Leading reason for corneal transplants comes into focus

Guided by families with an unusual number of cases, scientists at Johns Hopkins have discovered the genetic origins of at least one form of Fuchs corneal dystrophy, FCD, the leading reason for corneal transplantation in the United States.

In one form or another, FCD's trademark deterioration of the cells covering the clear, outermost lens of the eye affects more than 4 percent of the population over 40. Late in life, the dystrophy causes swelling of the cornea and can severely affect vision, making it impossible to see well even with glasses or contact lenses. It's believed that various forms of FCD are due to multiple gene mutations.

In a report in the September issue of Investigative Ophthalmology, a team led by Hopkins ophthalmologist John Gottsch, M.D., says they were able to map a common form of Fuchs, found most often in women, to chromosome 18.

“Finding this chromosomal locus is putting us in the right neighborhood to find culprit genes,” says Gottsch. “Now we have to start knocking on every door.”

Gottsch is heartened by success with earlier Fuchs gene-hunting studies. The Hopkins group tracked down its first FCD-related gene in a Virginia family with multiple, early onset cases. That gene, labeled COL8A2, was mapped to chromosome 1.

Prior to that, a large Indiana family with FCD, including a boy of 10, led the team to yet another gene variant, on chromosome 13.

The scientists use linkage analysis, a process-of-elimination gene-hunting technique that analyzes inheritance patterns in families with relatively large numbers of affected individuals and trace genetic traits co-inherited or “linked” with the disorder. Researchers search for a common location for all the linked traits until they wind up with a single chromosome address.

In his latest study, Gottsch used not only linkage analysis but also a method of identifying variations in DNA sequences to examine three FCD families in which 43 members had the disease and 33 did not. He and his coworkers were able to narrow down the linked traits in all three families to the short arm of chromosome 18 (the whole “address” is 8q21.2-q21.32).

“Because the same location popped up for three different families with similar forms of Fuchs dystrophy, we believe we have the chromosome locus for the most common genetic mutation resulting in Fuchs,” he said. “It's a painstaking process of elimination, but now we are closing in on the gene that causes what we believe is the most widespread form of Fuchs, not just the rare types in individual families. Our methods have clearly shown that Fuchs is not just one disease, but rather a disorder with several genetic flavors.”

Gottsch became interested in FCD more than six years ago when he treated a woman with a corneal dystrophy of unknown origin that looked remarkably similar to FCD despite slightly different symptoms. “I knew it wasn't classic Fuchs, but rather something new,” remembers Gottsch. “In the end, it wasn't Fuchs at all, but a sort of mutated distant cousin of the disease. It made me wonder, however, if there were more genetic variants of the disease out there.”

He stopped wondering a few years later when he examined the Indiana family and discovered what he thought at the time was the youngest case of FCD ever described in the scientific literature, the 10-year-old boy. However, literature published 25 years ago described a Virginia family with a 3-year-old girl with the disease. Gottsch contacted the original investigator and was able to reexamine the family. He was then able to determine the gene that afflicted this family and that it resulted in a unique and severe form of FCD.

“I knew Fuchs was not one but several diseases with multiple genes involved when I started comparing the symptoms of the two families,” Gottsch says. “The Indiana family members developed their disease late in life, women were mostly affected, and those who were had large bumps, or guttae, on the back of the cornea. The Virginia family had severe early disease with men and women equally affected, and the cornea had smaller, finer bumps.”

Gottsch is looking to one day use various gene therapies to suppress the mutations that he has found. It is hoped that someday the millions of people who suffer from FCD in the United States will eventually benefit from having the genetic basis of their disease identified and gene therapies developed. At present, corneal transplantation is the only solution for those severely affected.