Inability to see well in the dark may be an ominous sign in a child. Though it could just signal a need to eat more carrots or take vitamin A supplements, for more than a million people around the world (one out of every 4,000) it is the first symptom of retinitis pigmentosa (RP), a genetic disorder that may leave them totally blind by the age of 40.
"Sometime between their teens and their thirties, depending on the family, their retinas begin to degenerate," says Jeremy Nathans, an HHMI investigator at the Johns Hopkins University School of Medicine who has been studying the genetic errors that cause the disease.
First, the rod cells die at the retina's periphery. Then these zones of cell death slowly expand, leaving only a small patch of functioning retinal cells near the center of vision. The patients' visible world contracts to a narrow tunnel of light. Finally, the dying tissue may take everything with it, including the precious cones in the central retina, which are responsible for high-acuity vision.
"The retina doesn't regenerate," explains Nathans. "If any part of it goes, you won't get it back. And so far, there is no effective therapy for RP."
Until five years ago, no one even knew the cause of RP. Thinking the disease might be related to a defect in rhodopsin, the receptor protein of rod cells (which are responsible for night vision), Nathans began to collect blood samples from patients so he could study their DNA.
In 1989, Peter Humphries at Trinity College in Dublin, Ireland, found the location of a gene defect in a very large Irish family that had a dominant form of the disease (in which the inheritance of a mutated gene from just one parent causes the disease).
Remarkably, Humphries mapped the defect to the same region of chromosome 3 where Nathans had located the gene for rhodopsin. Since then, two teams of scientistsThaddeus Dryja at the Massachusetts Eye and Ear Infirmary, and Nathans and HHMI associate Ching-Hwa Sung at Johns Hopkinshave shown that about one-fourth of patients with the dominant form of the disease have mutations in their gene for rhodopsin. Other forms of RP result from mutations in different genes.
Most of the errors in the rhodopsin gene cause the protein to be unstable, Nathans says. "Either it doesn't fold correctly to start with, or once it folds, it falls apart." There seems to be a correlation between the kind of mutation and the severity of the disease.
To find out how these mutations damage the retina and what drugs might be designed to prevent this process, several groups of researchers recently inserted defective genes for rhodopsin into mice, where these mutant genes cause an RP-like disease. They hope to use this mouse model to develop new treatments.
Nathans points out that the retina normally consumes more energy per gram than any other tissue in the body. A rod cell that needs to dispose of mutant rhodopsin must expend further energy still, which may "push the cell over the edge, so that it runs out of energy and dies," taking along the adjoining cones. Nathans speculates that perhaps a drug that reduced energy consumption in the rod cells might minimize or delay the retina's degenerationand thereby save the patient's cones.
"RP is a slow disease," says Nathans. "It may take 30 years to develop, so if we can delay its progression by another 30 years, that's virtually a cure."
For more information on Jeremy Nathans and the study of vision, see 1997 Holiday Lectures.
A healthy retina (left), as seen through an ophthalmoscope, has a regular structure. In RP (right), retinal cells die, starting at the periphery. Cells laden with the black pigment melanin invade the dead retinal tissue, producing black deposits that are the hallmarks of RP.
Photo: BPEI, Univ. of Miami
Cones are tightly packed in the fovea, which is specialized for high-acuity vision. In a healthy retina (top), cones appear tall and straight. In the retinas of people with advanced RP, cones lose their light-sensitive outer segments (shown with an "*"), and then die.
So many cones have died in the retina seen in the bottom picture that only one layer of cones remains (n indicates the cones' nuclei) and the whole area has shrunk. The two pictures were taken under a microscope at the same magnification.
Photo: Ann Milam