Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

Nat Commun. 2015 Jan 23:6:6006. doi: 10.1038/ncomms7006.

Abstract

The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crosses, Genetic
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics*
  • Dependovirus
  • Electroretinography / methods
  • Fear
  • Female
  • Fundus Oculi
  • Genetic Therapy / methods*
  • Genotype
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Genetic
  • Mutation
  • Plasmids / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Retinal Degeneration / genetics*
  • Retinal Degeneration / metabolism
  • Time Factors
  • Tomography, Optical Coherence

Substances

  • GPR179 protein, mouse
  • Receptors, G-Protein-Coupled
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • Pde6b protein, mouse