ArticleHuman molecular genetics2014
Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 37 citations in OpenAlex.
- Treatment and Visual Outcomes in Pediatric Patients with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy: A Cohort Study.Ocular immunology and inflammation · 2024Article
- 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
- The C2 domain of calpain 5 contributes to enzyme activation and membrane localization.Biochimica et biophysica acta. Molecular cell research · 2021Article
- Piccolo is essential for the maintenance of mouse retina but not cochlear hair cell function.Aging · 2021Article
- Effects of functionally diverse calpain system on immune cells.Immunologic research · 2021Review
- 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
- CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials.Human mutation · 2019Article
- Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy.Scientific reports · 2019Article
- In Vivo Expression of Mutant Calpains in the Eye Using Lentivirus.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Two Novel CAPN5 Variants Associated with Mild and Severe Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy Phenotypes.Ocular immunology and inflammation · 2019Article
- Capn5 Expression in the Healthy and Regenerating Zebrafish Retina.Investigative ophthalmology & visual science · 2018Article
- Calpain-5 gene expression in the mouse eye and brain.BMC research notes · 2017Article
- An anti-CAPN5 intracellular antibody acts as an inhibitor of CAPN5-mediated neuronal degeneration.Oncotarget · 2017Article
- Small-angle X-ray scattering of calpain-5 reveals a highly open conformation among calpains.Journal of structural biology · 2016Article
- CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Calpain-5 Expression in the Retina Localizes to Photoreceptor Synapses.Investigative ophthalmology & visual science · 2016Article
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Exome sequencing indicated that the gene encoding the calpain-5 protease, CAPN5, is the likely cause of retinal degeneration and autoimmune uveitis in human patients with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, OMIM #193235). To explore the mechanism of ADNIV, a human CAPN5 disease allele was expressed in mouse retinas with a lentiviral vector created to express either the wild-type human (h) CAPN5 or the ADNIV mutant hCAPN5-R243L allele under a rhodopsin promoter with tandem green fluorescent protein (GFP) expression. Vectors were injected into the subretinal space of perinatal mice. Mouse phenotypes were analyzed using electroretinography, histology and inflammatory gene expression profiling. Mouse calpain-5 showed high homology to its human ortholog with >98% sequence identity that includes the ADNIV mutant residue. Calpain-5 protein was expressed in the inner and outer segments of the photoreceptors and in the outer plexiform layer. Expression of the hCAPN5-R243L allele caused loss of the electroretinogram b-wave, photoreceptor degeneration and induction of immune cell infiltration and inflammatory genes in the retina, recapitulating major features of the ADNIV phenotype. Intraocular neovascularization and fibrosis were not observed during the study period. Our study shows that expression of the hCAPN5-R243L disease allele elicits an ADNIV-like disease in mice. It further suggests that ADNIV is due to CAPN5 gain-of-function rather than haploinsufficiency, and retinal expression may be sufficient to generate an autoimmune response. Genetic models of ADNIV in the mouse can be used to explore protease mechanisms in retinal degeneration and inflammation as well as preclinical therapeutic testing.
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