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Venkata R. Chavali, Naheed W. Khan, Catherine A. Cukras, Dirk-Uwe G. Bartsch, Monica M. Jablonski, Radha Ayyagari; A Ctrp5 Gene Knock-in Mouse Model With S163R Mutation Develops Phenotype Similar To L-ORD At Older Age. Invest. Ophthalmol. Vis. Sci. 2011;52(14):970.
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© ARVO (1962-2015); The Authors (2016-present)
A single missense mutation S163R in the human C1QTNF5/CTRP5 gene causes autosomal dominant late onset retinal degeneration (L-ORD). In the present study, we describe the retinal phenotype in the Ctrp5+/- mice until 24 months of age.
The retina of 12 to 24 months old Ctrp5+/- mice was evaluated by fundoscopy, fundus autofluorescence (FAF) imaging, fluorescein angiography (FA), electroretinography (ERG), histology, immunohistochemistry (IHC) and Transmission Electron Microscopy. Expression levels of photoreceptor specific genes were determined by RT-PCR.
The Ctrp5+/- mice had normal fundus appearance even at age 24 months. However the FAF imaging revealed an increase in the accumulation of hyperautofluorescence spots as Ctrp5+/- mice age. FA revealed foci of fluorescein leakage in a subset of mice at 21 months old. Morphological analyses show structural abnormalities in inner segments, RPE apical processes and in the sub-RPE space that worsened with age. By 24 months, numerous autofluorescent deposits in retinal sections were observed by fluorescence microscopy. These deposits stained positive for unesterified cholesterol, neutral lipids and glycogen. Photoreceptor marker genes were expressed at significantly low levels in the Ctrp5+/- mice retina. Rod saturated ERG b- wave amplitude and sensitivity k obtained from Naka-Rushton fits, a- and b-wave amplitudes at brighter intensities and the cone-mediated b-wave amplitude were consistently lower than control at all ages. Human L-ORD patients manifest early dark-adaptation abnormalities. To evaluate whether mice show a similar dysfunction, recovery of rod b-wave amplitude from intense bleach in 13 month old Ctrp5+/- and C57BL/6 mice was compared. The b-wave amplitude recovered to only 75% of the pre-bleach amplitude in the Ctrp5+/- mice when compared to the C57BL/6 mice after 60 minutes. IHC analysis revealed significant cone loss in the Ctrp5+/- mice with age with a greater loss of S-cones compared to M-cones.
The Ctrp5+/- mice develop abnormal ERG response, RPE atrophy, fluorescein dye leakage; drusen-like deposits with autofluorescent material and significant loss of photoreceptors as they age. Unlike other animal models for AMD, the Ctrp5+/- mice are unique in displaying a range of pathological retinal phenotypic features of AMD making them a good model to study not only LORD but also AMD.
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