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Abstract
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
Highlights
Inherited retinal degenerations (IRDs) include a group of diverse retinal degenerative diseases presenting both genetic and clinical heterogeneities
guanylyl cyclase-activating protein 1 (GCAP1) is a critical component in the phototransduction cascade, which acts as a calcium sensor in the recovery of photoreceptors from photon capture by regulating the retinal guanylate cyclase 1 –medicated cyclic guanosine monophosphate production in a calciumsensing manner.[5,6]
In this study we found a novel GUCA1A mutation to be disease causative in a five-generation family affected with variable maculopathies ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy (CACD)
Summary
Inherited retinal degenerations (IRDs) include a group of diverse retinal degenerative diseases presenting both genetic and clinical heterogeneities. To date, according to RetNet (https://sph.uth.edu/retnet/), 293 loci (including 256 identified genes) have been associated with IRDs. Among the 256 identified genes, the guanylate cyclase activator 1A gene (GUCA1A; MIM 600364) has been implicated in dominant cone dystrophy, cone-rod dystrophy, and macular dystrophy.[1,2,3] GUCA1A, located in 6p21.1, encodes the guanylyl cyclase-activating protein 1 (GCAP1), a photoreceptor-specific protein with more expression in the inner segment/outer segment (OS) layer of cones than rods in mammals.[4] GCAP1 is a critical component in the phototransduction cascade, which acts as a calcium sensor in the recovery of photoreceptors from photon capture by regulating the retinal guanylate cyclase 1 (retGC1) –medicated cyclic guanosine monophosphate production in a calciumsensing manner.[5,6] RetGC1 is encoded by the guanylate cyclase 2D gene (GUCY2D; MIM 600179). The important roles of GCAP1 and retGC1 in regulating hemostasis of calcium and cyclic guanosine monophosphate in photoreceptors have been well addressed
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