PUBLICATION

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

Authors
Chen, X., Sheng, X., Zhuang, W., Sun, X., Liu, G., Shi, X., Huang, G., Mei, Y., Li, Y., Pan, X., Liu, Y., Li, Z., Zhao, Q., Yan, B., Zhao, C.
ID
ZDB-PUB-170127-1
Date
2017
Source
Genetics in medicine : official journal of the American College of Medical Genetics   19(8): 945-954 (Journal)
Registered Authors
Zhao, Qingshun
Keywords
GUCA1A, maculopathy, medical genetics, ophthalmology, pathogenic mechanism
MeSH Terms
  • Adult
  • Animals
  • Family Health
  • Female
  • Genetic Linkage
  • Guanylate Cyclase-Activating Proteins/genetics*
  • Humans
  • Male
  • Mutation*
  • Pedigree
  • Retinal Degeneration/genetics*
  • Retinal Degeneration/pathology
  • Retinal Degeneration/physiopathology
  • Whole Exome Sequencing
  • Zebrafish
PubMed
28125083 Full text @ Genet. Med.
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 2017Genetics in Medicine (2017); doi:10.1038/gim.2016.217.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping