title: R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal.
abstract: RPE65 is a retinal pigment epithelial protein essential for the regeneration of 11-cis-retinal, the chromophore of cone and rod visual pigments. Mutations in RPE65 lead to a spectrum of retinal dystrophies ranging from Leber's congenital amaurosis to autosomal recessive retinitis pigmentosa. One of the most frequent missense mutations is an amino acid substitution at position 91 (R91W). Affected patients have useful cone vision in the first decade of life, but progressively lose sight during adolescence. We generated R91W knock-in mice to understand the mechanism of retinal degeneration caused by this aberrant Rpe65 variant. We found that in contrast to Rpe65 null mice, low but substantial levels of both RPE65 and 11-cis-retinal were present. Whereas rod function was impaired already in young animals, cone function was less affected. Rhodopsin metabolism and photoreceptor morphology were disturbed, leading to a progressive loss of photoreceptor cells and retinal function. Thus, the consequences of the R91W mutation are clearly distinguishable from an Rpe65 null mutation as evidenced by the production of 11-cis-retinal and rhodopsin as well as by less severe morphological and functional disturbances at early age. Taken together, the pathology in R91W knock-in mice mimics many aspects of the corresponding human blinding disease. Therefore, this mouse mutant provides a valuable animal model to test therapeutic concepts for patients affected by RPE65 missense mutations.
authors.affiliation: Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Frauenklinikstr. 24, 8091 Zurich, Switzerland. samam@opht.uzh.ch
authors.forename: Marijana
authors.initials: M
authors.lastname: Samardzija
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Vitus
authors.initials: V
authors.lastname: Oberhauser
authors.forename: Markus
authors.initials: M
authors.lastname: Thiersch
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Remé
authors.forename: Mathias
authors.initials: M
authors.lastname: Seeliger
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
authors.forename: Andreas
authors.initials: A
authors.lastname: Wenzel
mesh_terms: D017668:Age of Onset; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D010786:Photoreceptor Cells / Q000378:metabolism; D017354:Point Mutation; D012164:Retinal Diseases / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D012172:Retinaldehyde / Q000378:metabolism*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D012172:Retinaldehyde; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase