Abstract
Purpose :
To investigate the genetic basis and pathogenic mechanism for a five-generation family affected with variable maculopathies ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD).
Methods :
Clinical characterizations, whole exome sequencing and genome-wide linkage analysis were applied 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 GCAP1, 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 (RPE), together with atrophies of retinal vessels and choroicapillaris. 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 RPE and photoreceptors in zebrafish, but likely via a dominant negative effect.
Conclusions :
We conclude that GUCA1A mutations could cause significant variability of maculopathies, including CACD, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.