Mutation in the Gene GUCA1A, Encoding Guanylate Cyclase-Activating Protein 1, Causes Cone, Cone-Rod, and Macular Dystrophy

doi:10.1016/j.ophtha.2005.02.024

Ophthalmology

Volume 112, Issue 8, August 2005, Pages 1442-1447

https://doi.org/10.1016/j.ophtha.2005.02.024 Get rights and content

Purpose

To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 4-generation family and to examine the phenotype and the degree of intrafamilial variability.

Design

Prospective case series.

Participants

Six affected individuals from a nonconsanguineous British family.

Methods

Detailed ophthalmologic examination, color fundus photography, autofluorescence imaging, and electrophysiologic assessment were performed. Blood samples were taken for DNA extraction, and mutation screening of GUCA1A, the gene encoding guanylate cyclase-activating protein 1 (GCAP1), was undertaken.

Results

All affected subjects complained of mild photophobia and reduced central and color vision. Onset was between the third and fifth decade, with subsequent gradual deterioration of visual acuity and color vision. Visual acuity ranged between 6/9 and counting fingers. Color vision was either absent or markedly reduced along all 3 color axes. A range of macular appearances was seen, varying from mild retinal pigment epithelial disturbance to extensive atrophy. Electrophysiologic testing revealed a range of electrophysiologic abnormalities: isolated cone electroretinography abnormalities, reduced cone and rod responses (with cone loss greater than rod), and isolated macular dysfunction. The 4 coding exons of GUCA1A were screened for mutations in affected and unaffected family members. A single transition, A319G, causing a nonconservative missense substitution, Tyr99Cys, segregated uniquely in all affected subjects.

Conclusions

The Tyr99Cys GUCA1A mutation has been previously shown to cause autosomal dominant progressive cone dystrophy. This is the first report of this mutation also causing both cone-rod dystrophy and isolated macular dysfunction. The phenotypic variation described here exemplifies the intrafamilial heterogeneity of retinal dysfunction that can be observed in persons harboring the same mutation and chromosomal segment.

Section snippets

Patients and Methods

A 4-generation British family with an autosomal dominant retinal dystrophy was ascertained. After informed consent was obtained, blood samples from affected and unaffected family members were taken for DNA extraction and subsequent mutation screening of GUCA1A. The protocol of the study adhered to the provisions of the Declaration of Helsinki and was approved by the local ethics committee.

Results

Six affected and 6 unaffected individuals of a nonconsanguineous 4-generation British family were assessed (Fig 1). There was evidence of male-to-male transmission, with males and females equally affected, thereby suggesting autosomal dominant inheritance. All affected subjects complained of mild photophobia and reduced central and color vision. Onset of visual symptoms was between the third and fifth decade, with subsequent gradual deterioration of visual acuity and color vision. Only 1

Discussion

Isolated cone dysfunction has, to date, been the phenotype consistently associated with the GCAP1 missense mutations, Tyr99Cys (Y99C),4, 9 Glu155Gly (E155G),¹⁰ and Ile143AsnThr.8, 11 Pro50Leu has been the only GCAP1 mutation associated with a variable phenotype, ranging from pure loss of cone function to rod-cone dystrophy.⁹ We describe the first report of the Y99C mutation associated with intrafamilial phenotypic variability, including isolated macular dysfunction, cone dystrophy, and cone-rod

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A G86R mutation in the calcium-sensor protein GCAP1 alters regulation of retinal guanylyl cyclase and causes dominant cone-rod degeneration
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Citation Excerpt :
The clinical spectrum due to GUCA1A mutations thus includes macular degeneration, and retina-wide cone and rod dysfunction where cone disease may be equal to or greater than rod disease. The majority of the known examples of retinopathies linked to the GUCA1A gene originate from mutations in GCAP1 EF-hand motifs that disable Ca2+ binding in EF-hands 3 and 4 (28–40, 58, 59). Reduction of Ca2+ affinity in these EF-hands leads to overly active production of cGMP at normal free Ca2+ concentrations in the dark, increasing the fraction of the open cGMP-gated channels and accelerating the influx of Ca2+ into photoreceptor outer segment (17, 18, 41).
The guanylyl cyclase-activating protein, GCAP1, activates photoreceptor membrane guanylyl cyclase (RetGC) in the light, when free Ca²⁺ concentrations decline, and decelerates the cyclase in the dark, when Ca²⁺ concentrations rise. Here, we report a novel mutation, G86R, in the GCAP1 (GUCA1A) gene in a family with a dominant retinopathy. The G86R substitution in a “hinge” region connecting EF-hand domains 2 and 3 in GCAP1 strongly interfered with its Ca²⁺-dependent activator-to-inhibitor conformational transition. The G86R-GCAP1 variant activated RetGC at low Ca²⁺ concentrations with higher affinity than did the WT GCAP1, but failed to decelerate the cyclase at the Ca²⁺ concentrations characteristic of dark-adapted photoreceptors. Ca²⁺-dependent increase in Trp⁹⁴ fluorescence, indicative of the GCAP1 transition to its RetGC inhibiting state, was suppressed and shifted to a higher Ca²⁺ range. Conformational changes in G86R GCAP1 detectable by isothermal titration calorimetry (ITC) also became less sensitive to Ca²⁺, and the dose dependence of the G86R GCAP1–RetGC1 complex inhibition by retinal degeneration 3 (RD3) protein was shifted toward higher than normal concentrations. Our results indicate that the flexibility of the hinge region between EF-hands 2 and 3 is required for placing GCAP1-regulated Ca²⁺ sensitivity of the cyclase within the physiological range of intracellular Ca²⁺ at the expense of reducing GCAP1 affinity for the target enzyme. The disease-linked mutation of the hinge Gly⁸⁶, leading to abnormally high affinity for the target enzyme and reduced Ca²⁺ sensitivity of GCAP1, is predicted to abnormally elevate cGMP production and Ca²⁺ influx in photoreceptors in the dark.
GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity
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Citation Excerpt :
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
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
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Prospective cross-sectional study at an academic referral center.
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View all citing articles on Scopus

Manuscript no. 2004-364.

Supported by grants from the British Retinitis Pigmentosa Society, London, United Kingdom, and the Guide Dogs for the Blind Association, Reading, United Kingdom.

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Original ArticleMutation in the Gene GUCA1A, Encoding Guanylate Cyclase-Activating Protein 1, Causes Cone, Cone-Rod, and Macular Dystrophy

Purpose

Design

Participants

Methods

Results

Conclusions

Section snippets

Patients and Methods

Results

Discussion

Am J Hum Genet

Am J Ophthalmol

Am J Hum Genet

Biochem Biophys Res Commun

Am J Hum Genet

J Biol Chem

Neuron

Neuron

J Biol Chem

Exp Eye Res

Exp Eye Res

Vision Res

Genomics

Retinal cone dysfunction and mental retardation associated with a de novo balanced translocation 1;6(q44;q27)

Ophthal Paediatr Genet

A mutation in guanylate cyclase activator 1A (GUCA1A) in autosomal dominant cone dystrophy mapping to a new locus on chromosome 6p21.1

Hum Mol Genet

Mutations in the RPGR gene cause X-linked cone dystrophy

Hum Mol Genet

Progressive cone dystrophy associated with mutation in CNGB3

Invest Ophthalmol Vis Sci

Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1

Arch Ophthalmol

A novel mutation (I143NT) in guanylate cyclase-activating protein 1 (GCAP1) associated with autosomal dominant cone degeneration

Invest Ophthalmol Vis Sci

The destabilization of human GCAP1 by a proline to leucine mutation might cause cone-rod dystrophy

Hum Mol Genet

Original Article
Mutation in the Gene GUCA1A, Encoding Guanylate Cyclase-Activating Protein 1, Causes Cone, Cone-Rod, and Macular Dystrophy