A novel recessive GUCY2D mutation causing cone–rod dystrophy and not Leber's congenital amaurosis

İşeri, Sibel Aylin Uğur; Durlu, Yusuf K.; Tolun, Aslıhan

doi:10.1038/ejhg.2010.81

Cited by 18 publications

(6 citation statements)

References 17 publications

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“…Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1) (Perrault et al, 1996) as well as dominant and recessive forms of cone-rod dystrophy, CORD6 (Kelsell et al, 1998;Perrault et al, 1998;WeigellWeber et al, 2000), and CORD (Ugur Iseri et al, 2010), respectively. LCA is a clinically and genetically heterogeneous group of severe, early-onset retinal dystrophies characterized by a reduced or absent electroretinogram (ERG), nystagmus, digito-ocular signs, and apparently normal fundus appearance (Perrault et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

et al. 2013

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Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical-and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.

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Section: Introductionmentioning

confidence: 99%

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

et al. 2013

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“…GC1 is encoded by GUCY2D and restores intracellular cGMP levels and allows reopening of cGMP-gated cation channels in both rods and cones. While GUCY2D that encodes for GC1 is one of the most frequently mutated genes associated with Leber congenital amaurosis 16 – 18 , GUCY2D mutations have also been associated with cone-rod dystrophy 6 (CORD6) in humans 19 – 21 . GC1 stabilizes cone transducin and cone PDE 22 but the mechanism by which defects in GC1 primarily affect cone function in CORD6 patients remains unexplained.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, known cilia markers were assessed to determine if there were potential alterations in morphology that may impact ciliary function. The cilia were of particular interest because the two disease-associated genes RPGRIP1 and MAP9 are both localized to the cilia 21 , 23 . Microtubules (MTs) are important elements of the ciliary structure and cytoskeletons.…”

Section: Discussionmentioning

confidence: 99%

Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology

Das

Marinho

Iwabe

et al. 2017

Sci Rep

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Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and cone-rod dystrophy in humans. A form of canine cone-rod dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1 ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9 del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1 ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, cone ERGabsent RPGRIP1 ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and cone ERGabsent RPGRIP1 ins/ins littermates. Cone morphology of the dogs lacking cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, cone ERGabsent RPGRIP1 ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-cones, and lack GC1 in all cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects.

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“…It was recently shown that GUCY2D replacement by gene therapy quickly improves cone and rod sensitivity after decades of blindness [ 65 , 66 ]. Other, less common phenotypes associated with mutations in GUCY2D include autosomal recessive CRD (arCRD) [ 67 ] and autosomal recessive congenital stationary night blindness (arCSNB) [ 68 ]. It should be noted that the GUCY2D arCSNB patients show some age-related rod loss in the peripheral retina [ 68 ].…”

Section: Dysregulation Of Cgmp Signaling In Photoreceptor Degenerationmentioning

confidence: 99%

cGMP Signaling in Photoreceptor Degeneration

Yang

et al. 2023

IJMS

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Photoreceptors in the retina are highly specialized neurons with photosensitive molecules in the outer segment that transform light into chemical and electrical signals, and these signals are ultimately relayed to the visual cortex in the brain to form vision. Photoreceptors are composed of rods and cones. Rods are responsible for dim light vision, whereas cones are responsible for bright light, color vision, and visual acuity. Photoreceptors undergo progressive degeneration over time in many hereditary and age-related retinal diseases. Despite the remarkable heterogeneity of disease-causing genes, environmental factors, and pathogenesis, the progressive death of rod and cone photoreceptors ultimately leads to loss of vision/blindness. There are currently no treatments available for retinal degeneration. Cyclic guanosine 3′, 5′-monophosphate (cGMP) plays a pivotal role in phototransduction. cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission. By gating the CNG channels, cGMP regulates cellular Ca2+ homeostasis and signal transduction. As a second messenger, cGMP activates the cGMP-dependent protein kinase G (PKG), which regulates numerous targets/cellular events. The dysregulation of cGMP signaling is observed in varieties of photoreceptor/retinal degenerative diseases. Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration. In line with this, strategies to reduce cellular cGMP signaling result in photoreceptor protection in mouse models of retinal degeneration. The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways. Thus, targeting the cellular cGMP/PKG signaling and the Ca2+-regulating pathways represents a significant strategy for photoreceptor protection in retinal degenerative diseases.

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A novel recessive GUCY2D mutation causing cone–rod dystrophy and not Leber's congenital amaurosis

Cited by 18 publications

References 17 publications

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology

cGMP Signaling in Photoreceptor Degeneration

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