Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders

Thiadens, Alberta A H J; Hollander, Anneke I. den; Roosing, Susanne; Nabuurs, Sander B.; Zekveld-Vroon, Renate C.; Collin, Rob W.J.; Baere, Elfride De; Koenekoop, Robert K.; Schooneveld, Mary J. van; Strom, Tim M.; Lith-Verhoeven, Janneke J.C. van; Lotery, Andrew; Moll-Ramirez, Norka van; Leroy, Bart P.; Born, L. Ingeborgh van den; Hoyng, Carel B.; Cremers, Frans P.M.; Klaver, Caroline C.W.

doi:10.1016/j.ajhg.2009.06.016

Cited by 183 publications

(143 citation statements)

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“…Achromatopsia (ACHM) is a stationary congenital AR cone disorder that is characterized by low visual acuity, photophobia, nystagmus, severe color vision defects, diminished cone ERG responses, and normal rod ERG responses. The literal meaning of ACHM (absence of color vision) does not fully capture the clinical picture, as ACHM patients generally show more severe visual acuity defects than, for example, patients with cone dystrophy (CD) in the early stage of disease (6). CD is a progressive cone disorder in which patients may initially have normal cone function but a pale optic disc predominant in the temporal side.…”

Section: Introductionmentioning

confidence: 99%

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Hollander

Black²,

Bennett³

et al. 2010

J. Clin. Invest.

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Nonsyndromic recessive retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. Molecular genetic studies in the last two decades have revealed the underlying molecular causes in approximately two-thirds of patients. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with an early-onset nonsyndromic recessive retinal dystrophy due to mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.

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Section: Introductionmentioning

confidence: 99%

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Hollander

Black²,

Bennett³

et al. 2010

J. Clin. Invest.

Self Cite

183

100

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“…Mutations in five genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H) that encode proteins of the phototransduction pathway have been implicated in the pathogenesis of ACHM and result in clinically indistinguishable forms of the disease. [16][17][18] However, the cause of ACHM in 10-20% patients remains unresolved, implying further heterogeneity. A zebrafish model of human achromatopsia (pde6c w59 ) has been recently identified displaying rapid degeneration of cone photoreceptors caused by a mutation in the cone phosphodiesterase a-subunit gene (pde6c).…”

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confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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“…Mutations in their cone counterparts, PDE6C and PDE6H, cause autosomal recessive achromatopsia (7)(8)(9)(10).…”

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confidence: 99%

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

Gopalakrishna

Boyd

Yadav

et al. 2016

Journal of Biological Chemistry

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Phosphodiesterase 6 (PDE6) is the effector enzyme in the phototransduction cascade and is critical for the health of both rod and cone photoreceptors. Its dysfunction, caused by mutations in either the enzyme itself or AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1), leads to retinal diseases culminating in blindness. Progress in research on PDE6 and AIPL1 has been severely hampered by failure to express functional PDE6 in a heterologous expression system. Here, we demonstrated that AIPL1 is an obligate chaperone of PDE6 and that it enables low yield functional folding of cone PDE6C in cultured cells. We further show that the AIPL1-mediated production of folded PDE6C is markedly elevated in the presence of the inhibitory P␥-subunit of PDE6. As illustrated in this study, a simple and sensitive system in which AIPL1 and P␥ are co-expressed with PDE6 represents an effective tool for probing structure-function relationships of AIPL1 and reliably establishing the pathogenicity of its variants.Cyclic nucleotide phosphodiesterases of the sixth family (PDE6) 2 are the key effectors in the visual transduction cascade in rod and cone photoreceptors. In the dark, activity of the PDE6 catalytic dimers is restrained by two tightly bound inhibitory ␥-subunits (P␥). This allows cGMP to maintain depolarizing "dark" current through a cGMP-gated channel in the photoreceptor plasma membrane. Photoexcitation leads to G-protein-mediated activation of PDE6 followed by a drop in cytoplasmic cGMP, channel closure, and propagation of an electrical signal to downstream retinal neurons (1, 2). In addition to being essential to photoreceptor physiology, PDE6 is critical to the health and survival of rods and cones. Malfunctions caused by mutations in genes that encode either PDE6 or its putative chaperone, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1), lead to severe blinding retinal diseases.Mutations in the PDE6A, PDE6B, and PDE6G genes, which encode the catalytic PDE6AB subunits and P␥ of rod PDE6, respectively, are responsible for a significant proportion of cases of recessive retinitis pigmentosa (3-5) and can also lead to autosomal dominant congenital stationary night blindness (6). Mutations in their cone counterparts, PDE6C and PDE6H, cause autosomal recessive achromatopsia (7-10).PDE6 deficiency also appears to underlie one of the most severe forms of Leber congenital amaurosis (LCA type 4), a condition caused by mutations in the AIPL1 gene (11,12). LCA is an early onset inherited retinopathy and one of the main causes of blindness in children (13). The link between PDE6 and AIPL1 was discovered in studies of AIPL1 knock-out and knockdown mouse models, which revealed rapid severe retinal degeneration and a marked reduction in PDE6 protein levels and activity prior to the loss of photoreceptor cells (14, 15). Thus, the animal models recapitulated the hallmarks of LCA and suggested that AIPL1 is a potential chaperone of PDE6. This notion is consistent with the fact that AIPL1 contains an FK506-binding pro...

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Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders

Cited by 183 publications

References 22 publications

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Lighting a candle in the dark: advances in genetics and gene therapy of recessive retinal dystrophies

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client

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