MEDICINE GENETICS : Gene Linked to Retinitis Pigmentosa Believed Isolated by UCLA Scientists

UCLA researchers believe they have isolated the gene that causes loss of vision in a strain of mice, a defect that serves as a model for retinitis pigmentosa, an inherited disease that has produced blindness in about 100,000 Americans and 1.5 million people worldwide.

Retinitis pigmentosa, commonly known as RP, is thought to be caused by a number of different genes. The gene isolated at UCLA, whose discovery is reported today in the prestigious Proceedings of the National Academy of Sciences, is the third that has been discovered this year--one in humans and two in mice--and the fifth overall.

The researchers believe that isolation of the mouse genes will lead to discovery of their human counterparts within a few months. Identification of the human genes will make it possible to screen fetuses for the genetic defect in families with a history of RP.

“This is really a great step forward for us because it will allow us to begin thinking . . . about more rational pathways for treatment,” said molecular geneticist John Nickerson of the National Eye Institute in Bethesda, Md. Currently, there is no therapy for RP.

The discovery will also help researchers understand how normal vision works. “Every time a new gene is found, we learn something more about the normal process (of vision),” said geneticist Jeanette Felix of the RP Foundation Fighting Blindness in Baltimore.

But researchers cautioned that there may be other, as yet unidentified genes that also cause RP. And because there are a number of different genes involved in causing the disease, it will probably be necessary to develop multiple therapies for it, Felix said.

Scientists know that there are three major inheritance patterns for RP: X-linked, dominant and recessive.

In the X-linked form, which accounts for about 10% of RP cases, the defective gene is found on the X chromosome, which occurs only in males. Such genes are the easiest to identify because they are already known to be on the X chromosome, and two different X-linked RP genes have been identified in the past.

In the dominant form, which accounts for about 20% of RP cases, a child who receives the gene from either parent will develop the disease. In July, researchers from Ireland and Texas reported that they had identified the dominant gene that causes RP in a large Irish family.

In the recessive form, which also accounts for about 20% of RP cases, a fetus will develop the disease only if it receives a defective gene from both parents. In March, Texas researchers reported that they had found a recessive RP gene in a strain of mice different from the mice used by the UCLA researchers. The UCLA researchers have now found a second recessive gene.

In the remaining 50% of RP cases, only one member of a family has the disease , so researchers are not able to identify an inheritance pattern. The disease in these cases might be caused by one of the five known RP genes, or it might be caused by as-yet-unknown genes.

The UCLA team, led by geneticist Debora B. Farber of the Jules Stein Eye Institute, has been working with a strain of mice called rd, for retinal degeneration. In the rd mice, the photoreceptor cells in their eyes, which convert light waves into an electrical signal for transmission to the brain, begin to degenerate about nine days after birth.

Within 15 days after birth, half the photoreceptors are gone and by the end of the first month, the mice are completely blind. Farber’s group had previously identified the biochemical defect that causes this cell death, a defective enzyme that allows a chemical normally present in the photoreceptor cells to build up to toxic levels.

Farber and her colleagues have now isolated from the photoreceptor cells of these mice a piece of DNA (deoxyribonucleic acid, the genetic blueprint of life) that is different from its counterpart in healthy mice. They believe, but have not yet conclusively proved, that the DNA fragment is the gene that causes the disease.

The group is currently trying to identify each of the 3,600 individual chemicals, called bases, of which the fragment is composed. When they have done that, they will know whether the fragment is the blueprint for the enzyme known to be defective in the rd mice, and thus whether it is the gene that causes the disease.

Because they are confident that it is the gene, however, they are already searching for a corresponding piece of DNA in human cells. Because of their similarity in function, the human gene should be closely related to the mouse gene, making its identification relatively easy. Farber said the group hopes to find it “within a few months.”

And once the human gene has been identified, a prenatal test for it can be developed within a matter of weeks.