Original ArticleMutation in the Gene GUCA1A, Encoding Guanylate Cyclase-Activating Protein 1, Causes Cone, Cone-Rod, and Macular Dystrophy
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
References (40)
- et al.
Localization of a novel X-linked progressive cone dystrophy gene to Xq27evidence for genetic heterogeneity
Am J Hum Genet
(1997) - et al.
Mapping of autosomal dominant cone degeneration to chromosome 17p
Am J Ophthalmol
(1996) - et al.
CNGA3 mutations in hereditary cone photoreceptor disorders
Am J Hum Genet
(2001) - et al.
Guanylate cyclase-activating proteinsstructure, function, and diversity
Biochem Biophys Res Commun
(2004) - et al.
Identification and functional consequences of a new mutation (E155G) in the gene for GCAP1 that causes autosomal dominant cone dystrophy
Am J Hum Genet
(2001) - et al.
Constitutive activation of photoreceptor guanylate cyclase by Y99C mutant of GCAP-1Possible role in causing human autosomal dominant cone degeneration
J Biol Chem
(1998) - et al.
The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator
Neuron
(1994) - et al.
Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein
Neuron
(1994) - et al.
Cloning, sequencing, and expression of a 24-kDa Ca(2+)-binding protein activating photoreceptor guanylyl cyclase
J Biol Chem
(1995) - et al.
Ultrastructural localization of retinal guanylate cyclase in human and monkey retinas
Exp Eye Res
(1994)
Detailed localization of photoreceptor guanylate cyclase activating protein-1 and -2 in mammalian retinas using light and electron microscopy
Exp Eye Res
The synaptic complex of cones in the fovea and in the periphery of the macaque monkey retina
Vision Res
Characterization of a human fovea cDNA library and regional differential gene expression in the human retina
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
Cited by (44)
Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes
2024, Progress in Retinal and Eye ResearchTefluthrin induced toxicities in zebrafish: Focusing on enantioselectivity
2023, Pesticide Biochemistry and PhysiologyClinical vision and molecular loss: Integrating visual psychophysics with molecular genetics reveals key details of normal and abnormal visual processing
2021, Progress in Retinal and Eye ResearchA G86R mutation in the calcium-sensor protein GCAP1 alters regulation of retinal guanylyl cyclase and causes dominant cone-rod degeneration
2019, Journal of Biological ChemistryCitation 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).
GUCA1A mutation causes maculopathy in a five-generation family with a wide spectrum of severity
2017, Genetics in MedicineCitation 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
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.