Remodeling of the human retina in choroideremia: rab escort protein 1 (REP-1) mutations.
OBJECTIVE
To characterize in detail the disease expression in choroideremia (CHM), a blinding X-linked disease of the retina caused by loss-of-function mutations in Rab Escort Protein 1 (REP-1). CHM is readily diagnosed in the clinic and by molecular testing but has lacked an animal model to test hypotheses and therapeutics. The recent report of a mouse model for CHM prompts the need for reassessment of the human disease in anticipation of treatment initiatives.


METHODS
CHM hemizygotes with REP-1 mutations, spanning an age range of 7 decades, were studied with in vivo microscopy by optical coherence tomography.


RESULTS
The disease expression was complex. Earliest stages involved a thickening of the retina that was otherwise normally laminated. Loss of photoreceptors, either independent or associated with retinal pigment epithelium (RPE) depigmentation, was followed by disorganization and further thickening of the retina with interlaminar bridges. The dysmorphic retina then slowly thinned over decades. Laminopathy occurred first in more peripheral rod-rich regions and later in the cone-rich fovea.


CONCLUSIONS
The CHM disease sequence involves detectable retinal thickening, which may be due to Müller cell activation and hypertrophy from photoreceptor stress. Photoreceptor degeneration, RPE depigmentation, and retinal remodeling follow. The results represent in vivo evidence in humans for retinal remodeling and provide a marker for the earliest stage of this response to genetic retinal disease. For CHM and other candidate human retinopathies considered for therapy, there is now a framework for making informed decisions about timing, retinal location, and potential value of treatment.
Jacobson
Samuel G
SG
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jacobsos@mail.med.upenn.edu
Cideciyan
Artur V
AV
Sumaroka
Alexander
A
Aleman
Tomas S
TS
Schwartz
Sharon B
SB
Windsor
Elizabeth A M
EA
Roman
Alejandro J
AJ
Stone
Edwin M
EM
MacDonald
Ian M
IM
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D002648:Child; D015794:Choroideremia / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D006984:Hypertrophy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010857:Pigment Epithelium of Eye / Q000473:pathology; D011601:Psychophysics; D012160:Retina / Q000473:pathology*; D041623:Tomography, Optical Coherence; D020691:rab GTP-Binding Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D019883:Alkyl and Aryl Transferases; D020691:rab GTP-Binding Proteins