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OPHTHALMOLOGY
Mechanism Found for Rare Vision DefectRetinal Deactivation Eyed as CulpritImagine having 20/20 vision but not being able to see a moving ball. It seems counterintuitive, yet for a small fraction of the population, perhaps as few as one in a million, this may be the reality. It is not that these people have poor coordination, but that physically their eyes have trouble tracking moving objects. Oddly enough, these same people also complain of being completely blinded by rapid changes in light levels, as when they emerge from a dark building on a sunny day or drive into a tunnel.
In eye clinics all over the world such patients have left ophthalmologists scratching their heads because in standard vision tests most of them come out with flying colors. "In fact, some of them have even been misdiagnosed as having psychiatric problems because their doctors were concerned they were delusional," said Thaddeus Dryja, the David Glendenning Cogan professor of ophthalmology at HMS and the Massachusetts Eye and Ear Infirmary. That may be about to change. In a paper in the Jan. 1 Nature, Dryja and colleagues report that it is mutations in specific signaling molecules that prevent these people from being "on the ball." A Model in Search of a DiseaseIn a normal retina, light is converted to electrical energy by a phototransduction cascade that includes molecular light receptors such as rhodopsin and G proteins called transducins. Once that cascade has started, however, it must be turned off so it can be activated by another photon. This deactivation normally takes place in less than one thirtieth of a second, ensuring that a person can see flickering lights and follow moving objects.
To answer this question, Nishiguchi carried out an extensive survey to see if patients with the most predictable symptoms of slow retinal deactivation, such as trouble adjusting to changing light, had been reported in the literature. Sure enough, he found that in the early '90s Aart Koojiman, co-author on the paper, and his colleagues in the Netherlands had reported three patients who had a condition Koojiman had dubbed prolonged electroretinal response suppression, or PERRS. Pinpointing MutationsWhen Nishiguchi tested blood samples from PERRS patients, he found that they all had the same RGS9 point mutation, one that results in the replacement of a tryptophan with another amino acid, arginine. Polymorphisms are rampant throughout the genome, however, so the substitution in and of itself did not prove anything, but the nature of the mutation was telling. First, that particular tryptophan is one of the most highly conserved amino acids in the protein, lying in an alpha helix that is thought to interact directly with the transducins. Second, in the extended families of the Dutch patients, only those homozygous for the mutation exhibit slow retinal deactivation. And last, research fellow Kirill Martemyanov and associate professor Vadim Arshavsky, both at MEEI, expressed the mutant form of RGS9 in vitro and found that it has only 5 percent of the activity of wild type protein.With MEEI faculty members Eliot Berson, the William F. Chatlos professor of ophthalmology, and Michael Sandberg, HMS associate professor of ophthalmology, the group continued to search for patients with slow retinal deactivation, or bradyopsia, as they have named it. As director of the Berman-Gund Laboratory for the Study of Retinal Degeneration, Berson sits on a trove of electroretinograms (ERGs). The team searched this database and quickly recognized (from ERGs that became substantially reduced by successive flashes of light) one case of bradyopsia in a Guatemalan patient (see figure). But to their surprise, when the authors sequenced this patient's RGS9 gene, they found it was normal. As it turns out, this patient has a mutation in a gene for R9AP, an RGS9 anchor protein. R9AP increases the rate of retinal deactivation by almost 70-fold because it anchors RGS9 to the photoreceptor cell membrane where the phototransduction machinery is found. In the Guatemalan patient, a frameshift mutation in R9AP, caused by insertion of a single nucleotide, changes all but the first 65 amino acids of the protein. So what does all this mean for patients with bradyopsia? Most of these patients have optimal or slightly suboptimal vision, which can deteriorate to poor acuity (less than 20/200) in certain situations, such as when trying to track a moving object that is poorly lit. Sandberg was able to document this deficiency through a test of dynamic acuity, the ability to see moving letters. "One patient could not detect an inch-high, gray letter E moving across a computer screen about three feet away," said Nishiguchi. But being homozygous recessive for the mutations, the patients have had the condition from birth and, for the most part, have learned to deal with it. It is unlikely that there will be a cure for bradyopsia anytime soon. Those affected, who probably number a couple hundred in the U.S., can still take some consolation that the condition is unlikely to cause further deterioration. They may also get peace of mind from knowing that they really are not seeing things. --Tom Fagan |
Thaddeus Dryja (above, on left), Koji Nishiguchi, and colleagues have found a genetic basis for a rare vision problem that they call bradyopsia. Affected individuals respond normally to one photon, but fail to see a second one that follows shortly after. This can be detected by ERGs (at right) of mixed cone/rod responses (left) to 0.5 Hz single flashes and cone-isolated responses (right) to 30 Hz flickering light. In contrast to a normal patient (top), an R9AP patient (bottom) initially has normal (red) but subsequently diminished responses to successive light flashes. (Photo by Steve Gilbert)