Rpe65 Leu450Met variant is associated with reduced levels of the retinal pigment epithelium lipofuscin fluorophores A2E and iso-A2E.
There is a growing body of evidence that the nondegradable fluorophores that accumulate as the lipofuscin of retinal pigment epithelium (RPE) are involved in mechanisms leading to the degeneration of RPE in macular degeneration. Most of the constituents of RPE lipofuscin are inadvertent products of the retinoid visual cycle, the enzymatic pathway by which the 11-cis-retinal chromophore of rhodopsin is generated. Indeed, a major constituent of RPE lipofuscin, the pyridinium bisretinoid A2E, is a diretinal conjugate that forms in photoreceptor cells and is deposited in RPE cells as a consequence of the phagocytosis of the outer segment membrane by RPE cells. Given the adverse effects of A2E, there is considerable interest in combating its deposition so as to protect against vision loss. These efforts, however, necessitate an understanding of factors that modulate its formation. Here we show that an amino acid variant in murine Rpe65, a visual-cycle protein required for the regeneration of 11-cis-retinal, is associated with reduced A2E accumulation.
Department of Ophthalmology, Columbia University, New York, NY 10027, USA.
So Ra
SR
Kim
Nathan
N
Fishkin
Jian
J
Kong
Koji
K
Nakanishi
Rando
R
Allikmets
Janet R
JR
Sparrow
D000818:Animals; D002352:Carrier Proteins; D005136:Eye Proteins; D014644:Genetic Variation; D007536:Isomerism; D008062:Lipofuscin / Q000096:biosynthesis*; D008268:Macular Degeneration; D051379:Mice; D008815:Mice, Inbred Strains; D020125:Mutation, Missense; D010857:Pigment Epithelium of Eye / Q000737:chemistry*; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011726:Pyridinium Compounds; D012176:Retinoids; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D005136:Eye Proteins; D008062:Lipofuscin; D011506:Proteins; D011726:Pyridinium Compounds; D012176:Retinoids; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C112040:A2-E (N-retinylidene-N-retinylethanolamine)