OVOL2 and Posterior Polymorphous Corneal Dystrophy 1

Posterior polymorphous corneal dystrophy 1 (PPCD1) is an autosomal-dominant endothelial dystrophy characterized by corneal clouding, gray endothelial lesions, thickened Descemet membrane and progressive loss of visual acuity. The locus for PPCD1 was mapped to chromosome 20 in multiple families, and subsequent sequencing of coding exons failed to identify causative missense or loss-of-function variants in protein-coding genes within the critical interval (PMID:27355326).

Targeted sequencing of the OVOL2 promoter in the original PPCD1 pedigree identified a heterozygous c.-307T>C variant that segregated with disease in multiple affected members of the kindred; luciferase assays demonstrated a significant increase in promoter activity compared to wild type (PMID:28046031).

A second unrelated family was found to harbor the heterozygous 5′ untranslated region variant c.-61G>A in OVOL2 in both a father and daughter with PPCD1. This variant was absent in unaffected relatives and increased promoter activity in dual-luciferase reporter assays (PMID:34469340).

No non-coding single-nucleotide or copy-number variants within OVOL2 were identified in additional PPCD1 probands beyond these two families, supporting locus heterogeneity and a specific regulatory mechanism rather than widespread coding defects (PMID:28046031; PMID:27355326).

Mechanistic studies in a mouse model carrying the human c.-307T>C promoter mutation showed increased corneal endothelial Ovol2 expression and low-penetrance ocular phenotypes such as irido-corneal adhesions and corneal opacity, recapitulating key aspects of human PPCD1 and confirming the pathogenic gain-of-function mechanism (PMID:37971355).

Although one allelic series of mouse Ovol2 promoter mutations revealed species-specific differences in phenotypic penetrance, the convergence of human genetic and functional data firmly supports OVOL2 promoter dysregulation as a cause of PPCD1.

Genetic testing for OVOL2 promoter variants should be incorporated into diagnostic workflows for autosomal-dominant PPCD1, enabling targeted counseling and early intervention for affected individuals.

References

• PLoS One • 2016 • Identification of Potentially Pathogenic Variants in the Posterior Polymorphous Corneal Dystrophy 1 Locus PMID:27355326
• PLoS One • 2017 • Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1 PMID:28046031
• Cornea • 2022 • c.-61G>A in OVOL2 is a Pathogenic 5' Untranslated Region Variant Causing Posterior Polymorphous Corneal Dystrophy 1 PMID:34469340
• Hum Mol Genet • 2024 • Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence PMID:37971355

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