Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia

• Published in: The Journal of clinical investigation Vol. 116; no. 2; pp. 386 - 394
• Main Authors: Tolmachova, Tanya, Anders, Ross, Abrink, Magnus, Bugeon, Laurence, Dallman, Margaret J, Futter, Clare E, Ramalho, José S, Tonagel, Felix, Tanimoto, Naoyuki, Seeliger, Mathias W, Huxley, Clare, Seabra, Miguel C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2006
• Subjects: Adaptor Proteins, Signal Transducing; Alkyl and Aryl Transferases - genetics; Alkyl and Aryl Transferases - metabolism; Animals; Biomedical research; Choroideremia - genetics; Choroideremia - metabolism; Choroideremia - pathology; Cloning; Disease Models, Animal; Electroretinography; Female; Females; Humans; Male; Mice; Mice, Knockout; Mutation; Pathogenesis; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptor Cells, Vertebrate - pathology; Photoreceptors; Pigment Epithelium of Eye - cytology; Pigment Epithelium of Eye - metabolism; Pigment Epithelium of Eye - pathology; Protein Prenylation; Proteins; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Retina - metabolism; Retina - pathology; Retina - ultrastructure
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci26617

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.