DARK-LIGHT - MODEL FOR NIGHTBLINDNESS FROM THE HUMAN RHODOPSIN GLY-90-]ASP MUTATION

A human rhodopsin mutation, Gly-90 --> Asp (Gly90Asp), cosegregated wi th an unusual trait of congenital nightblindness in 22 at-risk members of a large autosomal dominant kindred. Although rhodopsin mutations t ypically are associated with retinal degeneration, Gly90Asp-affected s ubjects up to age 33 did not show clinical retinal changes. Absolute t hreshold for visual perception was elevated nearly 3 logarithmic units in 7 individuals tested (ages 11-64), indicating greatly compromised rod threshold signaling. However, in vivo rhodopsin density was normal . Although the 38-year-old proband could not perceive dim lights, his rod increment threshold function was normal on brighter backgrounds. T he impaired rod vision for dim but not bright backgrounds is consisten t with a mechanism of increased basal ''dark-light'' from thermal isom erization equivalent to an increase of >10(4) over that of wild-type r hodopsin. The Gly90Asp mutation on the second transmembrane helix plac es an extra negative charge in the opsin pocket; this could contribute to partial deprotonation of the retinal Schiff base and thereby incre ase photoreceptor noise. In vitro evidence had suggested that transduc in is activated by the Gly90Asp mutation in the absence of both the re tinal chromophore and light, termed ''constitutive activity.'' The app arent preservation of functioning rods despite extensive and lifelong nightblindness in this kindred is inconsistent with one current hypoth esis that chronic rod activation from constitutively active mutant rho dopsin necessarily contributes significantly to photoreceptor demise i n human retinal dystrophies.