By David N. Leff
What hurricanes are to the Atlantic Ocean, typhoons are to the Western Pacific.
On a day in 1775, a typhoon struck the tiny coral atoll of Pingelap, an islet of three-quarter square miles roughly 1,000 miles south and 2,500 miles west of the Hawaiian Islands. Its flat, sandy, land surface rises only 7 feet above sea level, and the cyclone leveled it completely. It blew away 90 percent of the population, and the famine that followed killed all the rest, but for 20 women and a handful of men.
The young chief, reputedly a prolific begetter of children, survived the storm. He was a carrier of a gene for achromatopsia - total colorblindness - and became the genetic founder of the rare eye disorder. Of the 3,000 Pingelapese who now live on their islet of origin, and adjacent points of land, upwards of 5 percent have the autosomal, recessive affliction - and still counting.
But achromatopsia, though unusual, is not limited to this minute focus in Oceania. "It's found throughout the world," observed molecular geneticist Olof Sundin, at Johns Hopkins University. "In European and American populations, its frequency is about one case in 50,000 people. And inability to distinguish colors is only one of its symptoms.
"A major problem that these people have," Sundin pointed out, "is day blindness. If they go out in the daylight, they are essentially blinded, because the cone cells that our eyes use to see color are primarily designed to give us high-resolution vision in bright light. And these photoreceptor cells are completely inactivated by the disease mutation. That causes achromatopsia
"The basis of their affliction," Sundin explained, "is that they lack the high-acuity vision that we get from the central portion of our retina, the fovea, which is the center of our gaze. That's our high-resolution imaging center. So that center of the eye is completely dependent on the cones, which are the color-detecting photoreceptors.
"Then there's a second set of cells," he went on, "called the rod photoreceptors, which work in very dim light. And they're what we use when we see at night. If you go out when the light is very dim, your color sense is poor. In extremely dim light, you see no color at all. At that level you would be viewing the same kind of world as somebody with achromotopsia will be seeing. There's no medicinal treatment as such," Sundin added. "Only visual aids that can be used to deal with this disease.
"In addition to having to wear special glasses during the day to attenuate the light considerably, people with the disease also need to have special magnifiers. And if working with a computer monitor, they would have a special program that puts huge text on the screen.
Sundin, an assistant professor of ophthalmology, molecular biology and genetics at Hopkins, is first author of a paper in the just-released July issue of Nature Genetics. Its title: "Genetic basis of total colorblindness among the Pingelapese islanders." Its senior author is ophthalmic geneticist Irene Maumenee, director of the Johns Hopkins Center for Hereditary Eye Diseases.
Color Vision Blown Away
"The article's main finding," Sundin summed up, "is that we've identified the basis of this rare genetic disease, which affects the function of all the photoreceptors involved in color vision. There's also, of course, a clinical dimension to this. Ultimately we hope that our information will be useful for people who have this disease. Also, since the genetic defect is identified, we can in the future think about possible treatments involving gene therapy."
The co-authors' investigation actually started some 30 years ago. "The very first step was identifying the chromosomal locus of the disease," Sundin recounted. "It began by Dr. Maumenee surveying that achromatopsia population in the late 1960s. She visited the Pingelap atoll then, and was one of the first to characterize the disease there.
"In later years," Sundin went on, "Maumenee returned and collected the population data, first of all identifying who was affected with the disease. She worked out the pedigrees, who was related, the family trees - all extremely important for genetic analysis. Then she obtained DNA samples from individuals by drawing a blood specimen and extracting its DNA.
"Once the DNA and data were back here at Hopkins," Sundin continued, "where she and I are based, the DNA was tested using a panel of genetic polymorphism markers. These are the same kinds of markers that the police use for forensic genetic fingerprinting.
"When you have a large family," he explained, "as is possible with an island population, it becomes feasible to identify one unique site. And that's the region, in this case on chromosome 8, that contains the disease gene. So we used these markers to further narrow down the region to a relatively small portion of the human genome. We were able to bring it down to roughly 2 million base pairs. The genome has 3 billion, so we're doing a bit better than a thousandth of the genome.
"After identifying that small region, we faced trying to find the disease genes. We knew that the electrical activity of an eye that has this disease is slightly different in the response of the cones, which are the color-vision system. So it was an extremely good bet that the defect was expressed in the retina, in the eye itself, and not somewhere else - like in the brain."
Will Islanders Opt For Carrier Testing?
Eventually, with an injection of serendipity in their long linkage analysis search, the co-authors were able to report finding the achromatopsia gene on chromosome 8. What might this discovery mean to the Pingelapese islanders?
"We gave the Public Health department at the district center the promised information that the gene was found," Maumenee told BioWorld Today, "and that they can do carrier identification. We left it to them to come to a position and to put it up for a Pingelapese vote whether they want to now. I'm not sure they do. At the same time maybe they do.
"Obviously, nobody is in a position to do prenatal diagnosis for them," she observed. "Maybe they will use that information to identify all those marriages in which both parents are carriers. Since adoption is very widely practiced, perhaps those couples will adopt. But who knows how the population will handle this new technology."