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M. C. Seabra, M. Tulloch, C. Y. Gregory-Evans, N. Vargesson; Choroideremia Zebrafish: A Model for Human Disease?. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2997.
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Loss-of-function mutations in the Choroideremia (CHM) gene are responsible for X-linked retinal degeneration. CHM encodes Rab Escort Protein-1 (REP1), which mediates post-translational isoprenyl modification of newly synthesised Rab GTPases. A CHM mutation has been isolated in zebrafish in a gene homologous to human REP1. Fish homozygous for CHM mutations display retinal degeneration, but in association with other severe defects resulting in death within 6 days post fertilization (dpf).
CHM and wild type fish were thoroughly examined by histochemistry throughout development (n=5). Genome databases were queried with representative REP sequences and identified REP genes were aligned to reveal evolutionary path of REP genes. In vitro prenylation assays were used to determine REP activity in protein extracts.
Histological analysis reveals normal development of retinal architecture in the CHM zebrafish for 4 days, then rapid degeneration of the whole eye. Photoreceptors are initially lost in a band across the dorsal portion of the retina, while remaining retinal cells are supported by morphologically normal RPE. Photoreceptors are lost by 5dpf, the RPE is severely disrupted, and in some areas is completely absent. Bioinformatic studies revealed that the zebrafish genome encodes only one REP gene, whereas mammals contain two REP genes. In embryonic CHM zebrafish, REP is not functional. However, maternally-derived wild type REP transcript is present in the yolk sac. Consistently, there is a reduction in REP activity in vitro in CHM extracts.
We suggest that fish, unlike mammals are dependent on a single REP gene. Maternal wild type REP is responsible for initial successful development of CHM embryos. Once REP activity declines, Rab functions also decline leading to generalized cell death. These observations provide an explanation for the severe and catatastrophic phenotype of CHM zebrafish observed at 6 dpf. In its current form, the CHM zebrafish model has limited applications in the study of human CHM. Successful introduction of transgenic mammalian REP-2 may yield a suitable CHM animal model.
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