ZEB1 and Fuchs' Endothelial Corneal Dystrophy

Heterozygous ZEB1 (TCF8) variants have been reported in a small number of late-onset Fuchs' endothelial corneal dystrophy (FECD) patients, including a single case with a triple corneal dystrophy phenotype (keratoconus, EBMCD, FECD) bearing a novel exon 7 frameshift (ZEB1) identified in one proband (PMID:25408666) and a recurring missense c.2522A>C (p.Gln841Pro) variant segregating in a single multigenerational FECD pedigree (PMID:20036349). Large cohort screens in Chinese (74 probands; 1 variant) (PMID:18172091), African American (47 probands; benign p.Pro559Ser) (PMID:24348007), and Indian (82 probands; novel nonsense p.Leu947Ter and two missense in 2 cases) (PMID:26622166; 57 cases; 1 recurrent p.Gln841Pro) (PMID:29799290) have identified ZEB1 variation only in 1–2 individuals per study without replication or clear segregation.

Functional studies of ZEB1 missense mutations in corneal endothelial cells demonstrate normal protein abundance and nuclear localization for all tested missense alleles, whereas only truncating PPCD3-associated mutants show impaired stability or mis-localization (PMID:25190660). A recent systematic review of FECD genes concluded no ZEB1 variants meet pathogenic criteria and found no endothelial expression evidence supporting ZEB1 in FECD (PMID:37441688).

References

• Case Reports in Ophthalmology • 2014 • First identification of a triple corneal dystrophy association: keratoconus, epithelial basement membrane corneal dystrophy and Fuchs' endothelial corneal dystrophy PMID:25408666
• American Journal of Human Genetics • 2010 • Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p PMID:20036349
• Investigative Ophthalmology & Visual Science • 2008 • Analysis of the posterior polymorphous corneal dystrophy 3 gene, TCF8, in late-onset Fuchs endothelial corneal dystrophy PMID:18172091
• Molecular Vision • 2013 • Genetic screen of African Americans with Fuchs endothelial corneal dystrophy PMID:24348007
• Investigative Ophthalmology & Visual Science • 2014 • Functional impact of ZEB1 mutations associated with posterior polymorphous and Fuchs' endothelial corneal dystrophies PMID:25190660
• Molecular Vision • 2015 • Association of ZEB1 and TCF4 rs613872 changes with late onset Fuchs endothelial corneal dystrophy in patients from northern India PMID:26622166
• Ophthalmic Genetics • 2018 • Analysis of candidate genes ZEB1 and LOXHD1 in late-onset Fuchs' endothelial corneal dystrophy in an Indian cohort PMID:29799290
• Frontiers in Medicine • 2023 • Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs' endothelial corneal dystrophy PMID:37441688

Evidence Based Scoring (AI generated)