Constitutive "light" adaptation in rods from G90D rhodopsin: A mechanism for human congenital nightblindness without rod cell loss

A dominant form of human congenital nightblindness is caused by a gly90-->a sp (G90D) mutation in rhodopsin. G90D has been shown to activate the photot ransduction cascade in the absence of light in vitro. Such constitutive act ivity of G90D rhodopsin in vivo would desensitize rod photoreceptors and le ad to nightblindness. In contrast, other rhodopsin mutations typically give rise to nightblindness by causing rod cell death. Thus, the proposed desen sitization without rod degeneration would be a novel mechanism for this dis order. To explore this possibility, we induced mice to express G90D opsin i n their rods and then examined rod function and morphology, after first cro ssing the transgenic animals with rhodopsin knock-out mice to obtain approp riate levels of opsin expression. The G90D mouse opsin bound the chromophor e and formed a bleachable visual pigment with lambda (max) of 492 nm that s upported rod photoresponses. (G+/-, R+/-) retinas, heterozygous for both G9 0D and wildtype (WT) rhodopsin, possessed normal numbers of photoreceptors and had a normal rhodopsin complement but exhibited considerable loss of ro d sensitivity as measured electroretinographically. The rod photoresponses were desensitized, and the response time to peak was faster than in (R+/-) animals. An equivalent desensitization resulted by exposing WT retinas to a background light producing 82 photoisomerizations rod(-1) sec(-1), suggest ing that G90D rods in darkness act as if they are partially "light-adapted. " Adding a second G90D allele gave (G+/+, R+/-) animals that exhibited a fu rther increase of equivalent background light level but had no rod cell los s by 24 weeks of age. (G+/+, R-/-) retinas that express only the mutant rho dopsin develop normal rod outer segments and show minimal rod cell loss eve n at 1 year of age. We conclude that G90D is constitutively active in mouse rods in vivo but that it does not cause significant rod degeneration. Inst ead, G90D desensitizes rods by a process equivalent to light adaptation.