PUBLICATION
Single choroideremia gene in non-mammalian vertebrates explains early embryonic lethality of the zebrafish model of choroideremia
- Authors
- Moosajee, M., Tulloch, M., Baron, R.A., Gregory-Evans, C.Y., Pereira-Leal, J.B., and Seabra, M.C.
- ID
- ZDB-PUB-090106-39
- Date
- 2009
- Source
- Investigative ophthalmology & visual science 50(6): 3009-3016 (Journal)
- Registered Authors
- Keywords
- retinal degeneration, genetic diseases, development, ocular, photoreceptor dystrophy, retinal pigment epithelium
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Animals
- Animals, Genetically Modified
- Apoptosis
- Choroideremia/genetics*
- Choroideremia/pathology
- Disease Models, Animal
- Embryo Loss/genetics*
- Embryo, Nonmammalian/pathology*
- Embryonic Development/genetics
- Evolution, Molecular
- Genes, Lethal*
- Immunoblotting
- In Situ Nick-End Labeling
- Phenotype
- Photoreceptor Cells, Vertebrate/pathology
- Protein Prenylation
- Retina/embryology*
- Retinal Degeneration/genetics
- Retinal Degeneration/pathology
- Subcellular Fractions
- Zebrafish/embryology
- Zebrafish/genetics*
- rab GTP-Binding Proteins/metabolism
- PubMed
- 19117920 Full text @ Invest. Ophthalmol. Vis. Sci.
Citation
Moosajee, M., Tulloch, M., Baron, R.A., Gregory-Evans, C.Y., Pereira-Leal, J.B., and Seabra, M.C. (2009) Single choroideremia gene in non-mammalian vertebrates explains early embryonic lethality of the zebrafish model of choroideremia. Investigative ophthalmology & visual science. 50(6):3009-3016.
Abstract
PURPOSE : Mutations of the CHM gene underlie the X-linked chorioretinal degeneration, choroideremia (CHM). The affected gene product, Rab Escort Protein-1 (REP1) mediates the post-translational prenyl modification of Rab GTPases. In CHM patients, the related REP2 partly compensates for the loss-of-function of REP1. The objective was to study the natural history of disease in a zebrafish model of CHM. METHODS : Zebrafish chm-/- were bred and subjected to extensive histological analysis and TUNEL assays, and cellular extracts used for immunoblot and in vitro prenylation assays. A detailed evolutionary analysis was performed on the REP family. RESULTS : We report that the retina of chm-/- zebrafish develops normally for the first 4 days post-fertilisation (dpf) followed by a catastrophic multi-layer degeneration, synchronously with severe multisystemic disease. The mean survival is 4.8 dpf. At the onset of generalized disease, we demonstrate a significant reduction in rep expression levels and activity, with unprenylated rabs accumulating in the cytosol. Extensive bioinformatic analysis of the REP family of proteins revealed a single rep isoform in fish, other non-mammalian vertebrates and invertebrates, which is more similar to mammalian REP1. CONCLUSIONS : REP1 appears to be the ancestral gene in the family whilst the intronless REP2 gene is restricted to the mammalian lineage. We propose that in chm-/- zebrafish, maternally-derived rep allows initial successful development of the embryo, but its gradual loss leads to the multisystemic disease and invariable lethality observed. In its current form, the chm-/- zebrafish has limited utility.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping