ArticleHuman molecular genetics2013
Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 100 citations in OpenAlex.
- Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect.Nature medicine · 2019Trial
- Assessment of full-field stimulus test results in Stargardt disease: correlations with full-field electroretinography, multifocal electroretinography, and optical coherence tomography.Documenta ophthalmologica. Advances in ophthalmology · 2026Article
- Measuring Rod- and Cone-Photoreceptor-Specific Vision in Inherited Retinal Diseases Using a Commercial Perimeter.Investigative ophthalmology & visual science · 2025Article
- Article
- Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness.Investigative ophthalmology & visual science · 2025Article
- Retinal Degeneration Associated With Biallelic RDH12 Variants: Longitudinal Evaluation of Retinal Structure and Visual Function in Pediatric Patients.Investigative ophthalmology & visual science · 2024Article
- Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases.Journal of clinical medicine · 2024Review
- IFT88 maintains sensory function by localising signalling proteins alongLife science alliance · 2024Article
- The Clinical Findings, Pathogenic Variants, and Gene Therapy Qualifications Found in a Leber Congenital Amaurosis Phenotypic Spectrum Patient Cohort.International journal of molecular sciences · 2024Article
- Full-field stimulus threshold testing: a scoping review of current practice.Eye (London, England) · 2024Article
- cGMP Signaling in Photoreceptor Degeneration.International journal of molecular sciences · 2023Review
- Preclinical studies in support of phase I/II clinical trials to treatMolecular therapy. Methods & clinical development · 2023Article
- Article
- Mobility test to assess functional vision in dark-adapted patients with Leber congenital amaurosis.BMC ophthalmology · 2022Article
- Regulation of retinal membrane guanylyl cyclase (RetGC) by negative calcium feedback and RD3 protein.Pflugers Archiv : European journal of physiology · 2021Review
- Macular Rod Function in Retinitis Pigmentosa Measured With Scotopic Microperimetry.Translational vision science & technology · 2021Article
- Review
- Durable vision improvement after a single treatment with antisense oligonucleotide sepofarsen: a case report.Nature medicine · 2021Article
- Leber Congenital Amaurosis Due toInternational journal of molecular sciences · 2021Article
- Current Clinical Applications of In Vivo Gene Therapy with AAVs.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 7 institutions in 2 countries.
Funding
Abstract
The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months-37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1.
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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 OpenQuestion graph.