ZEB1 – Posterior Polymorphous Corneal Dystrophy Type 3

ZEB1 encodes a two-handed zinc-finger homeodomain transcription factor essential for corneal endothelial cell identity. Heterozygous loss-of-function variants in ZEB1 cause autosomal dominant posterior polymorphous corneal dystrophy type 3 (PPCD3) through haploinsufficiency. Clinical hallmarks include endothelial vesicular lesions, corneal edema, steep keratometry and iris flocculi; onset is variable but often manifests by adulthood.

Genetic evidence for ZEB1–PPCD3 includes multiple unrelated probands harboring truncating ZEB1 variants. A 30-year-old man with a family history of PPCD3 carried a heterozygous nonsense mutation c.2157C>G (p.Tyr719Ter) segregating with disease in his mother (PMID:30950897). An international series identified six novel ZEB1 truncating alleles in seven families (c.1749_1750del; p.(Pro584Ter), c.1717_1718del; p.(Val573PhefsTer12), c.1176dup; p.(Ala393SerfsTer19), c.1100C>A; p.(Ser367Ter), c.627del; p.(Phe209LeufsTer11), c.685-2A>G) plus a recurrent c.1576dup; p.(Val526GlyfsTer3) in an eighth family (PMID:25441224).

Functional assays confirm a haploinsufficiency mechanism. Transient expression of 13 ZEB1 truncated proteins in endothelial cells demonstrated significantly decreased abundance and impaired nuclear localization for those lacking nuclear localization signals, whereas missense mutants retain proper localization (PMID:25190660). Electrophoretic mobility shift and luciferase reporter studies showed that ZEB1 binds multiple E2 box motifs in the COL4A3 promoter to repress transcription, and truncating mutations abolish this repression, explaining COL4A3 dysregulation in PPCD3 (PMID:27537263).

Conflicting evidence arises from two asymptomatic carriers of a novel LoF allele c.1279C>T (p.Glu427Ter) identified in population screening, indicating incomplete penetrance estimated at ~95% (PMID:33946386). Nonetheless, the weight of segregation and functional data supports a strong, autosomal dominant gene–disease relationship.

Key take-home: ZEB1 haploinsufficiency is a strong cause of PPCD3; targeted genetic testing and family screening facilitate early diagnosis and management.

References

• Cornea • 2019 • Coincidental Occurrence of Schnyder Corneal Dystrophy and Posterior Polymorphous Corneal Dystrophy Type 3. PMID:30950897
• Annals of Human Genetics • 2015 • Identification of six novel mutations in ZEB1 and description of the associated phenotypes in patients with posterior polymorphous corneal dystrophy 3. PMID:25441224
• Investigative Ophthalmology & Visual Science • 2014 • Functional impact of ZEB1 mutations associated with posterior polymorphous and Fuchs' endothelial corneal dystrophies. PMID:25190660
• Investigative Ophthalmology & Visual Science • 2016 • Investigating the Molecular Basis of PPCD3: Characterization of ZEB1 Regulation of COL4A3 Expression. PMID:27537263
• Genes • 2021 • Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles. PMID:33946386

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