title: Rpe65 as a modifier gene for inherited retinal degeneration.
abstract: Light accelerates progression of retinal degeneration in many animal models of retinitis pigmentosa (RP). A sequence variant in the Rpe65 gene (Rpe65(450Leu) or Rpe65(450Met)) can act as a modulator of light-damage susceptibility in mice by influencing the kinetics of rhodopsin regeneration and thus by modulating the photon absorption. Depending on exposure duration and light intensity applied, white fluorescent light induces photoreceptor apoptosis and retinal degeneration in wild-type mice by the activation of one of two known molecular pathways. These pathways depend, respectively, on activation of the transcription factor c-Fos/AP-1 and on phototransduction activity. Here we tested Rpe65 as a genetic modifier for inherited retinal degeneration and analysed which degenerative pathway is activated in a transgenic mouse model of autosomal dominant RP. We show that retinal degeneration was reduced in mice expressing the Rpe65(450Met) variant and that these mice retained more visual pigment rhodopsin than did transgenic mice expressing the Rpe65(450Leu) variant. In addition, lack of phototransduction slowed retinal degeneration whereas ablation of c-Fos had no effect. We conclude that sequence variations in the Rpe65 gene can act as genetic modifiers in inherited retinal degeneration, presumably by regulating the daily rate of photon absorption through the modulation of rhodopsin regeneration kinetics. Increased absorption of photons and/or light sensitivity appear to accelerate retinal degeneration via an apoptotic cascade which involves phototransduction but not c-Fos.
authors.affiliation: Laboratory for Retinal Cell Biology, University Eye Hospital, Frauenklinikstrasse 24, CH-8091 Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Samardzija
authors.forename: A
authors.initials: A
authors.lastname: Wenzel
authors.forename: M
authors.initials: M
authors.lastname: Naash
authors.forename: C E
authors.initials: CE
authors.lastname: Remé
authors.forename: C
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000367:Age Factors; D000818:Animals; D002352:Carrier Proteins; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D014644:Genetic Variation; D007930:Leucine / Q000235:genetics; D008715:Methionine / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012243:Rhodopsin / Q000235:genetics; D013997:Time Factors; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D007930:Leucine; D008715:Methionine; D012333:RNA, Messenger; D012243:Rhodopsin; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase