Mice carrying a targeted disruption of the rhodopsin gene develop a severe
degenerative retinopathy, failing to elaborate rod photoreceptor outer segm
ents (ROS), having no recordable rod electroretinogram (ERG) and losing all
of their rod cells over a period of similar to 12 weeks. Murine and human
rhodopsins differ in their amino acid sequences, Whether, or to what extent
, such variability might influence the ability of human rhodopsin to serve
as an adequate structural and functional substitute for the endogenous prot
ein in mouse rod cells bears direct relevance to exploiting the full utilit
y of Rho(-/-) animals as a model of degenerative retinal disease in man. We
crossed Rho(-/-) mice with mice expressing a wild-type human rhodopsin tra
nsgene at levels approximating to those of the endogenous protein, Immunohi
stological examination of retinal selections from such animals demonstrated
ROS of normal number and length and temporal expression of rhodopsin simil
ar to that observed in wild-type animals; that is, immunoreactivity to an a
nti-rhodopsin antibody became clearly evident by day 3 post-partum. Whereas
Rho(-/-) mice never display a rod ERG response, and even lose cone respons
es by 12 weeks of age, rescued mice showed 75% normal maximum amplitudes an
d had ERG b-wave thresholds (based on a 50 mu V criterion) within 0.1 log u
nit of normal wild-type at 20 weeks, and cone amplitudes remained normal at
this age. These data demonstrate very substantial structural and functiona
l rescue of the rod photoreceptors of Rho(-/-) mice and long-term preservat
ion by the human rhodopsin transgene.