ArticleHuman molecular genetics2016
Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Stem Cell Therapy: Past, Present, and Future Aspects.Biomedicines · 2026Review
- Anatomically Guided Non-Viral CRISPR/Cas9 Delivery in the Eye: Overcoming Barriers for Precision Gene Therapy.Pharmaceutics · 2026Review
- Identification of pathogenic variants in six Chinese families with keratoconus of autosomal dominant inheritance: pathogenicity analysis and variable phenotype.International ophthalmology · 2025Article
- Genotype-Phenotype Correlations in Corneal Dystrophies: Advances in Molecular Genetics and Therapeutic Insights.Clinical & experimental ophthalmology · 2025Review
- A novel variant in the keratin 12 gene in a four-generation Chinese family with high myopia.Eye (London, England) · 2024Article
- Development of Optical Nanosensors for Detection of Potassium Ions and Assessment of Their Biocompatibility with Corneal Epithelial Cells.ACS omega · 2024Article
- Application of Noggin-Coated Electrospun Scaffold in Corneal Wound Healing.Translational vision science & technology · 2023Article
- Corneal gene therapy: Structural and mechanistic understanding.The ocular surface · 2023Article
- Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort.Molecular genetics & genomic medicine · 2022Article
- Sulfur mustard corneal injury is associated with alterations in the epithelial basement membrane and stromal extracellular matrix.Experimental and molecular pathology · 2022Article
- From structural resilience to cell specification - Intermediate filaments as regulators of cell fate.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Review
- Development of a Corneal Bioluminescence Mouse for Real-Time In Vivo Evaluation of Gene Therapies.Translational vision science & technology · 2020Article
- Corneal dystrophies.Nature reviews. Disease primers · 2020Review
- A C1976Y missense mutation in the mouse Ip3r1 gene leads to short-term mydriasis and unfolded protein response in the iris constrictor muscles.Experimental animals · 2020Article
- Novel Mutations inFrontiers in cell and developmental biology · 2020Article
- Effective In Vivo Topical Delivery of siRNA and Gene Silencing in Intact Corneal Epithelium Using a Modified Cell-Penetrating Peptide.Molecular therapy. Nucleic acids · 2019Article
- Corneal cell therapy: with iPSCs, it is no more a far-sight.Stem cell research & therapy · 2018Review
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
Abstract
Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal dominant disorder caused by dominant-negative mutations within the KRT3 or KRT12 genes, which encode the cytoskeletal protein keratins K3 and K12, respectively. To investigate the pathomechanism of this disease, we generated and phenotypically characterized a novel knock-in humanized mouse model carrying the severe, MECD-associated, K12-Leu132Pro mutation. Although no overt changes in corneal opacity were detected by slit-lamp examination, the corneas of homozygous mutant mice exhibited histological and ultrastructural epithelial cell fragility phenotypes. An altered keratin expression profile was observed in the cornea of mutant mice, confirmed by western blot, RNA-seq and quantitative real-time polymerase chain reaction. Mass spectrometry (MS) and immunohistochemistry demonstrated a similarly altered keratin profile in corneal tissue from a K12-Leu132Pro MECD patient. The K12-Leu132Pro mutation results in cytoplasmic keratin aggregates. RNA-seq analysis revealed increased chaperone gene expression, and apoptotic unfolded protein response (UPR) markers, CHOP and Caspase 12, were also increased in the MECD mice. Corneal epithelial cell apoptosis was increased 17-fold in the mutant cornea, compared with the wild-type (P < 0.001). This elevation of UPR marker expression was also observed in the human MECD cornea. This is the first reporting of a mouse model for MECD that recapitulates the human disease and is a valuable resource in understanding the pathomechanism of the disease. Although the most severe phenotype is observed in the homozygous mice, this model will still provide a test-bed for therapies not only for corneal dystrophies but also for other keratinopathies caused by similar mutations.
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