Insights into the function of Rim protein in photoreceptors and etiology of Stargardt's disease from the phenotype in abcr knockout mice.
Rim protein (RmP) is an ABC transporter of unknown function in rod outer segment discs. The human gene for RmP (ABCR) is affected in several recessive retinal degenerations. Here, we characterize the ocular phenotype in abcr knockout mice. Mice lacking RmP show delayed dark adaptation, increased all-trans-retinaldehyde (all-trans-RAL) following light exposure, elevated phosphatidylethanolamine (PE) in outer segments, accumulation of the protonated Schiff base complex of all-trans-RAL and PE (N-retinylidene-PE), and striking deposition of a major lipofuscin fluorophore (A2-E) in retinal pigment epithelium (RPE). These data suggest that RmP functions as an outwardly directed flippase for N-retinylidene-PE. Delayed dark adaptation is likely due to accumulation in discs of the noncovalent complex between opsin and all-trans-RAL. Finally, ABCR-mediated retinal degeneration may result from "poisoning" of the RPE due to A2-E accumulation, with secondary photoreceptor degeneration due to loss of the RPE support role.
Weng
J
J
Center for Basic Neuroscience and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Mata
N L
NL
Azarian
S M
SM
Tzekov
R T
RT
Birch
D G
DG
Travis
G H
GH
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000221:Adaptation, Ocular; D000818:Animals; D003624:Darkness; D004596:Electroretinography; D015698:Genomic Library; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000503:physiopathology; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism; D012160:Retina / Q000502:physiology / Q000503:physiopathology; D012172:Retinaldehyde / Q000493:pharmacokinetics; D012243:Rhodopsin / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000737:chemistry / Q000503:physiopathology*
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D010743:Phospholipids; D012243:Rhodopsin; D012172:Retinaldehyde