title: Rod and cone visual cycle consequences of a null mutation in the 11-cis-retinol dehydrogenase gene in man.
abstract: Vertebrate vision starts with photoisomerization of the 11-cis-retinal chromophore to all-trans-retinal. Biosynthesis of 11-cis-retinal is required to maintain vision. A key enzyme catalyzing the oxidation of 11-cis-retinol is 11-cis-retinol dehydrogenase (11-cis-RDH), which is encoded by the RDH5 gene. 11-cis-RDH is expressed in the RPE and not in the neural retina. The consequences of a lack of 11-cis-RDH were studied in a family with fundus albipunctatus. We identified the causative novel RDH5 mutation, Arg157Trp, that replaces an amino acid residue conserved among short-chain alcohol dehydrogenases. Three-dimensional structure modeling and in vitro experiments suggested that this mutation destabilizes proper folding and inactivates the enzyme. Studies using RPE membranes indicated the existence of an alternative oxidizing system for the production of 11-cis-retinal. In vivo visual consequences of this null mutation showed complex kinetics of dark adaptation. Rod and cone resensitization was extremely delayed following full bleaches; unexpectedly, the rate of cone recovery was slower than rods. Cones showed a biphasic recovery with an initial rapid component and an elevated final threshold. Other unanticipated results included normal rod recovery following 0.5% bleach and abnormal recovery following bleaches in the 2-12% range. These intermediate bleaches showed rapid partial recovery of rods with transitory plateaux. Pathways in addition to 11-cis-RDH likely provide 11-cis-retinal for rods and cones and can maintain normal kinetics of visual recovery but only under certain constraints and less efficiently for cone than rod function.
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle.
authors.forename: Françoise
authors.initials: F
authors.lastname: Haeseleer
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle.
authors.forename: Geeng-Fu
authors.initials: GF
authors.lastname: Jang
authors.affiliation: Biological Structure and BioMolecular Structure Center, University of Washington, Seattle.
authors.forename: Christophe L M J
authors.initials: CLMJ
authors.lastname: Verlinde
authors.affiliation: Department of Ophthalmology, Stanford University, Stanford.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Marmor
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle.|Department of Chemistry, University of Washington, Seattle.|Department of Pharmacology, University of Washington, Seattle.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D000221:Adaptation, Ocular / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D000595:Amino Acid Sequence / Q000235:genetics; D000918:Antibody Specificity; D004252:DNA Mutational Analysis; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014785:Vision, Ocular / Q000235:genetics
chemical_list: D009249:NADP; D000429:Alcohol Oxidoreductases; C022520:retinol dehydrogenase