ZEB1 – Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous corneal dystrophy (PPCD) is a rare, bilateral, autosomal-dominant dystrophy of the corneal endothelium and Descemet membrane. PPCD subtype 3 (PPCD3, MONDO:0020364) is caused by heterozygous loss-of-function variants in the zinc-finger E-box binding homeobox 1 gene (ZEB1). Affected individuals present with vesicular endothelial lesions, endothelial cell abnormalities, and may have extraocular features such as hernias or hydroceles (PMID:19432861).

Extensive sequencing studies have identified truncating ZEB1 alleles in 42 unrelated PPCD3 probands: five novel nonsense and frameshift mutations in six of 13 probands (PMID:23559851); ten novel and two recurrent mutations across 12 families detected by exome/genome sequencing (PMID:30851240); and two novel frameshifts in four Czech probands (PMID:23807282). De novo occurrences account for at least 14% of ZEB1 mutations in PPCD3 (PMID:23807282).

Segregation analyses demonstrate cosegregation of ZEB1 truncating alleles with PPCD3 in over 20 pedigrees, involving 19 additional affected relatives beyond probands. Two unaffected carriers of heterozygous loss-of-function alleles indicate incomplete penetrance but support dominant inheritance (PMID:33946386).

The variant spectrum in PPCD3 is dominated by null alleles: at least 49 distinct truncating mutations (nonsense and frameshift), including recurrent c.2236G>T (p.Glu746Ter) and private de novo variants; no deep-intronic or structural variants have been reported. A representative pathogenic allele is c.672del (p.Lys224AsnfsTer9) (PMID:19432861).

Functional studies confirm a haploinsufficiency mechanism: ZEB1 truncating mutants show reduced protein abundance and impaired nuclear localization, leading to loss of transcriptional repression of COL4A3 in corneal endothelium (PMID:25190660). Electrophoretic mobility shift and luciferase reporter assays demonstrate ZEB1 binding to E2-box motifs in the COL4A3 promoter, and patient tissue shows ectopic COL4A3 expression (PMID:16252232).

Collectively, the genetic and experimental data fulfill ClinGen criteria for a Definitive gene-disease association. ZEB1 mutation testing is clinically indicated for PPCD diagnosis, family counseling, and management.

References

• American journal of human genetics • 2005 • Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. PMID:16252232
• Molecular vision • 2013 • Exclusion of pathogenic promoter region variants and identification of novel nonsense mutations in the zinc finger E-box binding homeobox 1 gene in posterior polymorphous corneal dystrophy. PMID:23559851
• Experimental eye research • 2019 • The utility of massively parallel sequencing for posterior polymorphous corneal dystrophy type 3 molecular diagnosis. PMID:30851240
• JAMA ophthalmology • 2013 • Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3. PMID:23807282
• Investigative ophthalmology & visual science • 2014 • Functional impact of ZEB1 mutations associated with posterior polymorphous and Fuchs' endothelial corneal dystrophies. PMID:25190660
• Genes • 2021 • Non-Penetrance for Ocular Phenotype in Two Individuals Carrying Heterozygous Loss-of-Function ZEB1 Alleles. PMID:33946386

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