Generation and analysis of transgenic mice expressing P216L-substituted rds/peripherin in rod photoreceptors.
OBJECTIVE
In this study, the authors present the biochemical, morphologic, and physiological analyses of a transgenic mouse model for retinal degeneration slow (RDS)-mediated retinitis pigmentosa caused by a proline 216 to leucine (P216L) amino acid substitution in rds/peripherin.


METHODS
The authors assembled a mutant rds transgene that encodes rds/peripherin with a P216L substitution. Transgenic mice were generated on wild-type (+/+), heterozygous (rds-/+), and homozygous (rds-/rds-) null genetic backgrounds. These mice were analyzed biochemically, by light and electron microscopy, and by electroretinography.


RESULTS
In P216L-transgenic mice on a +/- background, the authors observed expression-level-dependent photoreceptor degeneration and outer-segment shortening. Expression of the P216L transgene on an rds-/+ background resulted in more severe photoreceptor degeneration and outer-segment dysplasia than seen in nontransgenic rds-/+ mutants. Severely dysplastic outer segments were detectable in P216L transgenics on an rds-/rds-null background. The reduction in b-wave amplitudes by electroretinography were well correlated with the degree of photoreceptor degeneration, but not outer-segment dysplasia in these different rds mutants.


CONCLUSIONS
The phenotype in P216L-transgenic mice on an rds-/+ genetic background probably is caused by a combination of two genetic mechanisms: a direct dominant effect of the P216L substituted protein, and a reduction in the level of normal rds/peripherin. The expression pattern of the normal and mutant genes in these animals is similar to that predicted for humans with RDS-mediated autosomal-dominant retinitis pigmentosa. These mice may thus be considered an animal model for this disease.
Kedzierski
W
W
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9111, USA.
Lloyd
M
M
Birch
D G
DG
Bok
D
D
Travis
G H
GH
D000818:Animals; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D004596:Electroretinography; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D007381:Intermediate Filament Proteins / Q000096:biosynthesis* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins; D064531:Peripherins; D010641:Phenotype; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D019076:Transgenes
D017931:DNA Primers; D005136:Eye Proteins; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C578994:PRPH protein, human; C578997:PRPH2 protein, human; D064531:Peripherins; C578996:Prph2 protein, mouse