A substitution of G to C in the cone cGMP-phosphodiesterase ? subunit gene found in a distinctive form of cone dystrophy

Piri, Natik; Gao, Yong; Danciger, Michael; Mendoza, Emmanuel; Fishman, Gerald A.; Farber, Débora B.

doi:10.1016/j.ophtha.2004.07.011

Cited by 33 publications

(22 citation statements)

References 27 publications

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“…Mutations in the cone-specific PDE6C are less well characterized, but are associated with cone photoreceptor loss and recessive achromatopsia (Chang et al 2001;Chang et al 2002). Mutations in the rod PDE6G subunit are associated with recessive retinitis pigmentosa (Tsang et al 1996), while cone PDE6H subunit mutations lead to a recessive form of cone dystrophy (Piri et al 2005). The heterogeneity of disease phenotypes reflects the spatial expression of different PDE6 subunits, and that disease-associated mutations are present in catalytic and inhibitory subunits of the PDE6 holoenzyme.…”

Section: Retinal Disorders Associated With Mutations In Retgcs and Pde6mentioning

confidence: 99%

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

Collery

Kennedy

2009

Retinal Degenerative Diseases

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Tightly regulated control of cGMP levels is critical for proper functioning of photoreceptors, and mutations in cGMP synthesis or degradation factors can lead to various forms of retinal disorder. Here we review heterogenous human retinal disorders associated with mutant retinal guanylate cyclases (RetGCs) and phosphodiesterase 6 (PDE6), and describe how zebrafish are being used to examine phototransduction components and their roles in these diseases. Though mutations in RetGCs and PDE6 lead to retinal disorders, there is a lack of molecular and biochemical data on routes of subsequent photoreceptor degeneration and visual impairment. Use of animal model systems provides important information to connect in vitro biochemical analyses of mutant genes with clinically observed pathologies of human retinal diseases. Zebrafish are an excellent in vivo system to generate animal models of human retinal disorders and study photoreceptor components, and have already provided valuable data on retinal diseases caused by phototransduction component mutations.

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Section: Retinal Disorders Associated With Mutations In Retgcs and Pde6mentioning

confidence: 99%

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

Collery

Kennedy

2009

Retinal Degenerative Diseases

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“…It is rather curious, however, that no naturally occurring mutation has been found on PDEγ [162, 198, 200]. Only one case for the cone PDEγ has been reported, in which a mutation in the 5´-untranslated region of the cone PDEγ gene was correlated with a cone dystrophy [201]. The exceptionally high conservation and wide distribution of PDEγ could possibly explain the lack of natural occurrence of PDEγ mutation.…”

Section: Pdeγ and Eye Diseasesmentioning

confidence: 99%

The Retinal cGMP Phosphodiesterase γ-Subunit — A Chameleon

Ruoho¹

2008

CPPS

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Intrinsically disordered proteins (IDPs) represent an emerging class of proteins (or domains) that are characterized by a lack of ordered secondary and tertiary structure. This group of proteins has recently attracted tremendous interest primarily because of a unique feature: they can bind to different targets due to their structural plasticity, and thus fulfill diverse functions. The inhibitory γ-subunit (PDEγ) of retinal PDE6 is an intriguing IDP, of which unique protein properties are being uncovered. PDEγ critically regulates the turn on as well as the turn off of visual signaling through alternate interactions with the PDE6 catalytic core, transducin, and the regulator of G protein signaling RGS9-1. The intrinsic disorder of PDEγ does not compromise, but rather, optimizes its functionality. PDEγ “curls up” when free in solution but “stretches out” when binding with the PDE6 catalytic core. Conformational changes of PDEγ also likely occur in its C-terminal PDE6-binding region upon interacting with transducin during PDE6 activation. Growing evidence shows that PDEγ is also a player in non-phototransduction pathways, suggesting additional protein targets. Thus, PDEγ is highly likely to be adaptive in its structure and function, hence a “chameleon”.

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“…Mutations in genes involved in cGMP synthesis (RetGCs and GCAPs) or degradation (PDE6) (Chang et al, 2009;Dizhoor, 2000;Grau et al, 2011;Piri et al, 2005;Hunt et al, 2010) can lead to various forms of retinal dystrophies such as some types of retinitis pigmentosa (Bowes et al, 1990;McLaughlin et al, 1993), progressive cone dystrophy (Thiadens et al, 2009), dominant cone degeneration (Behnen et al, 2010;Jiang and Baehr, 2010), cone-rod dystrophy (Buch et al, 2011;Sokal et al, 2005;Tucker et al, 1999) and Leber congenital amaurosis (Perrault et al, 2000(Perrault et al, , 1996.…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina

Cámara

Sequedo

Gómez‐Pinedo

et al. 2013

Experimental Eye Research

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Inherited retinal degenerations affecting both rod and cone photoreceptors constitute one of the causes of incurable blindness in the developed world. Cyclic guanosine monophosphate (cGMP) is crucial in the phototransduction and, mutations in genes related to its metabolism are responsible for different retinal dystrophies. cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4-5% of the retinitis pigmentosa, a rare form of retinal degeneration. The aim of this study was to evaluate whether pharmacological PDE6 inhibition induced retinal degeneration in cone-enriched cultures of porcine retina similar to that found in murine models. PDE6 inhibition was induced in cone-enriched retinal explants from pigs by Zaprinast. PDE6 inhibition induced cGMP accumulation and triggered retinal degeneration, as determined by TUNEL assay. Western blot analysis and immunostaining indicated that degeneration was accompanied by caspase-3, calpain-2 activation and poly (ADP-ribose) accumulation. Oxidative stress markers, total antioxidant capacity, thiobarbituric acid reactive substances (TBARS) and nitric oxide measurements revealed the presence of oxidative damage. Elevated TNF-alpha and IL-6, as determined by enzyme immunoassay, were also found in cone-enriched retinal explants treated with Zaprinast. Our study suggests that this ex vivo model of retinal degeneration in porcine retina could be an alternative model for therapeutic research into the mechanisms of photoreceptor death in cone-related diseases, thus replacing or reducing animal experiments.

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A substitution of G to C in the cone cGMP-phosphodiesterase ? subunit gene found in a distinctive form of cone dystrophy

Cited by 33 publications

References 27 publications

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

The Retinal cGMP Phosphodiesterase γ-Subunit — A Chameleon

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina

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A substitution of G to C in the cone cGMP-phosphodiesterase ? subunit gene found in a distinctive form of cone dystrophy

Cited by 33 publications

References 27 publications

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

Photoreceptor Guanylate Cyclases and cGMP Phosphodiesterases in Zebrafish

The Retinal cGMP Phosphodiesterase &#947;-Subunit — A Chameleon

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina

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The Retinal cGMP Phosphodiesterase γ-Subunit — A Chameleon