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Martha Neuringer, Lauren Renner, Jonathan Stoddard, Samuel Peterson, Betsy Ferguson, Anne Lewis, Lois Colgin, Kamm Prongay, Cassandra Cullin, Brandy Dozier, David J Wilson, Jacqueline Gayet, Teresa Puthussery, Trevor J McGill; Identification of a Novel Nonhuman Primate Model of Bardet-Biedl Syndrome. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6067. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy linked to mutations in over 20 BBS genes. It is characterized by rod-cone degeneration in conjunction with renal dysfunction, polydactyly, obesity, hypogonadism and/or intellectual disability. We identified and characterized rhesus monkeys with retinal and renal pathology associated with a spontaneous mutation in BBS7.
Monkeys were genotyped by whole exome sequencing. Retinal phenotype was characterized by color, autofluorescence, sdOCT and ultra wide-field imaging and by full-field electroretinogram (ERG). Retina and kidney pathology were examined by histopathology and immunohistochemistry (IHC).
Three offspring of one sire--a 4-year-old male and 3- and 6-year-old females--were homozygous for a basepair deletion in exon 3 of BBS7 predicted to cause an early frameshift and resulting protein truncation. The sire, two dams, 3 full siblings and 47 other individuals (35 now living) were heterozygous for the same mutation. Retinal imaging of homozygotes showed altered pigmentation and narrow vessels, peripheral hyperfluorescence but macular hypofluorescence, and dramatic thinning and disorganization of retinal layers. In the 3-year-old, the cone ERG was extinguished and rod responses were ~10% of normal amplitude and delayed. By IHC, the central retina of the 4-year-old showed regions of complete photoreceptor degeneration and RPE loss; a single layer of cone nuclei remained in mid-peripheral retina, and both rods and cones were present in peripheral retina (ONL 3-5 nuclei thick). The 6-year-old showed profound loss of photoreceptors across the entire retina, with some remaining only in the far periphery. Central retina showed dramatic thinning and disorganization, abundant microglia, absent or displaced RPE, and significant gliosis in the subretinal space. The 4- and 6-year-old cases had renal pathology, including interstitial inflammation and fibrosis, with the 6-year-old also having cystic changes, extensive nephron loss and renal failure. The 4-year-old male had abnormally small testes, and moderate obesity was seen in the 3-year-old female. No polydactyly was observed.
We have established a nonhuman primate model of BBS that mirrors key features of the human syndrome. This new model provides the potential for selective breeding and the use of affected animals for evaluation of therapies for this devastating disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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