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Misfolded proteins in eye cells implicated in retinitis pigmentosa

Misfolded proteins in certain cells of the eye may be responsible for one form of blindness, MIT scientists led by Nobel laureate Har Gobind Khorana reported in the May 14 Proceedings of the National Academy of Sciences. The defective proteins are the consequence of genetic mutations associated with the disease retinitis pigmentosa.

The work, which defines for the first time the result of the mutations, is "an important contribution to unfolding the mystery of some forms of retinitis pigmentosa," said Eliot L. Berson, MD, of Harvard Medical School and the Massachusetts Eye and Ear Infirmary in a commentary accompanying the two MIT papers.

Authors of the papers are Pere Garriga and Xun Liu, both postdoctoral fellows in the Department of Biology, and Dr. Khorana, the Alfred P. Sloan Professor Emeritus of Biology and Chemistry. Professor Khorana shared the 1968 Nobel Prize in medicine or physiology.

Retinitis pigmentosa affects about 1.5 million people worldwide, most of whom are legally blind by age 60. The disease is inherited; mutations linked to it have been found in several genes.

The MIT work focused on mutations associated with the gene for rhodopsin, a photosensitive pigment found in the rod cells of the eye. Mutations in the rhodopsin gene "represent the most common cause of retinitis pigmentosa for which a molecular genetic basis is known," Dr. Berson wrote.

Said Professor Khorana, "In these papers we describe and characterize what the chemical consequence of these mutations is. That consequence is really an effect on the structure of one protein."

Rhodopsin is normally formed when a precursor protein, opsin, binds to 11-cis retinal, a molecule related to Vitamin A. To do so, the opsin must be properly folded in the cell to form a pocket for 11-cis retinal. The scientists found that the two classes of rhodopsin mutations they studied resulted in either completely misfolded opsin, or a mixture of correctly folded and misfolded opsin. "Misfolded opsins don't bind to 11-cis retinal, so they are not functional," Professor Khorana said. In addition, the researchers report that "the misfolded proteins appear to be less compact and more open than the correctly folded proteins."

The MIT findings may help doctors understand certain clinical observations associated with retinitis pigmentosa. For example, doctors are puzzled by the fact that people of about the same age with the same gene defect often show different levels of disease. The discovery of a mixture of correctly folded and misfolded opsins "raises the possibility that rod [cells] with this mutation contain different ratios of folded and misfolded opsins," Dr. Berson wrote. "Varying amounts of misfolded opsin perhaps could lead to [the] variable amount of rod malfunction seen among patients of comparable age with the. mutation."

The work also gives insight into the biochemical nature of opsin folding. Specifically, the scientists showed that correctly folded opsin is characterized by a unique chemical bond at two different sites along the opsin molecule.

With this week's two PNAS papers, Professor Khorana and colleagues in his laboratory have now published 16 papers on the structure and function of rhodopsin. "We've been working on rhodopsin for about 10 years," he said. "As a result of this really very basic research, we have now defined what the mutations actually do."

The rhodopsin research itself grew out of Professor Khorana's work on bacteriorhodopsin (a form of rhodopsin found in bacteria). He studied that protein for some 19 years.

The work reported in PNAS was supported by a grant from the NIH and fellowships from the Ministerio de Educacion y Ciencia and Direccio General de Recerca de Catalunya of Spain.

A version of this article appeared in MIT Tech Talk on May 15, 1996.

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