Abstract
Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.
Highlights
High-acuity vision is dependent on the cone photoreceptor visual pathway in all species with macular function
Since damage to cone photoreceptors underlies the mechanism of visual acuity loss in each of these processes, understanding the biology of this retinal cell type is paramount to promoting retinal health and preserving vision
Immunoblots from lysates of these transfected cells showed PDE6C or Achromatopsia presents in humans in infancy with photophobia, nystagmus, hemeralopia, absent color discrimination, and poor visual acuity
Summary
High-acuity vision is dependent on the cone photoreceptor visual pathway in all species with macular function. In humans with retinal disease, the final common pathway of visual acuity loss is cone photoreceptor dysfunction, or the pathway carrying conemediated information. Phototransduction is the most commonly affected cellular process in cone disorders This process depends on at least 10 genes that code for proteins in photoreceptor outer segments. We report the genetic screening, identification of the causative mutation, predicted structural abnormality in the enzyme, stability of the protein product in vitro, and degree of biochemical function. These animals, genealogically related and presumably the descendants of a common founder, have characteristic signs, symptoms, and functional testing results that parallel humans with PDE6C-related cone photoreceptor disease
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