Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia.
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.
Tolmachova
Tanya
T
Molecular and Cellular Medicine Section, Division of Biomedical Sciences, Imperial College London, London, United Kingdom.
Anders
Ross
R
Abrink
Magnus
M
Bugeon
Laurence
L
Dallman
Margaret J
MJ
Futter
Clare E
CE
Ramalho
José S
JS
Tonagel
Felix
F
Tanimoto
Naoyuki
N
Seeliger
Mathias W
MW
Huxley
Clare
C
Seabra
Miguel C
MC
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
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D019883:Alkyl and Aryl Transferases; D020691:rab GTP-Binding Proteins