Fuchs corneal dystrophy (FCD) accounts for the majority of corneal grafts performed at Mayo Clinic and is the most common indication for corneal transplantation in the United States. Corneal guttae, the hallmark of FCD, are present in approximately 5% of individuals over the age of 40 years.
Until recently, investigations into the genetic causes of FCD revealed a few genes that are rare causes of the dystrophy. A research team that includes Keith H. Baratz, M.D., and
William L. Brown, O.D., of the Mayo Clinic Department of Ophthalmology and collaborators at the University of Oregon and University of Michigan, however, has discovered a strong association between the transcription factor 4 gene (TCF4) on chromosome 18 and FCD.
A genome-wide association study (GWAS) compared 100 affected study participants with 200 controls. GWAS techniques identify genetic variation of individual alleles, or single nucleotide polymorphisms, at thousands of sites along the entire genome.
"This study allowed a simultaneous comparison of 330,000 alleles between the affected and unaffected subjects. The strength of the association between FCD and variation at the TCF4 gene was unprecedented. The TCF4 gene may be responsible for 75% of FCD," says Dr. Baratz. The results of the initial GWAS were confirmed in an additional 160 Mayo patients affected by FCD.
"This finding is a major advance in understanding the cause of FCD. Once the primary gene is known, research can elucidate the pathophysiology and treatment of the disease. Newer corneal transplantation techniques are very good, but not perfect. It would be great to have an alternative to halt progression in patients identified with an early stage of the disease," according to Dr. Baratz.
TCF4 encodes the E2-2 protein, which is in the class of basic helix-loop-helix proteins. These proteins regulate the expression of other genes, controlling tissue differentiation and differential expression of tissue-specific proteins.
The function of E2-2 in the eye is not known, but in other tissues, the protein participates in diverse biochemical pathways. E2-2 has been implicated both as a tumor suppressor, by inhibiting the cyclin-dependent kinase pathway, and as a tumor promoter, through E2-2 control of epithelial-to-mesenchymal transition.
Tumor promoters involve a complex array of pathways that influence the balance between tissues with an epithelial phenotype, including apicobasal polarity, basement membrane production, and strong intercellular junctions and tissues with a mesenchymal phenotype. Mesenchymal characteristics, which are typical of invasive tumors, include a loss of polarity and a disorganized growth pattern.
Dr. Baratz notes: "One of the causes of cancer may also play a role in FCD. The disease may result from a complex alteration in the differentiation or phenotypical expression of corneal endothelial cells. This process is a lot more interesting than is the simple equation of 1 gene resulting in 1 abnormal protein. It also presents a much bigger challenge in defining FCD on a molecular level. Eye research doesn't get any more exciting than this."