Fuchs'endothelial corneal dystrophy (FECD) affects nearly 4% of the U.S. population over 40 years of age and may cause corneal edema with decreased vision and pain. FECD is the leading indication for corneal transplantation in the country. Genetic variants in COL8A2, SLC4A11, and TCF8 have been linked to FECD but account for only a small fraction of cases. A recent GWAS study found an association between SNPs spanning a 1 Mb region of chr 18q including TCF4/FLJ45743 and late-onset FECD, but the underlying causal variant remains elusive. With CTSA and departmental funds, we have built a large repository of genomic DNA from well-phenotyped patients with corneal disorders including over 250 FECD cases. Our research team has recently begun to apply genetics and genomics-based approaches to investigate the molecular basis of FECD. We have performed genome-wide linkage analysis and have initiated next-generation sequencing on a three generation, Texas family from our cohort with bilineal inheritance of late-onset FECD that segregates as an autosomal dominant trait. Linkage analysis revealed promising intervals on chr 15q (LOD score of 3.93) and chr 1p (LOD score of 2.29). We hypothesize that two disease predisposing genes, one for each lineage, segregate in this unique, inter-married family and when they are co-inherited cause an early-onset, severe FECD. We now propose to: Identify the causal variant(s) underlying an autosomal dominant form of FECD. We will apply next-generation sequencing to the genomic intervals linked to FECD, determine which potential disease causing variants co-segregate with the FECD phenotype in our large pedigree, screen potential pathogenic variants in a cohort of unrelated FECD subjects, and finally assess these novel FECD mutations in a population sample.

Public Health Relevance

Fuchs'endothelial corneal dystrophy (FECD) occurs in nearly 4% of the United States population over the age of 40. With no proven medical treatment, FECD is the leading indication for corneal transplantation accounting for 4,400 operations performed annually in this country. The proposed project aims to define the genes operative in FECD which could be targeted in future medical treatments.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022161-02
Application #
8461549
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2012-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$302,100
Indirect Cost
$112,100
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Cunnusamy, Khrishen; Bowman, Charles B; Beebe, Walter et al. (2016) Congenital Corneal Endothelial Dystrophies Resulting From Novel De Novo Mutations. Cornea 35:281-5
Hulleman, John D; Nguyen, Annie; Ramprasad, V L et al. (2016) A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome. Mol Vis 22:73-81
Bennett, Adam; Mahmoud, Shahira; Drury, Donna et al. (2015) Impact of Donor Age on Corneal Endothelium-Descemet Membrane Layer Scroll Formation. Eye Contact Lens 41:236-9
Soliman, Ahmed Z; Xing, Chao; Radwan, Salma H et al. (2015) Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion in TCF4. JAMA Ophthalmol 133:1386-91
Mootha, V Vinod; Hussain, Imran; Cunnusamy, Khrishen et al. (2015) TCF4 Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy. Invest Ophthalmol Vis Sci 56:2003-11
Mootha, V Vinod; Gong, Xin; Ku, Hung-Chih et al. (2014) Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 55:33-42
Ali, Zahra; Xing, Chao; Anwar, Didar et al. (2014) A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Möbius syndrome. Mol Vis 20:368-75
Xing, Chao; Gong, Xin; Hussain, Imran et al. (2014) Transethnic replication of association of CTG18.1 repeat expansion of TCF4 gene with Fuchs' corneal dystrophy in Chinese implies common causal variant. Invest Ophthalmol Vis Sci 55:7073-8
Zhang, Xiaolin; Igo Jr, Robert P; Fondran, Jeremy et al. (2013) Association of smoking and other risk factors with Fuchs' endothelial corneal dystrophy severity and corneal thickness. Invest Ophthalmol Vis Sci 54:5829-35