GRHL2 – Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant endothelial disorder characterized by vesicular lesions and epithelial-like cell transformation of the corneal endothelium. Three genetic subtypes have been described: PPCD1 (OVOL2), PPCD3 (ZEB1), and PPCD4 (GRHL2). The GRHL2 transcription factor normally represses epithelial-to-mesenchymal transition in non-endothelial tissues, and its dysregulation in PPCD4 leads to disease.

Genetic mapping in a large Czech PPCD4 family localized the disease to 8q22.3–q24.12, and whole-genome sequencing identified three intronic regulatory variants in GRHL2: c.20+133del, c.20+257delT and c.20+544G>T. These variants were found in four unrelated PPCD-affected families, including one de novo event, and segregated with disease status under an autosomal dominant model [PMID:29499165].

Inheritance is autosomal dominant with full penetrance of corneal endothelial lesions in variant carriers. Segregation analysis across multiple pedigrees supports pathogenicity, with each variant tracking with disease in first-degree relatives.

Variant spectrum in PPCD4 includes three distinct non-coding GRHL2 mutations that alter regulatory element function. The recurrent c.20+544G>T change and two smaller indels (c.20+257delT, c.20+133del) have not been observed in control datasets and recur in independent families [PMID:29499165].

Functional studies using luciferase reporter assays demonstrate that all three GRHL2 intronic variants increase enhancer activity. In PPCD4 corneal tissue, ectopic GRHL2 expression co-localizes with epithelial markers E-Cadherin and Cytokeratin 7, indicating a mesenchymal-to-epithelial transition (MET) within the endothelium [PMID:29499165].

Transcriptomic profiling and immunohistochemistry in PPCD1, PPCD3, and genetically unresolved PPCD cases reveal aberrant activation of Wnt signaling and dysregulation of the ZEB1-OVOL2-GRHL2 axis, underscoring a convergent pathogenic mechanism across PPCD subtypes [PMID:31233731].

A study of posterior corneal vesicles (PCVs) found no pathogenic GRHL2 variants in 38 individuals, confirming the specificity of GRHL2 mutations to PPCD and excluding PCVs as an allelic or phenotypic mimic [PMID:35174971].

Integration of genetic and experimental findings demonstrates that intronic regulatory mutations in GRHL2 cause autosomal dominant PPCD4 by inducing ectopic expression and epithelialization of the corneal endothelium. Identification of GRHL2 variants enables molecular diagnosis, informs genetic counseling, and suggests MET-targeted therapies could restore barrier function in affected patients.

References

• American journal of human genetics • 2018 • Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. PMID:29499165
• Experimental eye research • 2019 • Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy. PMID:31233731
• Acta ophthalmologica • 2022 • Posterior corneal vesicles are not associated with the genetic variants that cause posterior polymorphous corneal dystrophy. PMID:35174971

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