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GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity.

Genet. Med.2017 Aug;19(8):945-954. Epub 2017 Jan 26
Xue Chen 1 , Xunlun Sheng 2 , Wenjuan Zhuang 2 , Xiantao Sun 3 , Guohua Liu 4 , Xun Shi 5 , Guofu Huang 5 , Yan Mei 5 , Yingjie Li 5 , Xinyuan Pan 6 , Yani Liu 2 , Zili Li 2 , Qingshun Zhao 7 , Biao Yan 8 , Chen Zhao 9
Xue Chen 1 , Xunlun Sheng 2 , Wenjuan Zhuang 2 , Xiantao Sun 3 , Guohua Liu 4 , Xun Shi 5 , Guofu Huang 5 , Yan Mei 5 , Yingjie Li 5 , Xinyuan Pan 6 , Yani Liu 2 , Zili Li 2 , Qingshun Zhao 7 , Biao Yan 8 , Chen Zhao 9
+ et al

[No authors listed]

Author information
  • 1 Key Laboratory of Myopia of State Health Ministry (Fudan University) and Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
  • 2 Department of Ophthalmology, Ningxia Eye Hospital, People Hospital of Ningxia Hui Autonomous Region (First Affiliated Hospital of Northwest University for Nationalities), Yinchuan, China.
  • 3 Department of Ophthalmology, Children's Hospital of Zhengzhou, Zhengzhou, China.
  • 4 Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China.
  • 5 Department of Ophthalmology, The Third Affiliated Hospital of Nanchang University, Nanchang, China.
  • 6 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.
  • 7 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
  • 8 Research Center, Eye &ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
  • 9 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China.

摘要


PURPOSE: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. METHODS: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. RESULTS: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. CONCLUSION: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.