Severe retinal degeneration caused by a novel rhodopsin mutation

Haiquan Liu, Meng Wang, Chun Hong Xia, Xin Du, John G. Flannery, Kevin D. Ridge, Bruce Beutler, Xiaohua Gong

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

PURPOSE. To identify a new mouse mutation developing earlyonset 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 Arg185 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.

Original languageEnglish (US)
Pages (from-to)1059-1065
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Severe retinal degeneration caused by a novel rhodopsin mutation'. Together they form a unique fingerprint.

Cite this