Posterior polymorphous corneal dystrophy (PPCD) is an inherited disorder of the cornea that is associated with the development of corneal edema, glaucoma and loss of vision. Locus heterogeneity has been described for PPCD, with truncating mutations identified in the zinc finger E-box binding homeobox 1 gene (ZEB1) on chromosome 10 (the PPCD3 locus) in approximately 1/3 of affected pedigrees and linkage analysis in 4 families demonstrating linkage to overlapping regions on chromosome 20 (the PPCD1 locus). Identification of the genetic basis of PPCD1 and characterization of ZEB1-mediated transcriptional control of COL4A3 in the pathogenesis of PPCD3 will provide important insights into the corneal endothelial cell transformation and dysfunction that characterize PPCD and reveal potential targets for gene- based therapeutic strategies.
Specific Aim I is to identify the genetic basis of posterior polymorphous corneal dystrophy 1 through next generation (whole exome) sequencing in affected and unaffected individuals from 29 PPCD families in which a ZEB1 mutation has not been identified. In addition, corneal endothelial expression of positional candidate genes implicated as potentially playing a role in the PPCD1 mouse will be measured.
Specific Aim II is to characterize the effect of ZEB1 mutations on ZEB1 protein function, COL4A3 expression and corneal endothelial cell phenotype in posterior polymorphous corneal dystrophy 3. This will be accomplished by: determining ZEB1-dependent gene regulation through comparing the gene expression profile between ex vivo control corneal endothelial cells, cultured control corneal endothelial cells, ex vivo PPCD3 corneal endothelial cells and cultured corneal endothelial cells with altered ZEB1 protein levels;determining the effects of ZEB1 mutations on cellular localization of mutant ZEB1 protein in transformed corneal endothelial cells and the effect of ZEB1 mutations and reduced ZEB1 protein on the morphology, proliferation, viability and motility of cultured corneal endothelial cells;and demonstrating using DNA-protein binding assays and transfection of an immortalized corneal endothelial cell line that ZEB1-mediated repression of COL4A3 expression is dependent upon ZEB1 binding to the E2 box motifs in the COL4A3 promoter.

Public Health Relevance

The corneal endothelial dystrophies, which include posterior polymorphous corneal dystrophy, are inherited disorders of the cornea that result in loss of corneal clarity and vision. Mutations in the ZEB1 gene have been identified in approximately one-third of families with posterior polymorphous corneal dystrophy as well as in a smaller percentage of families with Fuchs endothelial corneal dystrophy, which is the most common indication for corneal transplantation in the United States. We propose to determine how mutations in the ZEB1 gene cause posterior polymorphous corneal dystrophy, and to identify the gene(s) that is (are) responsible for causing posterior polymorphous corneal dystrophy in the other two-thirds of families.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Mckie, George Ann
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Cervantes, Aleck E; Gee, Katherine M; Whiting, Martha F et al. (2018) Confirmation and refinement of the heterozygous deletion of the small leucine-rich proteoglycans associated with posterior amorphous corneal dystrophy. Ophthalmic Genet 39:419-424
Vahedi, Farnoosh; Chung, Doug D; Gee, Katherine M et al. (2018) Epithelial Recurrent Erosion Dystrophy Secondary to COL17A1 c.3156C>T Mutation in a Non-white Family. Cornea 37:909-911
Zakharevich, Marina; Kattan, Jaffer M; Chen, Judy L et al. (2017) Elucidating the molecular basis of PPCD: Effects of decreased ZEB1 expression on corneal endothelial cell function. Mol Vis 23:740-752
Chung, Doug D; Frausto, Ricardo F; Cervantes, Aleck E et al. (2017) Confirmation of the OVOL2 Promoter Mutation c.-307T>C in Posterior Polymorphous Corneal Dystrophy 1. PLoS One 12:e0169215
Kattan, Jaffer M; Serna-Ojeda, Juan Carlos; Sharma, Anushree et al. (2017) Vortex Pattern of Corneal Deposits in Granular Corneal Dystrophy Associated With the p.(Arg555Trp) Mutation in TGFBI. Cornea 36:210-216
Chung, Doug D; Frausto, Ricardo F; Lin, Benjamin R et al. (2017) Transcriptomic Profiling of Posterior Polymorphous Corneal Dystrophy. Invest Ophthalmol Vis Sci 58:3202-3214
Afshari, Natalie A; Igo Jr, Robert P; Morris, Nathan J et al. (2017) Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. Nat Commun 8:14898
Lin, Benjamin R; Frausto, Ricardo F; Vo, Rosalind C et al. (2016) Identification of the First De Novo UBIAD1 Gene Mutation Associated with Schnyder Corneal Dystrophy. J Ophthalmol 2016:1968493
Kao, Liyo; Azimov, Rustam; Shao, Xuesi M et al. (2016) Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants. Am J Physiol Cell Physiol 311:C820-C830
Le, Derek J; Chung, Duk-Won D; Frausto, Ricardo F et al. (2016) Identification of Potentially Pathogenic Variants in the Posterior Polymorphous Corneal Dystrophy 1 Locus. PLoS One 11:e0158467

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