Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy

Gill, Jasdeep; Georgiou, Michalis; Kalitzeos, Angelos; Moore, Anthony T.; Michaelides, Michel

doi:10.1136/bjophthalmol-2018-313278

Cited by 145 publications

(182 citation statements)

References 95 publications

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“…4 Different sequence variants in GUCY2D are common causes of autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). 2,[7][8][9] GUCY2D encodes the photoreceptor enzyme guanylate cyclase 2D (GC-E), which synthesizes the intracellular messenger of photoreceptor excitation, cGMP, and is regulated by intracellular Ca 2þ -sensor proteins named guanylate cyclase-activating proteins (GCAPs). To date there are 144 identified variants in GUCY2D, with the majority reported to cause LCA/ EOSRD (127 variants, 88%) and only 13 reported to cause AD-COD or AD-CORD.…”

Section: Purposementioning

confidence: 99%

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Bouzia

Georgiou

Hull

et al. 2020

American Journal of Ophthalmology

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The Wellcome Trust (099173/Z/12/Z), Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Retina UK, Fight for Sight UK, and the Foundation Fighting Blindness (USA). Financial Disclosures: Michalis Georgiou and Michel Michaelides consult for MeiraGTx. The other authors have no financial disclosures. All authors attest that they meet the current ICMJE criteria for authorship. Zaina Bouzia and Michalis Georgiou contributed equally and should be considered equivalent authors.

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Section: Purposementioning

confidence: 99%

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Bouzia

Georgiou

Hull

et al. 2020

American Journal of Ophthalmology

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“…3) -representing an example of the structural intrafamilial variability commonplace in inherited retinal diseases. 49 The other four affected individuals from the same pedigree showed a continuous EZ, with three of the subjects being older. Functional intrafamilial variability has also been reported in the same pedigree.…”

Section: Discussionmentioning

confidence: 93%

“…24 GNAT2 encodes guanine nucleotidebinding protein G(t) subunit alpha-2, which is part of the transducin complex, a G-protein participating in the visual cycle. 48,49 The α-subunit is released from βγ subunits after the interaction with light activated photopigment in cone cells and the exchange of GDP for GTP. The released αsubunit activates the cGMP phosphodiesterase (PDE6C), which lowers the cGMP and hyperpolarizes photoreceptors.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor Structure inGNAT2-Associated Achromatopsia

Georgiou

Singh

Kane

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention. METHODS. Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls. RESULTS. All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7−12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 μm (28.57−113.33, ± 25.46 μm) and 86.47 μm (28.57−113.33, ± 24.65 μm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 μm, 350 μm, and 500 μm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×10 3 cones/mm 2 , respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap. CONCLUSIONS. The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.

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“…Initially cone photoreceptors degenerate, followed by rod photoreceptor loss. These disorders typically present progressive loss of central vision, color vision disturbances, and photophobia [10].…”

Section: Zebrafish As a Model To Study Hereditary Eye Diseases In Humansmentioning

confidence: 99%

Zebrafish Photoreceptor Degeneration and Regeneration Research to Understand Hereditary Human Blindness

Iribarne¹

2020

Visual Impairment and Blindness - What We Know and What We Have to Know

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Humans with mutations in photoreceptor-related genes develop forms of retinal degeneration, such as retinitis pigmentosa, cone dystrophy, or Leber congenital amaurosis. Similarly, numerous photoreceptor mutant animal models present phenotypes that resemble retinal degeneration. Zebrafish retina manifests anatomical organization and development remarkably conserved in humans, making these fish a good model to study photoreceptor development and disease. Zebrafish are ideal for forward genetic screens to isolate mutants with visual defects. More recently, CRISPR/Cas system-mediated genome editing has enabled establishment of specific zebrafish photoreceptor mutants. Here, I review zebrafish models of inherited retinal diseases, focusing on rod versus cone photoreceptor mutants. Because zebrafish possess robust regeneration capacity to replace the lost photoreceptors, here I review the current understanding of molecular mechanisms underlying this response.Visual Impairment and Blindness -What We Know and What We Have to Know 2 2.1 Photoreceptors in the zebrafish retina Zebrafish neural retina, like those of other vertebrates, comprises three nuclear layers, separated by two synaptic layers (Figure 1). The outer nuclear layer (ONL) comprises rod and cone photoreceptors, the light-sensing neurons. The inner nuclear layer (INL) consists of bipolar, horizontal, and amacrine neurons, the second-order neurons. The ganglion cell layer is formed by ganglion cells, axons of which exit the retina, forming the optic nerve, which connects with the tectum. These neurons interconnect by synapses in the plexiform layers. The neural retina is located adjacent to the retinal pigment epithelium (RPE), which supports general homeostasis of photoreceptors, such as recycling 11-cis retinal for visual pigment regeneration [2,3].Photoreceptors are polarized neurons with characteristic morphology. They display very specialized cell regions, including outer segments (OSs), connecting cilia, cell bodies, and terminal synapses. OS structure is important for phototransduction. The cell bodies possess the machinery to support all cell functions, and their synaptic termini transduce signals to bipolar neurons. OSs are formed by hundreds of cell membrane discs stacked horizontally and associated with a high concentration of proteins for phototransduction. These proteins are synthetized in cell bodies, and then are transported to the OS through connecting cilia.Photoreceptors are sensory neurons that produce electrical responses when stimulated by light. In the OS, photons are captured by photopigment molecules to initiate phototransduction cascades [4]. Phototransduction is a complex signaling process that results in closing of voltage-gated ion channels, producing a change in membrane potential. Then, this electrical signal is amplified by other cell types in the inner retina and conducted to the brain. Although this signaling pathway is common to both rods and cones, signaling proteins are mostly encoded by distinct sets of rod-and cone-specifi...

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Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy

Cited by 145 publications

References 95 publications

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

GUCY2D-Associated Leber Congenital Amaurosis: A Retrospective Natural History Study in Preparation for Trials of Novel Therapies

Photoreceptor Structure inGNAT2-Associated Achromatopsia

Zebrafish Photoreceptor Degeneration and Regeneration Research to Understand Hereditary Human Blindness

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