title: GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.
abstract: The aim of this study was to investigate the genetic basis and pathogenic mechanism of variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in a five-generation family.
  
  
  
  Clinical characterizations, whole-exome sequencing, and genome-wide linkage analysis were carried out on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations.
  
  
  
  A novel mutation, GUCA1A p.R120L, was identified in the family and predicted to alter the tertiary structure of guanylyl cyclase-activating protein 1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium, together with atrophies of retinal vessels and choriocapillaris. Those phenotypes could not be fully rescued by exogenous wild-type GUCA1A, suggesting a likely gain-of-function mechanism for p.R120L. GUCA1A p.D100E, another mutation previously implicated in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative effect.
  
  
  
  We conclude that GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities.Genet Med advance online publication 26 January 2017.
authors.affiliation: Department of Ophthalmology and Vision Science, Eye &ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.|Key Laboratory of Myopia of State Health Ministry (Fudan University) and Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China.
authors.forename: Xunlun
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhuang
authors.affiliation: Department of Ophthalmology, Children's Hospital of Zhengzhou, Zhengzhou, China.
authors.forename: Xiantao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Guohua
authors.identifier: 0000-0002-0287-5068
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Xun
authors.identifier: 0000-0001-5088-5917
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Guofu
authors.identifier: 0000-0003-0398-2612
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Yan
authors.identifier: 0000-0002-6442-561X
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Yingjie
authors.identifier: 0000-0001-5455-7363
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Qingshun
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Research Center, Eye &ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Ophthalmology and Vision Science, Eye &ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.|Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.|Key Laboratory of Myopia of State Health Ministry (Fudan University) and Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.|Department of Ophthalmology, Children's Hospital of Zhengzhou, Zhengzhou, China.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China.
authors.forename: Chen
authors.identifier: 0000-0003-1373-7637
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000818:Animals; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D051604:Guanylate Cyclase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000073359:Exome Sequencing; D015027:Zebrafish
chemical_list: C496736:GUCA1A protein, human; D051604:Guanylate Cyclase-Activating Proteins