GUCY2D gene


Gene (OMIM no.)
Function of gene/protein
  • Protein: Retinal guanylyl cyclase (GC-E)
  • Expressed in the outer segments of cone and rod photoreceptors
  • Synthesizes intracellular cGMP when activated by guanylate cyclase-activating proteins (GCAPs)
  • Involved in photoreceptor recovery after photo-transduction
Clinical phenotype
(OMIM phenotype no.)
  • Autosomal dominant
  • Autosomal recessive
Signs for LCA
  • Poor pursuit and nystagmus
  • Photophobia
  • Oculodigital sign
  • Keratoconus
  • Hypermetropia (>+7.00D)
  • Relatively unremarkable fundal appearance
  • Some patients have a “salt-and-pepper” fundal appearance
  • Older patients may show peripheral and macular degeneration
Signs for AD cone/cone-rod dystrophy
  • Photophobia
  • High myopia (<-6.00D)
  • Variable macular alterations, ranging from RPE mottling to profound central chorioretinal atrophy
  • Macular changes progress over time
  • Peripheral fundal abnormalities rarely observed
Signs for AR cone-rod dystrophy
  • Macular atrophy
  • Peripheral chorioretinal atrophy with variable bone-spicule pigmentation
  • Retinal vessel attenuation
Signs for CSNB
  • No significant refractive error
  • Relatively normal fundal appearance in younger patients
  • Sparse sectoral bone-spicule pigmentation in the periphery and arteriolar narrowing in older patients
Visual functionLCA:
  • Early and severe visual impairment in LCA patients (majority have BCVA of HM to NPL)
  • Dyschromatopsia
  • Relatively stable or very slowly progressive disease course
  • Majority still have detectable rod function on full-field sensitivity testing
AD cone/cone-rod dystrophy:
  • Reduced VA in the 1st to 2nd decade of life which progressively worsens over time (to CF by the 5th decade)
  • Dyschromatopsia
  • Nyctalopia reported in some patients in addition to other visual symptoms
AR cone-rod dystrophy:
  • Severely reduced VA
  • Dyschromatopsia
  • Nyctalopia
  • Variable photophobia
  • Nyctalopia onset usually from early infancy or early childhood
  • Normal or slightly reduced VA
  • Slow progression to mild retinitis pigmentosa may develop in some patients
  • Full field ERG findings do not fit into either Riggs/Schubert-Bornschein type
  • Absent rod response with relatively preserved 30 Hz flicker response (isolated cone), and diminished but not electronegative dark- and light-adapted bright flash responses
Systemic features
  • No extraocular features reported
Key investigations
  • Full field and pattern ERG
  • FAF: Usually appears normal in LCA patients; AD cone/cone-rod dystrophy patients display small hypo-AF spots in the macula in earlier stages and a large, well-circumscribed area of hypo-AF surrounded by a hyper-AF ring in advanced stages
  • OCT: Early disruption/loss of foveal/parafoveal ellipsoid zone; relatively preserved retinal lamination in LCA while there is progressive outer retinal thinning in AD cone/cone-rod dystrophy and some CSNB patients
  • A hyporeflective foveal cavitation in the EZ layer may be observed in AD cone/cone-rod dystrophy patients
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Therapies under research
Further information
CF: Counting finger vision; HM: Hand movement vision; NPL: No perception of light vision

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Additional information

The vast majority of GUCY2D variants are associated with AR-LCA, accounting for 10-20% of total cases.[2] It is also a major cause of AD cone/cone-rod dystrophies (35% of AD cases), with 13 mutations reported and mostly clustered at codon 838 in exon 13, a known mutation hotspot for this phenotype.[1,6] Other less common phenotypes associated with pathogenic GUCY2D mutations that have been reported are:

  • AR cone-rod dystrophy (6 affected members in a consanguineous Turkish family)[10]
  • AR-CSNB (5 patients from 4 unrelated families)[11]

Genotype-phenotype correlations have been observed in LCA and AD cone/cone-rod dystrophy depending on the resultant activities of GC-E and GCAPs. Both proteins are crucial to photoreceptor recovery after phototransduction. GC-E synthesises cGMP which is converted to GTP upon light activation. The activity of GC-E is regulated by GCAPs (encoded by GUCA1A and GUCA1B), which are activated by low intracellular calcium concentration after photoreceptor hyperpolarisation (phototransduction).[1]

The LCA phenotype is associated with biallelic null mutations, where there is severely reduced or absent GC-E activity. On the other hand, AD cone/cone-rod dystrophy mutations (all missense variants) are functional, but GCAP activation is distorted due to a shift in calcium sensitivity which results in excessive cGMP production. This in turn leads to a persistent influx of calcium ions (depolarisation) into the photoreceptors. The increased calcium ion concentration triggers progressive photoreceptor degeneration.[1] 

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  1.  Sharon D, Wimberg H, Kinarty Y, Koch KW. Genotype-functional-phenotype correlations in photoreceptor guanylate cyclase (GC-E) encoded by GUCY2D. Prog Retin Eye Res. 2018;63:69-91
  2.  Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions [published correction appears in Br J Ophthalmol. 2019 Jun;103(6):862]. Br J Ophthalmol. 2017;101(9):1147-1154
  3.  Bouzia Z, Georgiou M, Hull S, et al. GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies. Am J Ophthalmol. 2020;210:59-70
  4.  Jacobson SG, Cideciyan AV, Sumaroka A, et al. Defining Outcomes for Clinical Trials of Leber Congenital Amaurosis Caused by GUCY2D Mutations. Am J Ophthalmol. 2017;177:44-57
  5.  Jacobson SG, Cideciyan AV, Peshenko IV, et al. Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants. Hum Mol Genet. 2013;22(1):168-183
  6.  Gill JS, Georgiou M, Kalitzeos A, Moore AT, Michaelides M. Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy [published online ahead of print, 2019 Jan 24]. Br J Ophthalmol. 2019;103(5):711-720
  7.  Lazar CH, Mutsuddi M, Kimchi A, et al. Whole exome sequencing reveals GUCY2D as a major gene associated with cone and cone-rod dystrophy in Israel. Invest Ophthalmol Vis Sci. 2014;56(1):420-430
  8.  Jiang F, Xu K, Zhang X, Xie Y, Bai F, Li Y. GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone-rod dystrophies. Doc Ophthalmol. 2015;131(2):105-114
  9.  Kelsell RE, Evans K, Gregory CY, Moore AT, Bird AC, Hunt DM. Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p. Hum Mol Genet. 1997;6(4):597-600
  10.  Ugur Iseri SA, Durlu YK, Tolun A. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber’s congenital amaurosis. Eur J Hum Genet. 2010;18(10):1121-1126
  11.  Stunkel ML, Brodie SE, Cideciyan AV, et al. Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D. Am J Ophthalmol. 2018;190:58-68

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Updated on November 30, 2020
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