title: Severe retinal degeneration caused by a novel rhodopsin mutation.
abstract: OBJECTIVE
  To identify a new mouse mutation developing early-onset dominant retinal degeneration, to determine the causative gene mutation, and to investigate the underlying mechanism.
  
  
  METHODS
  Retinal phenotype was examined by indirect ophthalmoscopy, histology, transmission electron microscopy, immunohistochemistry, Western blot analysis, and electroretinography. Causative gene mutation was determined by genomewide linkage analysis and DNA sequencing. Structural modeling was used to predict the impact of the mutation on protein structure.
  
  
  RESULTS
  An ENU-mutagenized mouse line (R3), displaying attenuated retinal vessels and pigmented patches, was identified by fundus examination. Homozygous R3/R3 mice lost photoreceptors rapidly, leaving only a single row of photoreceptor nuclei at postnatal day 18. The a- and b-waves of ERG were flat in R3/R3 mice, whereas heterozygous R3/+ mice showed reduced amplitude of a- and b-waves. The R3/+ mice had a slower rate of photoreceptor cell loss than compound heterozygous R3/- mice with a null mutant allele. The R3 mutation was mapped and verified to be a rhodopsin point mutation, a c.553T>C for a p.C185R substitution. The side chain of Arg(185) impacted on the extracellular loop of the protein. Mutant rhodopsin-C185R protein accumulated in the photoreceptor inner segments, cellular bodies, or both.
  
  
  CONCLUSIONS
  Rhodopsin C185R mutation leads to severe retinal degeneration in R3 mutant mice. A dosage-dependent accumulation of misfolded mutant proteins likely triggers or stimulates the death of rod photoreceptors. The presence of a wild-type rhodopsin allele can delay the loss of photoreceptor cells in R3/+ mice.
authors.affiliation: Vision Science Program and School of Optometry, University of California, Berkeley, Berkeley, California 94720-2020, USA.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Xia
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.forename: John G
authors.initials: JG
authors.lastname: Flannery
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Ridge
authors.forename: Bruce
authors.initials: B
authors.lastname: Beutler
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gong
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D004596:Electroretinography; D005038:Ethylnitrosourea / Q000633:toxicity; D005799:Genes, Dominant; D055106:Genome-Wide Association Study; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009887:Ophthalmoscopy; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D017433:Protein Structure, Secondary; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism
chemical_list: D012243:Rhodopsin; D005038:Ethylnitrosourea