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(1-7). Inheritance of t he diseases is generally autosomal dominant and about 40 different rho dopsin mutations have been documented. Although the cell death and ret inal degeneration associated with RP have been suggested to result fro m improper folding and accumulation of the mutant proteins in rod phot oreceptor cells(8), 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 prot ein in vitro(9-11); that is, the mutants can catalytically activate th e G protein transducin in the absence of chromophore and in the absenc e of light. Similarly, mutation of Ala 292 --> Glu activates opsin in vitro and causes night blindness(7). We show here that the mutation Gl y 90 --> Asp (G90D) in the second transmembrane segment of rhodopsin, which causes congenital night blindness(12), also constitutively activ ates opsin. Furthermore, we show that Asp 90 can substitute for the Sc hiff base counterion, Glu 113, which is located in the third transmemb rane segment of the protein. This demonstrates the proximity of Asp 90 and Lys 296 in the three-dimensional structure of rhodopsin and sugge sts that the constitutively activating mutations operate by a common m olecular mechanism, disrupting a salt bridge between Lys 296 and the S chiff base counterion, Glu 113.