program, Geisel School of Medicine, Dartmouth College, Hanover, NH.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurology, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zang
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China ; Chengdu Institute of Biology, Chinese Academy of Sciences and Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Peiquan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Sichuan Provincial Key Laboratory for Human Disease Gene Study, University of electronic science and technology affiliated hospital & Sichuan Provincial People's Hospital, Sichuan, China ; School of Medicine, University of Electronic Science and Technology, Sichuan, China ; Chengdu Institute of Biology, Chinese Academy of Sciences and Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D044466:Asian People; D001483:Base Sequence; D001681:Biological Assay; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005091:Exons; D015785:Eye Diseases, Hereditary; D005136:Eye Proteins / Q000235:genetics; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D012720:Severity of Illness Index; D059470:Tetraspanins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D005136:Eye Proteins; C081848:NDP protein, human; D009419:Nerve Tissue Proteins; C545100:TSPAN12 protein, human; D059470:Tetraspanins; D051176:beta Catenin