The color purple makes all the difference between sight andblindness, between light and dark. In the retina, a chemical calledvisual purple, or rhodopsin, starts incoming light on its way toforming images in the brain. Light falling on the visual purpleprotein activates it by bleaching its reddish-purplish color.
Rhodopsin is the photosensitive pigment in the retina's rodphotoreceptors. These structures are responsible for night vision, theability to see in very dim light. Rhodopsin gene mutations areresponsible for sight-threatening retinitis pigmentosa (RP). Thisdisease starts out as partial nightblindness, because of dysfunctioningrods. It ultimately progresses to total blindness, as the retina's rodsand cones both die.
How RP-associated mutant rhodopsin translates into thenightblindness and retinal degeneration that occurs in RP is notknown. But an article in the current Proceedings of the NationalAcademy of Sciences (PNAS), dated Jan. 31, documents congenitalnightblindness in one unusual family, and casts some light on thepathogenesis of RP.
In a paper titled, "Dark-light: model for nightblindness from thehuman rhodopsin Gly-90-to-Asp mutation," first author Paul Sievingand his colleagues at the University of Michigan Medical School,Ann Arbor, elucidate the underlying genetic cause of the familialnightblindness they saw in a single four-generation kindred. Of its 83members, 35 had nyctalopia, the ophthalmological name fornightblindness.
Rhodopsin: The Basic `Vision Thing'
Their study found that a change of one amino acid residue inrhodopsin _ from a glycine to an aspartic acid at position 90 _ isthe dominant mutation that afflicted this family with the inheritedinability to see in near darkness. It greatly increased spontaneousactivation of this mutant rhodopsin; affecting family members whocannot perceive dim-light images because the resulting sensory"noise" is too high. In essence, Sieving told BioWorld Today, theyapparently "see" a high background level of light when it is dark.
Sieving, a clinical neuroscientist, said that his work began one daywhen "an individual with no night vision came into the clinic. Hefunctioned well in bright light, but it apparently never got darkenough for him to see dim images." Sieving's first hypothesis wasthat this patient had a mutation in his rhodopsin gene thatdestabilized its expressed protein.
As detailed in PNAS, Sieving believes that the extra negative chargein the transmembrane helix of rhodopsin caused by the glycine-to-aspartic acid mutation allows the visual purple to react spontaneouslyeven in the absence of light. In fact, he reported, the mutantrhodopsin exhibits a 10,000-fold increase in its rate of thermalisomerization. The result for members of this family is a false visualsensation, even in the absence of light. They cannot distinguish thisso-called "dark-light" from a true light response.
Nightblindness, Yes; Retinal Degeneration, No
Paradoxically, the congenital nightblindness in this family resultingfrom the rhodopsin mutation is not associated with the usual retinaldegeneration seen in retinitis pigmentosa _ at least until membersreach middle age. "Surprisingly," Sieving said, "the retinas in ouroriginal patient looked fine."
But what about the retinal degeneration seen in RP sufferers? "Howone gets from rhodopsin mutations to retinal degeneration," Sievingobserved, "is a big question. At least 60 different mutations havebeen documented for the visual purple gene, and they result in avaried clinical picture."
Finding this particular mutation, he added, "is the first step in sortingout RP's symptoms. We now have the transgenes set up in mice.With this model system, we can do a lot more in terms of trying tounderstand the effect of this mutation, and possibly manipulating thesystem to circumvent it."
RP Therapy In Its Infancy
Given the complexity of the RP syndrome, where does treatmentdevelopment stand? Jeanette Felix, science director at the RetinitisPigmentosa Foundation Fighting Blindness, told BioWorld Today:"Research aimed at developing treatments for RP is just in itsinfancy. In addition to the rhodopsin gene, mutations in several othergenes, including one that is X-chromosome-linked, cause RP-likesyndromes. Both the mutations found and the resulting phenotypesare varied and complex, with clinical presentations ranging fromnightblindness to retinal degeneration, both peripheral and central."
Although sorting through these mutations and finding the commonthread that leads to retinal degeneration remains a major task, Felixobserved that "most forms of degenerative eye disease now seem tobe related. In fact, while the RP population is small, the apparentinterrelatedness of these diseases gives us hope that what is learnedin RP research will be applicable to other conditions, such as age-related macular degeneration, which affects 6 million people." n
-- Chester Bisbee, Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.