title: Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia.
abstract: 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.
authors.affiliation: Molecular and Cellular Medicine Section, Division of Biomedical Sciences, Imperial College London, London, United Kingdom.
authors.forename: Tanya
authors.initials: T
authors.lastname: Tolmachova
authors.forename: Ross
authors.initials: R
authors.lastname: Anders
authors.forename: Magnus
authors.initials: M
authors.lastname: Abrink
authors.forename: Laurence
authors.initials: L
authors.lastname: Bugeon
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Dallman
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.forename: José S
authors.initials: JS
authors.lastname: Ramalho
authors.forename: Felix
authors.initials: F
authors.lastname: Tonagel
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.forename: Clare
authors.initials: C
authors.lastname: Huxley
authors.forename: Miguel C
authors.initials: MC
authors.lastname: Seabra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015794:Choroideremia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism* / Q000473:pathology; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D017368:Protein Prenylation; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D019883:Alkyl and Aryl Transferases; D020691:rab GTP-Binding Proteins