ArticleHuman molecular genetics2018
BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Allele-specific suppression of pathogenic bestrophin-1 transcripts by CRISPR/Cas9-mediated genome editing.Genome medicine · 2026Article
- Novel BEST1 Variant Characterization in a Large French Cohort in Light of Updated Bestrophin-1 Structure-Function Correlation.Investigative ophthalmology & visual science · 2025Article
- Best Vitelliform Macular Dystrophy Natural History Study Report 1: Clinical Features and Genetic Findings.Ophthalmology · 2024Observational
- Detection of Novel BEST1 Variations in Autosomal Recessive Bestrophinopathy Using Third-generation Sequencing.Current medical science · 2024Article
- Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.Investigative ophthalmology & visual science · 2024Article
- Atypical Foveal Hypoplasia in Best Disease.Journal of personalized medicine · 2023Article
- ER-phagy: mechanisms, regulation, and diseases connected to the lysosomal clearance of the endoplasmic reticulum.Physiological reviews · 2022Review
- Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies.Acta ophthalmologica · 2022Article
- First Pediatric Case of Autosomal Recessive Homozygotic Bestrophinopathy due to Homozygous Mutation c.187G>C p. in Two Brothers.Journal of clinical medicine research · 2022Article
- Challenges and opportunities for modeling monogenic and complex disorders of the human retina via induced pluripotent stem cell technology.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in theInternational journal of molecular sciences · 2020Article
- Sensing through Non-Sensing Ocular Ion Channels.International journal of molecular sciences · 2020Review
- Human iPSC Modeling Reveals Mutation-Specific Responses to Gene Therapy in a Genotypically Diverse Dominant Maculopathy.American journal of human genetics · 2020Article
- Small Molecules Restore Bestrophin 1 Expression and Function of Both Dominant and Recessive Bestrophinopathies in Patient-Derived Retinal Pigment Epithelium.Investigative ophthalmology & visual science · 2020Article
- Association of Clinical and Genetic Heterogeneity With BEST1 Sequence Variations.JAMA ophthalmology · 2020Article
- Mutation-Dependent Pathomechanisms Determine the Phenotype in the Bestrophinopathies.International journal of molecular sciences · 2020Article
- Familial autosomal recessive bestrophinopathy: identification of a novel variant in BEST1 gene and the specific metabolomic profile.BMC medical genetics · 2020Article
- Genetic characterization of Stargardt clinical phenotype in South Indian patients using sanger and targeted sequencing.Eye and vision (London, England) · 2020Article
- Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction.Frontiers in cell and developmental biology · 2020Review
- Cellular Changes in Retinas From Patients WithFrontiers in cell and developmental biology · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
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Abstract
Mutations in bestrophin-1 (BEST1) are associated with distinct retinopathies, notably three forms with autosomal dominant inheritance and one condition with an autosomal recessive mode of transmission. The molecular mechanisms underlying their distinct retinal phenotypes are mostly unknown. Although heterozygous missense mutations in BEST1 reveal dominant-negative effects in patients with autosomal dominant Best disease (BD), heterozygous mutations associated with autosomal recessive bestrophinopathy (ARB) display no disease phenotype. Here we show that the recessive mutations trigger a strong and fast protein degradation process in the endoplasmic reticulum (ER), thereby favoring a decreased stoichiometry of mutant versus normal BEST1 subunits in the assembly of the homo-pentameric BEST1 chloride channel. In contrast, dominant mutations escape ER-associated degradation and are subjected to a slightly delayed post-ER degradation via the endo-lysosomal degradation pathway. As a result, increased formation of a non-functional BEST1 channel occurs due to a roughly equimolar incorporation of normal and mutant BEST1 subunits into the channel complex. Taken together, our data provide insight into the molecular pathways of dominantly and recessively acting BEST1 missense mutations suggesting that the site of subcellular protein quality control as well as the rate and degree of mutant protein degradation are ultimately responsible for the distinct retinal disease phenotypes in BD and ARB.
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