ArticlePloS one2015
Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Structural and functional characterization of Caenorhabditis elegans cyclic GMP-activated channel TAX-4 via molecular dynamics simulations.European biophysics journal : EBJ · 2026Article
- Canine models of inherited retinal diseases: from neglect to well-recognized translational value.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Review
- Genetic phenotypic characteristics and inheritance patterns of patients with achromatopsia at a large academic institution and a review of the literature and gene therapies.Molecular vision · 2025Review
- Differential gene expression between central and peripheral retinal regions in dogs and comparison with humans.Experimental eye research · 2024Article
- Canine and Feline Models of Inherited Retinal Diseases.Cold Spring Harbor perspectives in medicine · 2024Review
- Primary cilia as dynamic and diverse signalling hubs in development and disease.Nature reviews. Genetics · 2023Review
- Biology, Pathobiology and Gene Therapy of CNG Channel-Related Retinopathies.Biomedicines · 2023Review
- Achromatopsia: Genetics and Gene Therapy.Molecular diagnosis & therapy · 2022Review
- Article
- CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs.Scientific reports · 2020Article
- Sensing through Non-Sensing Ocular Ion Channels.International journal of molecular sciences · 2020Review
- Review
- Six Years and Counting: Restoration of Photopic Retinal Function and Visual Behavior Following Gene Augmentation Therapy in a Sheep Model ofHuman gene therapy · 2018Article
- Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy.International journal of molecular sciences · 2018Review
- Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs.Human gene therapy. Clinical development · 2017Article
- Concepts and Strategies in Retinal Gene Therapy.Investigative ophthalmology & visual science · 2017Article
- Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.Investigative ophthalmology & visual science · 2017Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
Cyclic nucleotide-gated (CNG) ion channels are key mediators underlying signal transduction in retinal and olfactory receptors. Genetic defects in CNGA3 and CNGB3, encoding two structurally related subunits of cone CNG channels, lead to achromatopsia (ACHM). ACHM is a congenital, autosomal recessive retinal disorder that manifests by cone photoreceptor dysfunction, severely reduced visual acuity, impaired or complete color blindness and photophobia. Here, we report the first canine models for CNGA3-associated channelopathy caused by R424W or V644del mutations in the canine CNGA3 ortholog that accurately mimic the clinical and molecular features of human CNGA3-associated ACHM. These two spontaneous mutations exposed CNGA3 residues essential for the preservation of channel function and biogenesis. The CNGA3-R424W results in complete loss of cone function in vivo and channel activity confirmed by in vitro electrophysiology. Structural modeling and molecular dynamics (MD) simulations revealed R424-E306 salt bridge formation and its disruption with the R424W mutant. Reversal of charges in a CNGA3-R424E-E306R double mutant channel rescued cGMP-activated currents uncovering new insights into channel gating. The CNGA3-V644del affects the C-terminal leucine zipper (CLZ) domain destabilizing intersubunit interactions of the coiled-coil complex in the MD simulations; the in vitro experiments showed incompetent trimeric CNGA3 subunit assembly consistent with abnormal biogenesis of in vivo channels. These newly characterized large animal models not only provide a valuable system for studying cone-specific CNG channel function in health and disease, but also represent prime candidates for proof-of-concept studies of CNGA3 gene replacement therapy for ACHM patients.
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Registered trials
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.