Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation

Judith Lechner, Durga P. Dash, Dorota Muszynska, Mohsen Hosseini, Fani Segev, Sonia George, David G. Frazer, Jonathan E. Moore, Stephen B. Kaye, Terri Young, David A. Simpson, Amanda J. Churchill, Elise Héon, Colin E. Willoughby

Research output: Contribution to journalArticlepeer-review


PURPOSE. Mutations in ZEB1 have been reported in posterior polymorphous corneal dystrophy (PPCD3; MIM #609141) and Fuchs' endothelial corneal dystrophy (FECD6; MIM #613270). Although PPCD and keratoconus are clinically and pathologically distinct, PPCD has been associated with keratoconus, suggesting a common genetic basis. The purpose of our study was to perform mutational screening of the ZEB1 gene in patients affected with keratoconus or PPCD. METHODS. Sanger sequencing of ZEB1 was performed in 70 unrelated patients with keratoconus and 18 unrelated patients with PPCD. Real-time quantitative PCR (RT-qPCR) was performed on RNA from cultured corneal keratocytes obtained from a keratoconic patient harboring a missense ZEB1 mutation (p.Gln640His) undergoing corneal transplantation. RESULTS. Mutational analysis of ZEB1 in PPCD identified a previously reported frameshift mutation (c.1578_1579insG) and a novel nonsense mutation (c.2249C > A) in exon 7 of ZEB1 causing the insertion of a stop codon: p.Ser750X. In the keratoconus cohort, a novel heterozygous pathogenic mutation in exon 7 (c.1920G > T; p.Gln640His) of ZEB1 was identified in a family affected with keratoconus and Fuchs' endothelial corneal dystrophy. RTqPCR performed on cultured corneal keratocytes harboring the missense ZEB1 mutation (p.Gln640His) demonstrated that COL4A1 and COL4A2 were markedly downregulated, and COL4A3, COL4A4, and COL8A2 were moderately downregulated. CONCLUSIONS. Our data combined with the previously reported mutational spectrum of ZEB1 support a genotype-phenotype correlation: missense substitutions in the ZEB1 protein are associated with FECD6 and keratoconus, whereas protein truncating ZEB1 mutations result in PPCD3. The dysregulation of a-type IV collagens represents a common link between ZEB1 mutation and the clinical phenotypes (PPCD3, FECD, and keratoconus).

Original languageEnglish
Pages (from-to)3215-3223
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Issue number5
StatePublished - 2013
Externally publishedYes


  • Corneal dystrophies
  • Fuchs' endothelial dystrophy
  • Hereditary
  • Keratoconus
  • Posterior polymorphous corneal dystrophy
  • ZEB1


Dive into the research topics of 'Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation'. Together they form a unique fingerprint.

Cite this