Functional abnormalities in transgenic mice expressing a mutant rhodopsin gene.
OBJECTIVE
To evaluate the consequences of the expression of a mutant mouse opsin gene on rod- and cone-mediated function. Experimental conditions were chosen to provide a basis of comparison to the results reported for patients with autosomal dominant retinitis pigmentosa (ADRP) in whom the proline at position 23 has been replaced by a histidine (P23H).


METHODS
The mutated gene product resulted in three substitutions in the rhodopsin molecule: P23H, glycine for valine at position 20 (V20G), and leucine for proline at position 27 (P27L). Mice positive for the transgene were differentiated from normal littermates by the polymerase chain reaction. Electroretinograms (ERGs) were obtained from anesthetized mice between 1 and 9 months of age. After photically bleaching approximately 18% of the available rhodopsin, the time course of rod dark adaptation was examined by monitoring rod ERG amplitude recovery. Rhodopsin densitometry was used to determine the relative amounts of rhodopsin in the retinae of normal and transgenic mice.


RESULTS
ERGs obtained from transgenic mice showed a significant reduction in rod-mediated response amplitude at 1 month of age and a relatively slow progressive decrease thereafter. Cone-mediated ERGs, on the other hand, were nearly normal in amplitude for approximately the first 5 months after birth, but at later ages response amplitudes also underwent a progressive decline. In the normal retina, rod ERG amplitudes returned to prebleach levels within 30 minutes, whereas in transgenic mice response amplitudes did not recover within a 2-hour test period. The age-related decline in rod-mediated electroretinal potentials seen in transgenic mice was paralleled by a concomitant fall in rhodopsin density, and the sensitivity losses obtained electroretinographically could be accounted for solely on the basis of reduced quantal absorption.


CONCLUSIONS
The pattern of functional changes seen in the transgenic mice are in good agreement with those reported in patients with ADRP with the P23H mutation in the rhodopsin gene. Particularly noteworthy is the fact that the changes in rhodopsin density and visual sensitivity are associated with a progressive shortening of the rod outer segments; the histologic changes induced by the disease process in patients with ADRP have yet to be determined.
Goto
Y
Y
Hines Veterans Administration Hospital.
Peachey
N S
NS
Ripps
H
H
Naash
M I
MI
D000818:Animals; D003623:Dark Adaptation; D003720:Densitometry; D004195:Disease Models, Animal; D004596:Electroretinography; D015870:Gene Expression; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D010786:Photoreceptor Cells / Q000737:chemistry / Q000502:physiology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000503:physiopathology; D012243:Rhodopsin / Q000032:analysis / Q000235:genetics*; D017299:Rod Opsins / Q000235:genetics
D017299:Rod Opsins; D012243:Rhodopsin