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EW CORNEA 82 February 2011 TC4 gene shows strong connection to Fuchs' A new gene, dubbed Tran- scription factor 4 (TC4), may point to many Fuchs' corneal dystrophy pa- tients and hopefully to treatment. The odds of having Fuchs' corneal dystrophy jump 30- fold for those having two copies of the TC4 gene, according to Albert O. Edwards, M.D., Ph.D., senior re- search associate, Institute of Molecu- lar Biology, University of Oregon, Eugene. Investigators reported on the likely association between the TC4 gene and Fuchs' dystrophy in the September 9, 2010, issue of the New England Journal of Medicine. From a genetic standpoint, Dr. Edwards described Fuchs' as a com- plex condition akin to macular de- generation, glaucoma, or heart disease. "All of these conditions in- cluding Fuchs' have a genetic com- ponent," he said. "The magnitude of the genetic component here was a bit of a surprise, so I would say that Fuchs' appears to be a bit more hereditary than other complex con- ditions like macular degeneration." TC4, found on chromosome 18, is a basic helix loop transcription factor. It encodes a member of the E- protein family (E2-2). "It's a protein that binds to DNA and controls genes, and it's involved in develop- ment and epithelial-mesenchymal transition," Dr. Edwards said. "This is the process where cells lift up, go off, and move around the body; that's involved in metastasis and de- velopment." Strong genetic link Investigators not only looked for copies of the gene in Fuchs' corneal dystrophy patients with guttae, but also in those believed to be free of the condition. When they analyzed the data they found a very strong correlation. "Seventy-one percent of patients with these guttae had at least one or two copies of this [TC4] variant," Dr. Edwards said. By con- trast, just 27% of the age and gen- der-match controls had one or more TC4 copies. Dr. Edwards sees the association as a very strong one. "The way to think about it is how much more likely is the patient to have guttae if he or she has a genetic variant," he said. "A person with one copy is 5½ times more likely to have guttae, and a person with two copies is 30 times more likely to have guttae—so this is huge." To highlight just how strong a genetic connection there can be, Dr. Edwards drew a comparison to AMD. Those with two copies of compliment factor H, which is asso- ciated with AMD, are known as ho- mozygotes. He pointed out that if you look at the 10q26 locus, ho- mozygous are just seven times more likely to have AMD. By comparison, the Fuchs' guttae connection ap- pears to be a much stronger one. "We have one genetic variant here that is 30 times more likely to have guttae," Dr. Edwards said. "The work has been replicated by at least one other group [besides us]." He found that the effect is even greater for those who have severe forms of the disease. Those who had severe forms of Fuchs' dystrophy with two copies of the gene who had experienced vision loss were 200-fold more likely to have guttae. Clinical potential Dr. Edwards thinks that the poten- tial for making clinical inroads based on this work is strong. He pointed again to macular degeneration. "In 2005 a couple of groups recorded that the alternative pathway compli- ment system played a major role in AMD from the risk perspective," he said. "Not that it was there and acti- vated, but that the genetic variants were in large part determining who did and who did not have the dis- ease." At the time, the clinical impli- cations were few. Now 5 years later it is a different story. "It was less than 5 years before there were drugs being tested in clinical trials," Dr. Edwards said. "I would say that that is hugely clinically relevant and that it provides us with an anchor around which to begin to under- stand the disease." Currently, the understanding of what is occurring due to the TC4 gene is limited. "What we think is happening is that the genetic varia- tion is somehow changing the ex- pression of the gene," Dr. Edwards said. This may mean that not enough of the gene is being ex- pressed, or perhaps too much, or maybe even that it is being ex- pressed at the wrong time. While the true answer is still unknown, scien- tists are much closer to finding this out. "Now we know how to start, whereas a few days ago we had no idea," he said. Dr. Edwards hopes that practi- tioners come away from the study with the understanding that an im- portant in-road has been made here. "The take-home message is that we now have a clear first step in under- standing why some people get Fuchs' and other people don't," he said. "As we begin to understand that we will gain insight into treat- ment strategies." He sees Fuchs' dystrophy as po- tentially being in an enviable posi- tion with regard to treatment development. "The fact that the cornea is easily accessible and a very protected environment makes the likelihood of therapy a lot greater than for many other diseases," he said. "This is a tissue site where we can easily get a very high concentra- tion of a drug, whether it's a drop or an injection into the eye. We can easily get it there very quickly and safely." Overall, Dr. Edwards is opti- mistic about the future. "I think we're going to see that therapy tar- geting those TCF4 pathways, like the alternative pathway of compliment in macular degeneration, is going to be beneficial," he said. "The animal model work has already been done for AMD and it's very clear that if we ramp down the compliment system, we ramp down many different fea- tures that comprise the macular de- generation phenotype." Dr. Edwards thinks that we're likely to see the same thing with Fuchs.' "The hardest part is the first step—there are a lot of different pos- sibilities," he said. "But at least we know from the biology of these E2-2 proteins where to start and how to go about studying this." EW Editors' note: Dr. Edwards has no fi- nancial interests related to his com- ments. Contact information Edwards: aoe102@gmail.com by Maxine Lipner Senior EyeWorld Contributing Editor Making a Fuchs' genetic connection An example of Fuchs' dystrophy Source: Ricardo Amin, M.D.

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