Mutations in the PDE6B Gene in Autosomal Recessive Retinitis Pigmentosa

Danciger, Michael; Blaney, John; Gao, Yong; Zhao, Deyu; Heckenlively, John R.; Jacobson, Samuel G.; Farber, Débora B.

doi:10.1006/geno.1995.0001

Cited by 108 publications

(76 citation statements)

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“…The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9,(46)(47)(48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12).…”

Section: Resultsmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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Section: Resultsmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

View full text Add to dashboard Cite

show abstract

“…Similar gain-of-function phenotypes have been discovered for mutations in the genes encoding other critical proteins involved in phototransduction, adaptation, and recovery processes. Recent evidence indicates that mutations which produce constitutively active guanylyl cyclase (30,46,62), or loss of rod cGMP PDE activity (10,26,63) result in increased intracellular cGMP levels. Increased intracellular cGMP, similarly to an increase in channel sensitivity to cGMP, might lead to inappropriate opening of the channels.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of progressive cone dystrophy-associated mutations in the human cone photoreceptor cyclic nucleotide-gated channel CNGA3 subunit

Liu

Varnum

2005

American Journal of Physiology-Cell Physiology

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-Progressive cone dystrophies are a genetically heterogeneous group of disorders characterized by early deterioration of visual acuity and color vision, together with psychophysical and electrophysiological evidence of abnormal cone function and cone degeneration. Recently, three mutations in the gene encoding the CNGA3 subunit of cone photoreceptor cyclic nucleotide-gated (CNG) channels have been linked to progressive cone dystrophy in humans. To investigate the functional consequences of these mutations, we expressed mutant human CNGA3 subunits in Xenopus oocytes, alone or together with human CNGB3, and studied these channels using patch-clamp recording. Compared with wild-type channels, homomeric and heteromeric channels containing CNGA3-N471S or CNGA3-R563H subunits exhibited an increase in apparent affinity for cGMP and an increase in the relative agonist efficacy of cAMP compared with cGMP. In contrast, R277C subunits did not form functional homomeric or heteromeric channels. Cell surface expression levels, determined using confocal microscopy of green fluorescent protein-tagged subunits and patch-clamp recording, were significantly reduced for both R563H and R277C but unchanged for N471S. Overall, these results suggest that the plasma membrane localization and gating properties of cone CNG channels are altered by progressive cone dystrophyassociated mutations, providing evidence that supports the pathogenicity of these mutations. phosphodiesterase NORMAL HIGH-ACUITY AND COLOR vision relies on the presence and functional integrity of three types of cone photoreceptors that are optimally sensitive to light of different wavelengths (for review, see Ref. 20). Located in the photoreceptor outer segment, cyclic nucleotide-gated (CNG) channels play a fundamental role in phototransduction by helping to convert sensory input into electrical responses. In the absence of light, the CNG channels are opened by binding of intracellular cGMP (29,73) and conduct a "dark current" carried mostly by an influx of Na ϩ and Ca 2ϩ (24). When photons are absorbed by the photopigments, sequential signaling events are initiated, including activation of a photoreceptor G protein transducin and activation of cGMP phosphodiesterase (PDE). The activated cGMP PDE then hydrolyzes and lowers the intracellular cGMP level. Hyperpolarization of the photoreceptors thus results from the closure of CNG channels in response to the lowered cGMP level, and the tonic release of neurotransmitter (glutamate) from the photoreceptor terminal decreases (70).

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“…4). The pathophysiological importance of GAF domains and cGMP-induced allostery in PDEs is illustrated by the fact that mutations in the GAF domains of human PDE6␤ subunit apparently cause autosomal-dominant congenital stationary night blindness and autosomalrecessive inheritance of retinitis pigmentosa (Gal et al, 1994;Danciger et al, 1995).…”

Section: Gaf Domain Structure and Functions In Pdesmentioning

confidence: 99%