Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium characterized by the formation of guttae, protrusions of the underlying collagen-rich extracellular matrix known as Descemets membrane. The average age of onset is 50, and patients typically reach end stage disease in their 60's and 70's, by which time guttae cover most of the cornea and ion transport functions of the endothelium are severely compromised. FCD is a common condition, with 4% of the population over age 40 affected. Despite the health and socioeconomic impact of the disorder, knowledge of the underlying mechanism and genetic load is sparse, with the only available treatment being corneal transplant surgery. This is the first competing renewal of a three year award, in which we will extend our previous clinical and genetic studies to a) expand our understanding of the clinical presentation and progression of FCD;b) identify its underlying genetic causes;and c) begin developing in vitro and in vivo models for FCD mutations. Our work consists of three specific aims that draw from the strengths of an interdisciplinary team. First, we will expand our patient collection and quantitatively document progression in families linked to known FCD loci (including two novel loci uncovered by our group in the past year). Second, taking advantage of our unique cohort, which is enriched for large, multigenerational families, we will identify novel genes for FCD using a combination of traditional genetics tools and exon capture coupled to next generation resequencing. Finally, we will extend on our recent discovery of familial loss of function mutations in TCF8 in late-onset FCD families, to generate in vitro and in vivo models of the disorder as a means of understanding its cellular basis. Completion of these studies will enhance significantly the understanding of the genetic basis of this common disorder, offer important new insights into its pathomechanism, and provide critical measures for establishing disease presentation and progression rates, which will be necessary for patient management and for the design of novel therapeutic paradigms.

Public Health Relevance

This grant proposal continues to expand our understanding of the clinical presentation of Fuchs corneal dystrophy, and its underlying genetic basis, which will lead to development of better therapeutic models and treatment for a corneal dystrophy that affects 4% of the population over age 40.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Riazuddin, S Amer; Vasanth, Shivakumar; Katsanis, Nicholas et al. (2013) Mutations in AGBL1 cause dominant late-onset Fuchs corneal dystrophy and alter protein-protein interaction with TCF4. Am J Hum Genet 93:758-64
Riazuddin, S Amer; Parker, David S; McGlumphy, Elyse J et al. (2012) Mutations in LOXHD1, a recessive-deafness locus, cause dominant late-onset Fuchs corneal dystrophy. Am J Hum Genet 90:533-9
Eghrari, Allen O; McGlumphy, Elyse J; Iliff, Benjamin W et al. (2012) Prevalence and severity of fuchs corneal dystrophy in Tangier Island. Am J Ophthalmol 153:1067-72
Iliff, Benjamin W; Riazuddin, S Amer; Gottsch, John D (2012) A single-base substitution in the seed region of miR-184 causes EDICT syndrome. Invest Ophthalmol Vis Sci 53:348-53
Li, Yi-Ju; Minear, Mollie A; Rimmler, Jacqueline et al. (2011) Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy. PLoS One 6:e18044
Riazuddin, S Amer; McGlumphy, Elyse J; Yeo, William S et al. (2011) Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus. Invest Ophthalmol Vis Sci 52:2825-9
Riazuddin, S Amer; Vithana, Eranga N; Seet, Li-Fong et al. (2010) Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy. Hum Mutat 31:1261-8
Eghrari, Allen O; Gottsch, John D (2010) Fuchs' corneal dystrophy. Expert Rev Ophthalmol 5:147-159
McGlumphy, Elyse J; Yeo, William S; Riazuddin, S Amer et al. (2010) Age-severity relationships in families linked to FCD2 with retroillumination photography. Invest Ophthalmol Vis Sci 51:6298-302
Bang, Stacy; Edell, Erica; Eghrari, Allen O et al. (2010) Treatment with voriconazole in 3 eyes with resistant Acanthamoeba keratitis. Am J Ophthalmol 149:66-9

Showing the most recent 10 out of 15 publications