Fuchs corneal dystrophy (FCD) is a degenerative disorder of the corneal endothelium that affects nearly 4% of the population above 40 years of age and accounts for the majority of transplants performed each year in the US. 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. In this competing renewal, 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), and investigate hearing loss as a new potential endophenotype of FCD. 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 re- sequencing. Finally, we will take advantage of the knock-in mouse model developed recently in our laboratory to understand the cellular basis of familial loss of function mutations in TCF8 in late-onset FCD families. These three aims represent a balance of valuable clinical and genetic analyses coupled with functional experiments designed to dissect the molecular components essential to corneal endothelial biology and understand biochemical and cellular mechanisms underlying the disease pathology. Completion of these studies will significantly enhance our 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 common corneal dystrophy that affects 4% of the population over age 40.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY016835-07A1
Application #
8579594
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Mckie, George Ann
Project Start
2005-07-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$767,331
Indirect Cost
$234,503
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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

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