Speaker
Description
Posterior polymorphous corneal dystrophy (PPCD) is a rare inherited corneal endothelial dystrophy caused by pathogenic variants in the transcription factor encoding genes OVOL2, GRHL2, and ZEB1, key regulators of epithelial-mesenchymal/mesenchymal-epithelial transition (EMT/MET) and cellular differentiation. In PPCD, reduced ZEB1 expression or ectopic expression of OVOL2 or GRHL2 is thought to promote an endothelial-to-epithelial cell fate transition. However, comprehensive transcriptomic studies of human PPCD tissue remain limited, and it is unclear whether distinct genetic subtypes converge on shared disease mechanisms.
Here, we performed the largest transcriptomic study of PPCD to date. Using primary corneal endothelial cell lines derived from five patients harbouring the Czech founder OVOL2 promoter variant, we show widespread transcriptomic dysregulation of EMT/MET-associated pathways, evidence of epithelial differentiation corresponding to disease severity, and dysregulated RNA-binding proteins, including ectopic expression of the epithelial splicing regulator ESRP1, accompanied by extensive alternative splicing changes. Functional modelling in an immortalised human corneal endothelial cell line overexpressing ESRP1 recapitulated multiple transcriptomic alterations observed in patient-derived cells, supporting a mechanistic role for ESRP1-mediated post-transcriptional regulation in PPCD pathogenesis. Analysis of additional cases carrying an independent OVOL2 variant and a ZEB1 variant demonstrated consistent molecular signatures across these distinct PPCD genotypes.
Together, these findings indicate that PPCD pathogenesis converges on a shared mechanism involving disruption of EMT/MET-associated transcriptional and post-transcriptional regulatory networks. This work establishes a disease framework for future mechanistic studies and supports the development of therapeutics targeting convergent downstream pathways across PPCD subtypes.
Lay Abstract
Posterior polymorphous corneal dystrophy (PPCD) is a rare inherited disease affecting the inner corneal layer which maintains corneal clarity. PPCD is caused by changes in genes that control how cells develop and maintain their specialized identity. In PPCD, these genetic changes cause an “identity crisis” and transition the corneal cells to a different cell type. However, the science behind this transformation is not fully understood.
Here, we performed the largest ever analysis of PPCD using corneal cells grown from patients with different genetic subtypes. We found that, despite being caused by different genetic changes, PPCD cases shared common patterns of abnormal gene activity linked to cell identity and RNA processing. In particular, we identified the abnormal presence of a protein called ESRP1, which controls how RNA messages are processed. We show that introducing ESRP1 into healthy corneal cells could reproduce many of the changes seen in patient cells, suggesting it plays an important role in PPCD.
Our findings show that different forms of PPCD converge on shared disease mechanisms. This improves understanding of how PPCD develops and suggests that future treatments may be able to target common downstream pathways across patients, rather than focusing on individual genetic mutations
| Lay Title | Looking for common ground in a rare inherited corneal disease |
|---|---|
| Role | Postdoctoral Researcher |