Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness.
Mutations in the gene for the visual pigment rhodopsin cause retinitis pigmentosa (RP) and congenital night blindness. Inheritance of the diseases is generally autosomal dominant and about 40 different rhodopsin mutations have been documented. Although the cell death and retinal degeneration associated with RP have been suggested to result from improper folding and accumulation of the mutant proteins in rod photoreceptor cells, this may not account for the disease in all cases. For example, RP mutations at Lys 296, site of Schiff base linkage to the retinal chromophore, result in constitutive activation of the protein in vitro; that is, the mutants can catalytically activate the G protein transducin in the absence of chromophore and in the absence of light. Similarly, mutation of Ala 292-->Glu activates opsin in vitro and causes night blindness. We show here that the mutation Gly 90-->Asp (G90D) in the second transmembrane segment of rhodopsin, which causes congenital night blindness, also constitutively activates opsin. Furthermore, we show that Asp 90 can substitute for the Schiff base counterion, Glu 113, which is located in the third transmembrane segment of the protein. This demonstrates the proximity of Asp 90 and Lys 296 in the three-dimensional structure of rhodopsin and suggests that the constitutively activating mutations operate by a common molecular mechanism, disrupting a salt bridge between Lys 296 and the Schiff base counterion, Glu 113.
Rao
V R
VR
Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254.
Cohen
G B
GB
Oprian
D D
DD
D002460:Cell Line; D006801:Humans; D009154:Mutation; D009755:Night Blindness / Q000151:congenital / Q000235:genetics*; D011487:Protein Conformation; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012545:Schiff Bases
D012545:Schiff Bases; D012243:Rhodopsin