Dark-light: Model for nightblindness from the human rhodopsin Gly-90 → Asp mutation

Paul A. Sieving, Julia E. Richards, Franklin Naarendorp, Eve L. Bingham, Kathy Scorrt, Mathew Alpern

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

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 >104 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.

Original languageEnglish (US)
Pages (from-to)880-884
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number3
DOIs
StatePublished - Jan 31 1995
Externally publishedYes

Keywords

  • electrophysiology
  • genetic disease
  • neurodegeneration
  • retina
  • signal transduction

ASJC Scopus subject areas

  • General

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