ArticleCellular signalling2017
Mechanisms of mutant PDE6 proteins underlying retinal diseases.
Article in Cellular signalling, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 46 citations in OpenAlex.
- Progressive cone dystrophy in PDE6C-associated achromatopsia with a likely pathogenic variant and a VUS.Documenta ophthalmologica. Advances in ophthalmology · 2026Article
- A highly dynamic active state for transducin-bound phosphodiesterase-6 in vertebrate phototransduction.bioRxiv : the preprint server for biology · 2026Article
- Coevolving residues distant from the ligand binding site are involved in GAF domain function.Communications chemistry · 2025Article
- Defining proteoform-specific interactions for drug targeting in a native cell signalling environment.Nature chemistry · 2025Article
- Structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Onset and Progression of Disease in Nonhuman Primates With PDE6C Cone Disorder.Investigative ophthalmology & visual science · 2024Article
- Analysis of PDE6G mutations in a patient with retinitis pigmentosa.BMC ophthalmology · 2024Article
- Gene Therapy for Retinitis Pigmentosa: Current Challenges and New Progress.Biomolecules · 2024Review
- Clinical characterizations and molecular genetic study of two co-segregating variants in PDZD7 and PDE6C genes leading simultaneously to non-syndromic hearing loss and achromatopsia.BMC medical genomics · 2024Article
- Probing the mechanism by which the retinal G protein transducin activates its biological effector PDE6.The Journal of biological chemistry · 2024Article
- The hypothalamic transcriptome reveals the importance of visual perception on the egg production of Wanxi white geese.Frontiers in veterinary science · 2024Article
- Updates on protein-prenylation and associated inherited retinopathies.Frontiers in ophthalmology · 2024Review
- Article
- The sleep quality- and myopia-linked PDE11A-Y727C variant impacts neural physiology by reducing catalytic activity and altering subcellular compartmentalization of the enzyme.bioRxiv : the preprint server for biology · 2023Article
- Cone dystrophy associated with autoimmune polyglandular syndrome type 1.Scientific reports · 2023Article
- cGMP Signaling in Photoreceptor Degeneration.International journal of molecular sciences · 2023Review
- Unique interface and dynamics of the complex of HSP90 with a specialized cochaperone AIPL1.Structure (London, England : 1993) · 2023Article
- Perspectives of PDE inhibitor on treating idiopathic pulmonary fibrosis.Frontiers in pharmacology · 2023Review
- Inhibition of the MAPK/c-Jun-EGR1 Pathway Decreases Photoreceptor Cell Death in theInternational journal of molecular sciences · 2022Article
- Genetic dissection of non-syndromic retinitis pigmentosa.Indian journal of ophthalmology · 2022Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.