OVOL2 – Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant endothelial dystrophy characterized by corneal clouding and vision impairment. Subtype PPCD1 has been linked to noncoding variants in the promoter and 5′ untranslated region of OVOL2, resulting in ectopic OVOL2 expression in corneal endothelium and driving a mesenchymal-to-epithelial transition (MET) phenotype that disrupts endothelial barrier function.

Initial genetic evidence arose from the demonstration of the c.-307T>C promoter variant segregating with disease in a large family (autosomal dominant inheritance), accompanied by increased luciferase reporter activity in endothelial cells, confirming gain-of-function (GOF) at the OVOL2 promoter (PMID:28046031). Subsequent screening of 26 additional PPCD probands excluded coding or CNV lesions in OVOL2 or ZEB1, underscoring the specificity of noncoding promoter mutations in PPCD1.

A second independent family harboring the heterozygous 5′ UTR variant c.-61G>A was identified in a father–daughter pair presenting with bilateral corneal clouding and endothelial vesicles; this variant was absent in unaffected relatives and demonstrated increased promoter activity via dual-luciferase assays (PMID:34469340). Collectively, two OVOL2 promoter/UTR variants have been confirmed in three affected individuals across two families, supporting robust segregation evidence.

No pathogenic OVOL2 coding variants have been detected in phenotypically similar posterior corneal vesicles, and screening of ZEB1 and GRHL2 in those cohorts did not reveal PPCD1-associated mutations (PMID:35174971; PMID:19574904). This distinction reinforces the unique genetic etiology of PPCD1.

Functional studies elucidate the mechanism of pathogenicity: RNA-seq of corneal endothelium from PPCD1 individuals revealed a 259-fold increase in OVOL2 expression concurrent with ZEB1 downregulation and aberrant Wnt signaling activation, consistent with MET-driven endothelial dysfunction (PMID:31233731). Mouse models with engineered Ovol2 promoter mutations replicate elevated endothelial Ovol2 expression but show species-specific penetrance of ocular phenotypes, highlighting developmental and cell-state differences between human and murine corneal endothelium (PMID:37971355).

In summary, AD inheritance of OVOL2 promoter and 5′ UTR gain-of-function variants is well-supported by segregation in two independent families, concordant in vitro functional assays, transcriptomic profiling, and mechanistic animal data. OVOL2 promoter testing should be incorporated into diagnostic panels for PPCD, enabling precise genetic diagnosis and informing prognosis.

Key Take-home: OVOL2 promoter/UTR gain-of-function variants cause PPCD1 via ectopic endothelial expression and MET, providing a clear target for genetic testing and mechanistic intervention.

References

• 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
• 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
• Human Molecular Genetics • 2024 • Ovol2 promoter mutations in mice and human illuminate species-specific phenotypic divergence. PMID:37971355
• Acta Ophthalmologica • 2022 • Posterior corneal vesicles are not associated with the genetic variants that cause posterior polymorphous corneal dystrophy. PMID:35174971
• Cornea • 2009 • Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval. PMID:19574904

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