ArticleHuman molecular genetics2015
CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
- Article
- The Identification of Proteolytic Substrates of Calpain-5 with N-Terminomics.International journal of molecular sciences · 2025Article
- Treatment and Visual Outcomes in Pediatric Patients with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy: A Cohort Study.Ocular immunology and inflammation · 2024Article
- T-type voltage-gated channels, NaCell communication and signaling : CCS · 2024Article
- Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Impaired activity and membrane association of most calpain-5 mutants causal for neovascular inflammatory vitreoretinopathy.Biochimica et biophysica acta. Molecular basis of disease · 2023Article
- Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics.EBioMedicine · 2022Article
- Calpains as mechanistic drivers and therapeutic targets for ocular disease.Trends in molecular medicine · 2022Review
- Long-Term Outcomes and Risk Factors for Severe Vision Loss in Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV).American journal of ophthalmology · 2022Observational
- Whole-Exome Sequencing of Patients With Posterior Segment Uveitis.American journal of ophthalmology · 2021Article
- Molecular Surgery: Proteomics of a Rare Genetic Disease Gives Insight into Common Causes of Blindness.iScience · 2020Review
- Phenotypic variance in Calpain-5 retinal degeneration.American journal of ophthalmology case reports · 2020Article
- Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration.EBioMedicine · 2020Article
- Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.Cell reports · 2020Article
- CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials.Human mutation · 2019Article
- Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy.Scientific reports · 2019Article
- Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes.Ocular immunology and inflammation · 2019Article
- Early Onset Neovascular Inflammatory Vitreoretinopathy Due to aOcular immunology and inflammation · 2019Article
- In Vivo Expression of Mutant Calpains in the Eye Using Lentivirus.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Capn5 Expression in the Healthy and Regenerating Zebrafish Retina.Investigative ophthalmology & visual science · 2018Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
A single amino acid mutation near the active site of the CAPN5 protease was linked to the inherited blinding disorder, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #193235). In homology modeling with other calpains, this R243L CAPN5 mutation was situated in a mobile loop that gates substrate access to the calcium-regulated active site. In in vitro activity assays, the mutation increased calpain protease activity and made it far more active at low concentrations of calcium. To test whether the disease allele could yield an animal model of ADNIV, we created transgenic mice expressing human (h) CAPN5(R243L) only in the retina. The resulting hCAPN5(R243L) transgenic mice developed a phenotype consistent with human uveitis and ADNIV, at the clinical, histological and molecular levels. The fundus of hCAPN5(R243L) mice showed enhanced autofluorescence (AF) and pigment changes indicative of reactive retinal pigment epithelial cells and photoreceptor degeneration. Electroretinography showed mutant mouse eyes had a selective loss of the b-wave indicating an inner-retina signaling defect. Histological analysis of mutant mouse eyes showed protein extravasation from dilated vessels into the anterior chamber and vitreous, vitreous inflammation, vitreous and retinal fibrosis and retinal degeneration. Analysis of gene expression changes in the hCAPN5(R243L) mouse retina showed upregulation of several markers, including members of the Toll-like receptor pathway, chemokines and cytokines, indicative of both an innate and adaptive immune response. Since many forms of uveitis share phenotypic characteristics of ADNIV, this mouse offers a model with therapeutic testing utility for ADNIV and uveitis patients.
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