Affinage

GUCY2D

Retinal guanylyl cyclase 1 · UniProt Q02846

Length
1103 aa
Mass
120.1 kDa
Annotated
2026-04-28
93 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GUCY2D encodes retinal guanylyl cyclase 1 (RetGC1/ROS-GC1), a photoreceptor-specific membrane guanylyl cyclase that synthesizes cGMP from GTP and is essential for phototransduction recovery. Its catalytic activity requires homodimerization via an α-helical coiled-coil dimerization domain and is stimulated at low Ca²⁺ by guanylyl cyclase-activating proteins (GCAP1 and GCAP2) binding to distinct juxtamembrane and C-terminal regulatory modules, with additional modulation by neurocalcin, S100B, RD3 (a high-affinity allosteric inhibitor), and bicarbonate (PMID:7777544, PMID:10504230, PMID:21928830, PMID:26858600). Recessive loss-of-function mutations in the catalytic domain cause Leber congenital amaurosis type 1 (LCA1) by abolishing cGMP synthesis, whereas dominant gain-of-function mutations at Arg838 in the dimerization domain cause cone-rod dystrophy (CORD6) by shifting GCAP-mediated Ca²⁺-sensitive feedback so that cGMP overproduction persists at elevated Ca²⁺, triggering photoreceptor degeneration through a GCAP-dependent mechanism (PMID:9618177, PMID:11328726, PMID:29440533, PMID:33109612). Suppression of aberrant cGMP production by an engineered inhibitor rescues photoreceptor degeneration in a CORD6 mouse model, confirming that dysregulated cyclase output is the proximal cause of disease (PMID:42045071).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    Establishing RetGC1 as a Ca²⁺-sensitive guanylyl cyclase answered the question of which enzyme regenerates cGMP in photoreceptors and how phototransduction feedback operates at the enzymatic level.

    Evidence Recombinant RetGC-1 expressed in HEK293 cells showed membrane GC activity stimulated by GCAP and inhibited by Ca²⁺ with EC50 ~50–100 nM

    PMID:7777544

    Open questions at the time
    • No structural model of the cyclase
    • Stoichiometry and binding mode of GCAP interaction unknown
    • In vivo validation of Ca²⁺ sensitivity parameters not yet performed
  2. 1998 High

    Identification of CORD6-causing mutations (E837D, R838C) in the dimerization domain and mapping of CD-GCAP and GCAP1 regulatory regions defined both the disease relevance and modular regulatory architecture of RetGC1.

    Evidence Genetic linkage and sequencing in affected families identified dimerization-domain mutations; deletion/hybrid cyclase constructs mapped CD-GCAP signaling to aa 736–1053 and GCAP1 regulation to juxtamembrane residues M445–L456 and L503–I522

    PMID:10571055 PMID:9439621 PMID:9618177

    Open questions at the time
    • Mechanism by which dimerization domain mutations cause dominant disease not yet biochemically resolved
    • Relationship between GCAP1 and CD-GCAP regulatory modules unclear
  3. 1999 High

    In vitro reconstitution of CORD6 (R838C) and LCA1 (F514S) mutations revealed that disease arises through fundamentally different mechanisms — gain-of-function Ca²⁺-sensitivity shift versus loss of catalytic activity — answering how the same gene causes dominant and recessive disease.

    Evidence R838C increased apparent GCAP-1 affinity and allowed cyclase stimulation at elevated Ca²⁺; F514S abolished intrinsic cyclase activity and CRM1 but not CRM2 regulation; neurocalcin identified as a distinct Ca²⁺-dependent activator acting through CRM4

    PMID:10430891 PMID:10504230 PMID:9888789

    Open questions at the time
    • In vivo confirmation of gain-of-function mechanism not yet obtained
    • Physiological relevance of neurocalcin regulation to photoreceptor function unclear
  4. 2001 High

    Demonstrating that RetGC1 functions as a dimer whose coiled-coil integrity determines both catalytic competence and Ca²⁺ sensitivity established the structural basis for Arg838 dominant mutations.

    Evidence Mutagenesis and molecular dynamics showed that Arg838 substitutions disrupt a salt-bridge network in the dimerization domain, enabling cGMP synthesis even at high Ca²⁺; catalytic-domain LCA mutations abolish GTP-to-cGMP conversion

    PMID:11306565 PMID:11328726

    Open questions at the time
    • No crystal or cryo-EM structure of the dimerization domain
    • How dimer interface perturbation propagates to catalytic domain activation unknown
  5. 2004 High

    Quantitative kinetic analysis revealed that CORD6 mutations shift Ca²⁺ sensitivity by altering the relative affinity of Ca²⁺-free versus Ca²⁺-bound GCAP1 for RetGC1, and that some LCA mutations act as dominant negatives through heterodimer poisoning.

    Evidence R838S raised the Ca²⁺ IC50 from 0.27 to 0.61 µM by changing GCAP1 binding equilibria; P858S and L954P reduced wild-type activity in co-expression assays; S100B mapped to Gly962–Asn981 in gustatory epithelium

    PMID:15123990 PMID:15504042 PMID:15556616

    Open questions at the time
    • Dominant-negative mechanism not validated in photoreceptor models
    • Physiological relevance of S100B regulation in taste versus retina unclear
  6. 2011 High

    Identification of RD3 as a high-affinity allosteric inhibitor of RetGC1 revealed a second layer of cyclase regulation beyond GCAPs and explained LCA12 pathogenesis.

    Evidence Recombinant RD3 suppressed basal and GCAP-stimulated RetGC1 activity at submicromolar concentrations noncompetitively; LCA12 truncation mutant lost inhibitory function

    PMID:21928830

    Open questions at the time
    • RD3 binding site on RetGC1 not mapped
    • In vivo dynamics of RD3-RetGC1 interaction in outer segments unknown
  7. 2016 Medium

    Discovery that bicarbonate directly activates the RetGC1 catalytic domain independently of Ca²⁺ added a metabolic regulatory input to phototransduction, and in vivo testing showed that the S248W LCA1 mutation impairs protein trafficking rather than catalysis.

    Evidence Bicarbonate activated recombinant RetGC1 synergistically with GCAP pathways; S248W showed normal HEK293 activity but failed to reach outer segments or restore ERG in AAV-treated Gucy2e KO mice

    PMID:26858600 PMID:27881908

    Open questions at the time
    • Bicarbonate regulation not confirmed in intact photoreceptors
    • Trafficking mechanism of RetGC1 to outer segments not elucidated
  8. 2018 High

    Genetic epistasis in transgenic mice proved that CORD6 photoreceptor degeneration is driven through GCAP-mediated Ca²⁺ feedback rather than cyclase-intrinsic toxicity, resolving the in vivo pathogenic mechanism.

    Evidence R838S transgenic mice showed elevated dark cGMP and degeneration prevented in GCAP1,2 double-knockout background; additional dimerization-domain mutants (E841K, K846N) confirmed shifted Ca²⁺ regulation while V902L showed constitutive activation

    PMID:29440533 PMID:30319355

    Open questions at the time
    • Cone-specific degeneration mechanism not fully characterized in vivo
    • Whether constitutively active mutants also require GCAPs for toxicity unknown
  9. 2020 High

    Systematic analysis of CSNB-linked mutations showed that loss of GCAP binding and/or RD3 binding represent separable disease mechanisms, and that R838S dominantly shifts Ca²⁺ sensitivity even in WT/mutant heterodimers.

    Evidence R666W and R761W lost GCAP1 binding; G982VfsX39 and L911F lost RD3 binding; WT+R838S heterodimer required ~6-fold more Ca²⁺ for deceleration versus WT homodimer

    PMID:33109612

    Open questions at the time
    • Heterodimer structure not resolved
    • Relative abundance of WT vs mutant allele in heterozygous photoreceptors unknown
  10. 2026 High

    Therapeutic rescue demonstrated that reducing aberrant cGMP production is sufficient to prevent CORD6 degeneration, validating cyclase output as the druggable node in dominant GUCY2D disease.

    Evidence Engineered protein inhibitor (PIGCY) in R838S transgenic mice preserved 70% photoreceptor nuclei at 6 months and maintained light sensitivity by ERG and single-photon recordings

    PMID:42045071

    Open questions at the time
    • Long-term durability of PIGCY-mediated rescue not established
    • Cone rescue not demonstrated
    • Optimal level of cyclase inhibition for clinical translation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structural models of full-length RetGC1 dimers, the precise binding interfaces for GCAPs and RD3, and the mechanism by which bicarbonate and metabolic signals integrate with Ca²⁺-dependent regulation in intact photoreceptors remain unresolved.
  • No cryo-EM or crystal structure of RetGC1 homodimer
  • GCAP and RD3 binding interfaces not structurally resolved
  • Cone-specific regulatory mechanisms poorly characterized in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 4
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-9709957 Sensory Perception 3
Partners
GUCA1AGUCA1BRD3S100BVILIP3
Complex memberships
RetGC1 homodimer

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 RetGC-1 (GUCY2D) is a photoreceptor-specific membrane guanylyl cyclase whose recombinant form expressed in HEK293 cells has membrane GC activity that is stimulated by the activator p24 (GCAP) and inhibited by Ca2+ with an EC50 of 50-100 nM, establishing its core enzymatic properties and Ca2+ sensitivity. Recombinant expression in HEK293 cells, membrane GC activity assay, Ca2+ inhibition assay Proceedings of the National Academy of Sciences of the United States of America High 7777544
1998 Dominant cone-rod dystrophy (CORD6) is caused by missense mutations (E837D, R838C) in GUCY2D specifically in the dimerization domain, establishing GUCY2D as a causal gene for autosomal dominant retinal degeneration. Mutation screening by sequencing of GUCY2D in affected families; segregation analysis Human molecular genetics High 9618177
1999 The F514S mutation in ROS-GC1 (GUCY2D), linked to Leber congenital amaurosis (LCA1), severely damages intrinsic cyclase activity and inactivates the GCAP1-regulated CRM1 Ca2+ switch but does not affect the CRM2 switch, demonstrating domain-specific functional dissection of the two Ca2+ regulatory modules. In vitro mutagenesis, cGMP synthesis assay, Ca2+ sensitivity measurement in COS cell-expressed mutants Biochemistry High 9888789
1999 The R838C substitution in the RetGC-1 dimerization domain reduces overall catalytic ability, dramatically reduces stimulation by GCAP-2, increases apparent affinity for GCAP-1, and alters Ca2+ sensitivity of the GCAP-1 response, allowing mutant to be stimulated by GCAP-1 at higher Ca2+ concentrations than wild type — demonstrating a gain-of-function dominant mechanism. In vitro mutagenesis, cGMP synthesis assay, GCAP activation assays, Ca2+ sensitivity measurements Proceedings of the National Academy of Sciences of the United States of America High 10430891
1999 Two short regulatory regions (M445-L456 and L503-I522) in the juxtamembrane domain (JMD) of ROS-GC1 are critical for activation by GCAP-1, as identified by peptide competition and mutagenesis studies. Peptide competition assays, site-directed mutagenesis, GC activity assay FEBS letters High 10571055
1999 Neurocalcin is identified as a novel Ca2+-dependent activator of ROS-GC1 (GUCY2D), stimulating it in a dose-dependent fashion with EC50 ~20 µM Ca2+; the neurocalcin-regulated domain (CRM4) maps to the C-terminal segment (aa 731-1054) but is distinct from the CRM2 domain regulated by CD-GCAP. Recombinant protein assay, deletion mapping, GC activity assay, domain reconstruction Biochemistry High 10504230
1998 CD-GCAP differentially activates ROS-GC1 and ROS-GC2; the CD-GCAP-regulated stimulatory switch resides within amino acids 736-1053 of the cyclase, established by deletion, hybrid, and reconstruction expression studies. Deletion mutants, hybrid cyclase construction, heterologous expression, GC activity assay Biochemical and biophysical research communications High 9439621
2001 cGMP synthesis by RetGC-1 requires dimerization, and an intact alpha-helical coiled-coil structure in the dimerization domain is required for catalytic function; Arg838 within the dimerization domain establishes Ca2+ sensitivity of RetGC-1 by determining coiled-coil interaction strength. Arg838 substitutions dominantly enhance cGMP synthesis even at high Ca2+ and disrupt a salt bridge network as shown by molecular dynamics. In vitro mutagenesis, cGMP synthesis assay, Ca2+ sensitivity assay, molecular dynamics simulation The Journal of biological chemistry High 11306565
2001 Complete abolition of retGC-1 catalytic activity (either by truncating mutations or by missense mutations in the catalytic domain) consistently leads to LCA; catalytic domain missense mutations abolish GTP-to-cGMP conversion in COS7 cells, while extracellular domain missense mutations mostly retain normal catalytic activity. In vitro mutagenesis, expression in COS7 cells, cGMP synthesis assay Investigative ophthalmology & visual science High 11328726
2004 The Ca2+ sensitivity of RetGC-1 regulation by GCAP-1 is determined by both the affinity of GCAP-1 for Ca2+ and the relative affinities of the Ca2+-free vs. Ca2+-bound GCAP-1 for RetGC-1. The R838S CORD6 mutation increases the Ca2+ concentration required for half-maximal inhibition from 0.27 to 0.61 µM, primarily by changing the relative affinity of the mutant cyclase for Ca2+-free vs. Ca2+-loaded GCAP-1. Quantitative kinetic binding assay, Ca2+ sensitivity measurements, Mg2+-dependence analysis of recombinant RetGC-1 Biochemistry High 15504042
2004 LCA-linked catalytic domain mutations P858S and L954P in RetGC-1 severely impair basal and GCAP-1/GCAP-2-stimulated catalytic activity and act as dominant negative proteins when co-expressed with wild-type allele, reducing wild-type RetGC-1 activity. Extracellular domain mutations C105Y and L325P reduce GCAP-stimulated but not basal activity. In vitro mutagenesis, expression in HEK-293 cells, cGMP synthesis assay, co-expression dominant-negative assay Molecular vision High 15123990
2011 RD3 protein is a high-affinity allosteric inhibitor of RetGC1 (GUCY2D), suppressing basal and GCAP-stimulated RetGC activity at submicromolar concentrations in a noncompetitive manner without significantly changing Ca2+ sensitivity; LCA12-associated RD3 truncation mutant fails to suppress RetGC1/GCAP complex, and several RD3 disease mutations decrease RD3 affinity for RetGC1. Recombinant protein expression in HEK293 cells, GC activity assay, mutagenesis, binding assay Biochemistry High 21928830
2012 Ca2+-sensor protein S100B coexists with ROS-GC1 (GUCY2D) in cones but not rods of the murine retina, upregulates ROS-GC1 activity with K1/2 for Ca2+ >500 nM, and modulates neural signal transmission to cone ON-bipolar cells, as demonstrated by gene deletion models and single-cell recordings. Gene deletion mouse models, biochemistry, immunohistochemistry, ERG, single-cell recordings Cellular physiology and biochemistry High 22508049
2018 The R838S mutation in RetGC1 causes CORD6 by deregulating Ca2+-sensitive feedback of phototransduction via GCAPs: transgenic mice expressing R838S RetGC1 show elevated dark cGMP, increased dark current, and altered rod photoresponses; photoreceptor degeneration is prevented in GCAP1,2-/- double knockout background, establishing GCAPs-mediated Ca2+ feedback as the primary trigger for degeneration. Transgenic mouse model, single-cell electrophysiology, ERG, genetic epistasis with GCAP KO The Journal of neuroscience High 29440533
2018 Multiple GUCY2D mutations in the dimerization domain (E841K, K846N) shift Ca2+-sensitive regulation by GCAPs; the catalytic domain mutant P873R causes loss of function; and V902L causes a >20-fold increase in GC activity (constitutively active), showing distinct gain- and loss-of-function mechanisms depending on mutation location. Expression in HEK293 cells, GC activity assay, Ca2+ sensitivity assay, RD3 interaction assay Frontiers in molecular neuroscience High 30319355
2020 CSNB-linked mutations R666W, R761W, and L911F disable RetGC1 activation by GCAP1, -2, and -3; R666W and R761W additionally compromise GCAP1 binding in HEK293 cells; G982VfsX39 and L911F retain GCAP1 binding but fail to bind RD3; R768W fails to bind either GCAP1 or RD3. The CORD6 mutation R838S dominantly shifts Ca2+ sensitivity in the RetGC1 heterodimer (WT+R838S), requiring ~6-fold higher Ca2+ to decelerate cyclase compared to WT homodimer. In vitro mutagenesis, expression in HEK293 cells, GC activity assay, Ca2+ sensitivity measurement, co-immunoprecipitation binding assay The Journal of biological chemistry High 33109612
1998 ROS-GC1 (GUCY2D) gene is composed of 20 exons and 19 introns spanning 18.5 kb, and the gene is induced by phorbol ester (protein kinase C activator), suggesting PKC-mediated transcriptional regulation of ROS-GC1 in photoreceptors. Gene structural analysis, luciferase reporter assay in COS cells, phorbol ester treatment Molecular and cellular biochemistry Medium 9879655
2004 S100B binds to domain amino acids Gly962-Asn981 of ROS-GC1 and signals through transduction domain aa Ile1030-Gln1041 to activate ROS-GC1 in gustatory epithelium, generating cGMP as a second messenger in gustatory transduction. Peptide competition, domain mutagenesis, GC activity assay, functional characterization in bovine gustatory epithelium FEBS letters Medium 15556616
2016 Bicarbonate (generated from CO2 via carbonic anhydrase) directly targets the core catalytic domain of ROS-GC1 and activates it independently of Ca2+, synergizing with GCAP- and S100B-mediated Ca2+-dependent pathways; GCAP1 and GCAP2 signal through distinct domain-specific modules of ROS-GC1. Recombinant reconstitution, GC activity assay with bicarbonate, mutagenesis of LCA1-linked F514S mutant Frontiers in molecular neuroscience Medium 26858600
2013 Expression of mutant human RETGC-1 (E837D/R838S) in zebrafish cone photoreceptors under the cone-specific gnat2 promoter causes aberrant cone morphology, reduced cone density, and reduced rod outer segment labeling, demonstrating that CORD6-linked GUCY2D mutations directly cause photoreceptor structural pathology in vivo. Transgenic zebrafish expression, fluorescent microscopy of retinal morphology, optokinetic response assay Experimental eye research Medium 23328348
2016 The S248W GUCY2D mutation fails to restore rod and cone ERG function and shows marginal protein expression in photoreceptor outer segments in AAV-treated Gucy2e knockout mouse retinas, despite normal enzymatic activity in HEK293 cells, indicating that this mutation causes LCA1 by impairing protein expression, processing, or transport rather than catalytic activity. AAV-mediated expression in Gucy2e KO mouse retinas, ERG, immunofluorescence, immunoblot, GC activity assay Molecular vision Medium 27881908
2026 An engineered protein inhibitor of retinal guanylyl cyclase (PIGCY) expressed in transgenic GUCY2D adCORD (R838S) mice suppresses aberrant cGMP production, prevents rod photoreceptor degeneration (70% of nuclei preserved vs. 20% in R838S alone at 6 months), and maintains functional light sensitivity, demonstrating that reducing cGMP synthesis is sufficient to rescue degenerating GUCY2D adCORD rods. Transgenic mouse model, ERG, single-photon response recording, photoreceptor nuclei counting, GC activity measurement The Journal of neuroscience High 42045071
2021 Gucy2d is selectively expressed in dynorphin-lineage inhibitory neurons in laminae I-III of the adult mouse spinal dorsal horn but not in the brain or DRG; Gucy2d knockout mice show no altered responses to itch or pain, indicating the protein is dispensable for these sensory functions in spinal cord. In situ hybridization, Gucy2d knockout mouse behavioral assays (pain, itch) Pain reports Medium 34296052

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Cloning and expression of a second photoreceptor-specific membrane retina guanylyl cyclase (RetGC), RetGC-2. Proceedings of the National Academy of Sciences of the United States of America 229 7777544
1998 Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Human molecular genetics 217 9618177
2005 CYGD: the Comprehensive Yeast Genome Database. Nucleic acids research 212 15608217
1999 Biochemical analysis of a dimerization domain mutation in RetGC-1 associated with dominant cone-rod dystrophy. Proceedings of the National Academy of Sciences of the United States of America 100 10430891
2001 Interactions within the coiled-coil domain of RetGC-1 guanylyl cyclase are optimized for regulation rather than for high affinity. The Journal of biological chemistry 85 11306565
2000 Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology 81 10647719
2005 Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. Journal of medical genetics 76 16272259
1999 Functional consequences of a rod outer segment membrane guanylate cyclase (ROS-GC1) gene mutation linked with Leber's congenital amaurosis. Biochemistry 73 9888789
2017 Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D. Progress in retinal and eye research 71 29061346
2018 Somatic Gene Editing of GUCY2D by AAV-CRISPR/Cas9 Alters Retinal Structure and Function in Mouse and Macaque. Human gene therapy 68 30358434
1999 Regions in vertebrate photoreceptor guanylyl cyclase ROS-GC1 involved in Ca(2+)-dependent regulation by guanylyl cyclase-activating protein GCAP-1. FEBS letters 67 10571055
2008 Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration. Investigative ophthalmology & visual science 66 18487367
2007 The yeast acylglycerol acyltransferase LCA1 is a key component of Lands cycle for phosphatidylcholine turnover. FEBS letters 61 17996202
2019 GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. American journal of ophthalmology 50 31704230
2004 Factors that determine Ca2+ sensitivity of photoreceptor guanylyl cyclase. Kinetic analysis of the interaction between the Ca2+-bound and the Ca2+-free guanylyl cyclase activating proteins (GCAPs) and recombinant photoreceptor guanylyl cyclase 1 (RetGC-1). Biochemistry 47 15504042
1996 Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and mapping of LCA1 to chromosome 17p13. Human genetics 46 8641699
2001 Complete abolition of the retinal-specific guanylyl cyclase (retGC-1) catalytic ability consistently leads to leber congenital amaurosis (LCA). Investigative ophthalmology & visual science 43 11328726
2011 Retinal degeneration 3 (RD3) protein inhibits catalytic activity of retinal membrane guanylyl cyclase (RetGC) and its stimulation by activating proteins. Biochemistry 42 21928830
1999 A second calcium regulator of rod outer segment membrane guanylate cyclase, ROS-GC1: neurocalcin. Biochemistry 41 10504230
2021 Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations. iScience 38 33997691
2003 Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis. Ophthalmology 37 12623820
2011 Bicistronic lentiviruses containing a viral 2A cleavage sequence reliably co-express two proteins and restore vision to an animal model of LCA1. PloS one 35 21647387
2004 Functional analyses of mutant recessive GUCY2D alleles identified in Leber congenital amaurosis patients: protein domain comparisons and dominant negative effects. Molecular vision 35 15123990
2017 Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations. American journal of ophthalmology 32 28212877
2003 Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance. Human mutation 31 12552567
2002 Electroretinographic abnormalities in parents of patients with Leber congenital amaurosis who have heterozygous GUCY2D mutations. Archives of ophthalmology (Chicago, Ill. : 1960) 28 12365911
2014 Whole exome sequencing reveals GUCY2D as a major gene associated with cone and cone-rod dystrophy in Israel. Investigative ophthalmology & visual science 27 25515582
2024 Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study. Lancet (London, England) 25 39244273
2018 GUCY2D Cone-Rod Dystrophy-6 Is a "Phototransduction Disease" Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 29440533
2018 Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D. American journal of ophthalmology 25 29559409
2012 Gucy2f zebrafish knockdown--a model for Gucy2d-related leber congenital amaurosis. European journal of human genetics : EJHG 25 22378290
2006 Novel triple missense mutations of GUCY2D gene in Japanese family with cone-rod dystrophy: possible use of genotyping microarray. Molecular vision 24 17200655
1998 Differential activation of rod outer segment membrane guanylate cyclases, ROS-GC1 and ROS-GC2, by CD-GCAP and identification of the signaling domain. Biochemical and biophysical research communications 24 9439621
2011 A recurrent mutation in GUCY2D associated with autosomal dominant cone dystrophy in a Chinese family. Molecular vision 23 22194653
2004 Novel complex GUCY2D mutation in Japanese family with cone-rod dystrophy. Investigative ophthalmology & visual science 23 15111605
2006 Phenotype of autosomal dominant cone-rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1. Eye (London, England) 22 17041576
2014 Leber congenital amaurosis caused by mutations in GUCY2D. Cold Spring Harbor perspectives in medicine 21 25256176
2022 The Natural History of Leber Congenital Amaurosis and Cone-Rod Dystrophy Associated with Variants in the GUCY2D Gene. Ophthalmology. Retina 20 35314386
2018 Photoreceptor Guanylate Cyclase (GUCY2D) Mutations Cause Retinal Dystrophies by Severe Malfunction of Ca2+-Dependent Cyclic GMP Synthesis. Frontiers in molecular neuroscience 20 30319355
2010 A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis. European journal of human genetics : EJHG 20 20517349
2002 Evidence of a founder effect for the RETGC1 (GUCY2D) 2943DelG mutation in Leber congenital amaurosis pedigrees of Finnish origin. Human mutation 20 12325031
2014 A detailed phenotypic description of autosomal dominant cone dystrophy due to a de novo mutation in the GUCY2D gene. Eye (London, England) 19 24480840
2012 S100B serves as a Ca(2+) sensor for ROS-GC1 guanylate cyclase in cones but not in rods of the murine retina. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 22508049
2008 A tomato ER-type Ca2+-ATPase, LCA1, has a low thapsigargin-sensitivity and can transport manganese. Archives of biochemistry and biophysics 18 19056336
2005 A novel mutation in the GUCY2D gene responsible for an early onset severe RP different from the usual GUCY2D-LCA phenotype. Human mutation 18 15643614
2004 Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the GUCY2D gene in Japanese patients. Japanese journal of ophthalmology 18 15175914
2004 A missense mutation in GUCY2D acts as a genetic modifier in RPE65-related Leber Congenital Amaurosis. Ophthalmic genetics 18 15512997
2021 Regulation of retinal membrane guanylyl cyclase (RetGC) by negative calcium feedback and RD3 protein. Pflugers Archiv : European journal of physiology 17 33537894
2013 A novel GUCY2D mutation in a Chinese family with dominant cone dystrophy. Molecular vision 17 23734073
2020 GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone-rod dystrophy but not for stationary night blindness. The Journal of biological chemistry 16 33109612
2017 Postretinal Structure and Function in Severe Congenital Photoreceptor Blindness Caused by Mutations in the GUCY2D Gene. Investigative ophthalmology & visual science 16 28403437
2004 S100B-modulated Ca2+-dependent ROS-GC1 transduction machinery in the gustatory epithelium: a new mechanism in gustatory transduction. FEBS letters 16 15556616
2000 Autosomal dominant cone-rod dystrophy due to a missense mutation (R838C) in the guanylate cyclase 2D gene (GUCY2D) with preserved rod function in one branch of the family. Ophthalmic genetics 16 11135490
2014 GUCY2D- or GUCA1A-related autosomal dominant cone-rod dystrophy: is there a phenotypic difference? Retina (Philadelphia, Pa.) 15 24875811
2012 A novel GUCY2D mutation, V933A, causes central areolar choroidal dystrophy. Investigative ophthalmology & visual science 15 22695961
2016 Novel GUCY2D mutation causes phenotypic variability of Leber congenital amaurosis in a large kindred. BMC medical genetics 14 27475985
2015 Novel GUCY2D Gene Mutations in Japanese Male Twins with Leber Congenital Amaurosis. Journal of ophthalmology 14 26097748
2008 New mutation, P575L, in the GUCY2D gene in a family with autosomal dominant progressive cone degeneration. Archives of ophthalmology (Chicago, Ill. : 1960) 14 18332321
2021 Leber Congenital Amaurosis Due to GUCY2D Mutations: Longitudinal Analysis of Retinal Structure and Visual Function. International journal of molecular sciences 13 33670772
1998 Rod outer segment membrane guanylate cyclase type 1 (ROS-GC1) gene: structure, organization and regulation by phorbol ester, a protein kinase C activator. Molecular and cellular biochemistry 13 9879655
2015 GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies. Documenta ophthalmologica. Advances in ophthalmology 12 26298565
2007 Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example. European journal of human genetics : EJHG 11 17684531
2013 Transgenic zebrafish expressing mutant human RETGC-1 exhibit aberrant cone and rod morphology. Experimental eye research 10 23328348
2016 Bicarbonate and Ca(2+) Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically. Frontiers in molecular neuroscience 9 26858600
2012 Antithetical modes of and the Ca(2+) sensors targeting in ANF-RGC and ROS-GC1 membrane guanylate cyclases. Frontiers in molecular neuroscience 9 22509151
2020 Variants at codon 838 in the GUCY2D gene result in different phenotypes of cone rod dystrophy. Ophthalmic genetics 8 32811265
2014 Ca(2+)-modulated ROS-GC1 transduction system in testes and its presence in the spermatogenic cells. Frontiers in molecular neuroscience 8 24808824
2013 Phenotypic characterization of a Chinese family with autosomal dominant cone-rod dystrophy related to GUCY2D. Documenta ophthalmologica. Advances in ophthalmology 7 23686677
1999 Alternative transcription initiation sites generate two LCA1 Ca2+-ATPase mRNA transcripts in tomato roots. Plant molecular biology 7 10394952
2023 Preliminary characterization of a novel form of progressive retinal atrophy in the German Spitz dog associated with a frameshift mutation in GUCY2D. Veterinary ophthalmology 6 36872573
2022 Preclinical studies in support of phase I/II clinical trials to treat GUCY2D-associated Leber congenital amaurosis. Molecular therapy. Methods & clinical development 6 36654798
2018 Long term follow-up of a family with GUCY2D dominant cone dystrophy. International journal of ophthalmology 6 30588428
2016 A Mini-review: Animal Models of GUCY2D Leber Congenital Amaurosis (LCA1). Advances in experimental medicine and biology 6 26427419
2021 Gucy2d selectively marks inhibitory dynorphin neurons in the spinal dorsal horn but is dispensable for pain and itch sensitivity. Pain reports 5 34296052
2008 Rod outer segment membrane guanylate cyclase type 1 (ROS-GC1) calcium-modulated transduction system in the sperm. Fertility and sterility 5 19111294
2018 CO2/bicarbonate modulates cone photoreceptor ROS-GC1 and restores its CORD6-linked catalytic activity. Molecular and cellular biochemistry 4 29427171
2020 The pathogenicity of novel GUCY2D mutations in Leber congenital amaurosis 1 assessed by HPLC-MS/MS. PloS one 3 32255808
2002 Calcium-sensitive ROS-GC1 signaling outside of photoreceptors: a common theme. Molecular and cellular biochemistry 3 11952086
2021 Homozygosity mapping coupled with whole-exome sequencing and protein modelling identified a novel missense mutation in GUCY2D in a consanguineous Pakistani family with Leber congenital amaurosis. Journal of genetics 2 34470921
2024 Development and characterization of a Gucy2d-cre mouse to selectively manipulate a subset of inhibitory spinal dorsal horn interneurons. PloS one 1 38483883
2024 Erratum: Safety and improved efficacy signals following gene therapy in childhood blindness caused by GUCY2D mutations. iScience 1 39540020
2020 Novel GUCY2D Variant (E843Q) at Mutation Hotspot Associated with Macular Dystrophy in a Japanese Patient. Journal of Nippon Medical School = Nippon Ika Daigaku zasshi 1 32009068
2016 Functional study of two biochemically unusual mutations in GUCY2D Leber congenital amaurosis expressed via adenoassociated virus vector in mouse retinas. Molecular vision 1 27881908
2003 Structure and Ca2+ regulation of frog photoreceptor guanylate cyclase, ROS-GC1. Molecular and cellular biochemistry 1 14674678
2002 GCAPs: Ca2+-sensitive regulators of retGC. Advances in experimental medicine and biology 1 12596930
2026 Protein Inhibitor of Retinal Membrane Guanylyl Cyclase Rescues Mouse Rod Photoreceptors from GUCY2D Retinal Dystrophy. The Journal of neuroscience : the official journal of the Society for Neuroscience 0 42045071
2025 De novo variant in GUCY2D gene causing atypical cone-rod dystrophy in a consanguineous family and literature review. International journal of ophthalmology 0 40688792
2025 GUCY2D-Associated Retinopathy: A Comparative Study Between Humans and German Spitz Dogs. Veterinary sciences 0 41012804
2025 A Novel GUCY2D Frameshift Deletion Identified in a Patient with Leber Congenital Amaurosis 1: A Case Report. Case reports in ophthalmology 0 41404193
2024 A GUCY2D variant associated cone-rod dystrophy with electronegative ERG: A case report and review. American journal of ophthalmology case reports 0 39100576
2022 Phenotypic characterization of autosomal dominant progressive cone dystrophies associated with a heterozygous variant c.2512C>T of GUCY2D gene in a large kindred. Eye (London, England) 0 36509996
2019 Possible dual contribution of a novel GUCY2D mutation in the development of retinal degeneration in a consanguineous population. European journal of medical genetics 0 31470097
2019 A novel deletion mutation in GUCY2D gene may be responsible for Leber congenital amaurosis-1 disease: A case report. Journal of current ophthalmology 0 31844802