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 novl 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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Mckie, George Ann
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Johns Hopkins University
Schools of Medicine
United States
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Shaaban, Sherin; MacKinnon, Sarah; Andrews, Caroline et al. (2018) Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci 59:4054-4064
Eghrari, Allen O; Mumtaz, Aisha A; Garrett, Brian et al. (2017) Automated Retroillumination Photography Analysis for Objective Assessment of Fuchs Corneal Dystrophy. Cornea 36:44-47
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
Eghrari, Allen O; Vasanth, Shivakumar; Wang, Jiangxia et al. (2017) CTG18.1 Expansion in TCF4 Increases Likelihood of Transplantation in Fuchs Corneal Dystrophy. Cornea 36:40-43
Eghrari, Allen O; Vahedi, Sina; Afshari, Natalie A et al. (2017) CTG18.1 Expansion in TCF4 Among African Americans With Fuchs' Corneal Dystrophy. Invest Ophthalmol Vis Sci 58:6046-6049
Rees, Elliott; Kendall, Kimberley; PardiƱas, Antonio F et al. (2016) Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia. JAMA Psychiatry 73:963-969
Eghrari, Allen O; Riazuddin, S Amer; Gottsch, John D (2016) Distinct Clinical Phenotype of Corneal Dystrophy Predicts the p.(Leu450Trp) Substitution in COL8A2. Cornea 35:587-91
Eghrari, Allen O; Riazuddin, S Amer; Gottsch, John D (2015) Overview of the Cornea: Structure, Function, and Development. Prog Mol Biol Transl Sci 134:7-23
Vasanth, Shivakumar; Eghrari, Allen O; Gapsis, Briana C et al. (2015) Expansion of CTG18.1 Trinucleotide Repeat in TCF4 Is a Potent Driver of Fuchs' Corneal Dystrophy. Invest Ophthalmol Vis Sci 56:4531-6
Eghrari, Allen O; Garrett, Brian S; Mumtaz, Aisha A et al. (2015) Retroillumination Photography Analysis Enhances Clinical Definition of Severe Fuchs Corneal Dystrophy. Cornea 34:1623-6

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