Journal of Clinical Investigation · 2006 · 132 citations · 26 references
MedicineGeneticsMolecular GeneticsGene ExpressionGene RegulationOcular GeneticsEye DevelopmentPhotoreceptor PhysiologyRab Gtpase RegulationRetinal DegenerationRetinal DevelopmentRetinal Pigment EpitheliumKnockout Mouse ModelsPost-translational Lipid ModificationRab PrenylationRetinal Degeneration MechanismsRetinal Pigment Epithelium DegenerationRetinal Pigment Epithelium Disease ModelsTissue-specific ExpressionTissue-specific Inducible Expression
Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choroid, caused by loss of function of the CHM/REP1 gene. REP1 is involved in lipid modification (prenylation) of Rab GTPases, key regulators of intracellular vesicular transport and organelle dynamics. To study the pathogenesis of CHM and to develop a model for assessing gene therapy, we have created a conditional mouse knockout of the Chm gene. Heterozygous-null females exhibit characteristic hallmarks of CHM: progressive degeneration of the photoreceptors, patchy depigmentation of the RPE, and Rab prenylation defects. Using tamoxifen-inducible and tissue-specific Cre expression in combination with floxed Chm alleles, we show that CHM pathogenesis involves independently triggered degeneration of photoreceptors and the RPE, associated with different subsets of defective Rabs.
26