Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation.
A human rhodopsin mutation, Gly-90-->Asp (Gly90Asp), cosegregated with an unusual trait of congenital nightblindness in 22 at-risk members of a large autosomal dominant kindred. Although rhodopsin mutations typically are associated with retinal degeneration, Gly90Asp-affected subjects up to age 33 did not show clinical retinal changes. Absolute threshold 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. The impaired rod vision for dim but not bright backgrounds is consistent with a mechanism of increased basal "dark-light" from thermal isomerization equivalent to an increase of > 10(4) over that of wild-type rhodopsin. The Gly90Asp mutation on the second transmembrane helix places an extra negative charge in the opsin pocket; this could contribute to partial deprotonation of the retinal Schiff base and thereby increase photoreceptor noise. In vitro evidence had suggested that transducin is activated by the Gly90Asp mutation in the absence of both the retinal chromophore and light, termed "constitutive activity." The apparent preservation of functioning rods despite extensive and lifelong night-blindness in this kindred is inconsistent with one current hypothesis that chronic rod activation from constitutively active mutant rhodopsin necessarily contributes significantly to photoreceptor demise in human retinal dystrophies.
Department of Ophthalmology, University of Michigan, Ann Arbor 48105.
P A
PA
Sieving
J E
JE
Richards
F
F
Naarendorp
E L
EL
Bingham
K
K
Scott
M
M
Alpern
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D003720:Densitometry; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009755:Night Blindness / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000503:physiopathology; D012243:Rhodopsin / Q000096:biosynthesis / Q000235:genetics*; D014796:Visual Perception
D012243:Rhodopsin