Fuchs corneal dystrophy (FCD) is a degenerative disorder characterized by the proliferation of guttae, which are microscopic protrusions of the collagen-rich extracellular matrix that supports the corneal endothelium. Initial stages of FCD show progressively increasing numbers of these guttae, while end stage disease exhibits, in addition, functional defects in the endothelium that cause an influx of water and severe clouding of the corneal stroma. How the guttae relate to this endothelial dysfunction remains unknown. About 4% of those who are 40 or older are affected by FCD. The only effective treatment for end stage disease is corneal transplant surgery, and FCD is now the most common reason for such surgery. Mutations in the COL8A2 gene, which encodes a subunit of collagen VIII, have been definitively associated with a rare childhood-onset form of FCD. Whether mutations in COL8A2 are also involved in the common adult-onset forms of the disease is less clear. We plan to investigate adult-onset FCD as follows: 1) We have recently mapped the first locus for adult-onset FCD to the chromosome 13pTel-q12.13 interval, with a maximum LOD scores of 3.91 and 3.80. We plan to refine this map and identify the mutant gene. 2) Our genome-wide linkage analysis of 3 additional large families with adult-onset FCD has revealed that each of them is linked to the same locus at 18q21, with a combined multi-point LOD score of 5.94 at 85% penetrance. The current disease interval contains 28 candidates; we propose to identify the gene by narrowing the interval by screening gene candidates by sequence analysis and more detailed mapping of the interval by SNP haplotype association. Our long term goal is to identify the genes underlying adult-onset FCD. Ultimately, knowing the identity of these genes will provide important insights into disease mechanisms. This should contribute towards improved early diagnosis and the development of non-surgical treatments for Fuchs Corneal Dystrophy. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY016835-01A2
Application #
7211054
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2007-02-01
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$409,479
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
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
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 (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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