Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous...

Area of Science:

• Genetics
• Ophthalmology
• Cell Biology

Background:

• Posterior polymorphous corneal dystrophy (PPCD) is a group of inherited eye disorders affecting the corneal endothelium.
• Previous research identified mutations in ZEB1 (PPCD3) and OVOL2 (PPCD1) as causes of PPCD, highlighting the role of epithelial-to-mesenchymal transition (EMT) pathways.

Purpose of the Study:

• To identify the genetic cause of posterior polymorphous corneal dystrophy 4 (PPCD4).
• To investigate the functional consequences of identified genetic variants in GRHL2 on corneal endothelial cells.

Main Methods:

• Whole-genome and targeted sequencing were used to identify variants in affected families.
• In vitro assays were performed to assess the transcriptional activity of GRHL2 variants.
• Immunohistochemistry was used to examine GRHL2 expression and cell markers in corneal tissue.

Main Results:

• A locus for PPCD4 was mapped to 8q22.3-q24.12, and intronic regulatory variants in GRHL2 were identified in affected families.
• These GRHL2 variants showed increased transcriptional activity in vitro.
• GRHL2 was detected in the corneal endothelium of PPCD4 patients, where cells exhibited epithelial markers, indicating a transition to an epithelial-like state.

Conclusions:

• Mutations in the regulatory regions of GRHL2 cause PPCD4.
• Induction of mesenchymal-to-epithelial transition (MET) in corneal endothelial cells is a convergent pathogenic mechanism for PPCD.
• Dysfunction of the corneal endothelial barrier due to MET contributes to disease development.