Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene.
- 15 June 1993
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 90 (12) , 5499-5503
- https://doi.org/10.1073/pnas.90.12.5499
Abstract
Autosomal dominant retinitis pigmentosa (ADRP), slowly progressing over decades, leads to severe visual impairment and in some cases to complete blindness. More than 40 mutations in the human opsin gene have been linked to some forms of this genetically heterogeneous disease. In photoreceptor cells of ADRP patients with mutations in the opsin gene, normal rhodopsin is thought to be synthesized concomitantly with mutated rhodopsin, which, by an unknown mechanism, causes the slow degeneration of the photoreceptor cells. To establish a transgenic mouse line that carries a mutated mouse opsin gene in addition to the endogenous opsin gene, we introduced a mouse opsin gene containing mutations in exon 1 into the germ line of a normal mouse. The alterations consisted of three amino acid substitutions near the N terminus of rhodopsin, Val-20-->Gly (V20G), Pro-23-->His (P23H), and Pro-27-->Leu (P27L). The P23H mutation is the most prevalent mutation in human ADRP patients. During early postnatal development, mice heterozygous for the mutated opsin gene appear to develop normal photoreceptors, but their light-sensitive outer segments never reach normal length. With advancing age, both rod and cone photoreceptors are reduced progressively in number. The slow degeneration of the transgenic retina is associated with a gradual decrease of light-evoked electroretinogram responses. Our results show that simultaneous expression of mutated and normal opsin genes induces a slow degeneration of both rod and cone photoreceptors and that the course of the retinal degeneration of the mutant mouse retina mimics the course of human ADRP.Keywords
This publication has 22 references indexed in Scilit:
- Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosaNeuron, 1992
- Photoreceptor degeneration induced by the expression of simian virus 40 large tumor antigen in the retina of transgenic mice.Proceedings of the National Academy of Sciences, 1992
- Pro-347-Arg mutation of the rhodopsin gene in autosomal dominant retinitis pigmentosaGenomics, 1991
- A 3-bp deletion in the rhodopsin gene in a family with autosomal dominant retinitis pigmentosa.1991
- Mouse opsin. Gene structure and molecular basis of multiple transcriptsJournal of Biological Chemistry, 1990
- Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesteraseNature, 1990
- Molecular characterization of human and bovine rod photoreceptor cGMP phosphodiesterase α-subunit and chromosomal localization of the human geneGenomics, 1990
- A point mutation of the rhodopsin gene in one form of retinitis pigmentosaNature, 1990
- Isolation and analysis of the mouse opsin geneFEBS Letters, 1988
- Effect of light history on retinal antioxidants and light damage susceptibility in the ratExperimental Eye Research, 1987