ArticleAmerican journal of human genetics2018
Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
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- Genotype-Phenotype Correlations in Corneal Dystrophies: Advances in Molecular Genetics and Therapeutic Insights.Clinical & experimental ophthalmology · 2025Review
- The Spatial Transcriptomic Atlas of Human Limbus and Vital Niche Microenvironment Regulating the Fate of Limbal Epithelial Stem Cells.Investigative ophthalmology & visual science · 2025Article
- Disruption ofHuman mutation · 2024Article
- OVOL2: an epithelial lineage determiner with emerging roles in energy homeostasis.Trends in cell biology · 2023Review
- A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele.Human molecular genetics · 2023Article
- Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature.International journal of molecular sciences · 2023Article
- Rare variant analyses across multiethnic cohorts identify novel genes for refractive error.Communications biology · 2023Article
- Snail Track Lesion with Flat Keratometry in Anterior Segment Dysgenesis Caused by a NovelJournal of clinical medicine · 2022Article
- Update on the genetics of corneal endothelial dystrophies.Indian journal of ophthalmology · 2022Review
- Emerging technologies for prenatal diagnosis: The application of whole genome and RNA sequencing.Prenatal diagnosis · 2022Review
- [Diagnostics, clinical aspects and genetics of congenital corneal opacities].Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft · 2022Review
- Bilateral posterior lamellar corneal transplant surgery in an infant of 17 weeks old: Surgical challenges and the added value of intraoperative optical coherence tomography.Clinical case reports · 2022Article
- Association analyses of rare variants identify two genes associated with refractive error.PloS one · 2022Article
- Should Patients with Kearns-Sayre Syndrome and Corneal Endothelial Failure Be Genotyped for aGenes · 2021Article
- Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-FunctionGenes · 2021Article
- Diseases of the corneal endothelium.Experimental eye research · 2021Review
- NovelGenes · 2021Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c.20+257delT and c.20+133delA) in unrelated PPCD-affected families. GRHL2 is a transcription factor that suppresses epithelial-to-mesenchymal transition (EMT) and is a direct transcriptional repressor of ZEB1. ZEB1 mutations leading to haploinsufficiency cause PPCD3. We previously identified promoter mutations in OVOL2, a gene not normally expressed in the corneal endothelium, as the cause of PPCD1. OVOL2 drives mesenchymal-to-epithelial transition (MET) by directly inhibiting EMT-inducing transcription factors, such as ZEB1. Here, we demonstrate that the GRHL2 regulatory variants identified in PPCD4-affected individuals induce increased transcriptional activity in vitro. Furthermore, although GRHL2 is not expressed in corneal endothelial cells in control tissue, we detected GRHL2 in the corneal "endothelium" in PPCD4 tissue. These cells were also positive for epithelial markers E-Cadherin and Cytokeratin 7, indicating they have transitioned to an epithelial-like cell type. We suggest that mutations inducing MET within the corneal endothelium are a convergent pathogenic mechanism leading to dysfunction of the endothelial barrier and disease.
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Registered trials
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