Papers by Simon M Petersen-Jones
Human Molecular Genetics, 2021
Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photo... more Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5−/− mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the c...
Eye, 1998
Naturally occurring retinal dystrophies in laboratory and companion animals represent a wealth of... more Naturally occurring retinal dystrophies in laboratory and companion animals represent a wealth of different conditions, some of which are important from a comparative point of view, and all of which offer opportunities to further the understanding of retinal function and reaction in health and disease. The study of animal models of retinal dystrophies has provided candidate genes for investigation in conditions of man such as retinitis pigmentosa and has also led to the identification of new genes and even new families of genes. Mutations in the gene for the beta subunit of cyclic GMP phosphodiesterase cause retinal dystrophies in man, mice and dog, and mutations in the gene for the structural protein peripherin/RDS result in a retinal dystrophy in the mouse and a spectrum of differing retinal dystrophies in man. Animals with homologous retinal dystrophies to man may make useful models for investigation of treatment either by drugs or by gene therapy. Furthermore the use of transgenics and gene targeting in laboratory mice offers the opportunity to create new models of human retinal dystrophies and also to investigate the effect of gene dysfunction.
Human Mutation, 2021
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Investigative Opthalmology & Visual Science, 2008
The use of canine models of retinal disease in the development of therapeutic strategies for inhe... more The use of canine models of retinal disease in the development of therapeutic strategies for inherited retinal disorders is a growing area of research. To evaluate accurately the success of potential vision-enhancing treatments, reliable methods for objectively assessing visual function in canine models is necessary. METHODS. A simple vision-testing device was constructed that consisted of a junction box with four exit tunnels. Dogs were placed in the junction box and given one vision-based choice for exit. The first-choice tunnel and time to exit were recorded and analyzed. Two canine models of retinal disease with distinct molecular defects, a null mutation in the gene encoding the ␣ subunit of rod cyclic GMP phosphodiesterase (PDE6A), and a null mutation in the gene encoding a retinal pigment epithelium-specific protein (RPE65) were tested and compared to those in unaffected dogs. RESULTS. With the use of bright light versus dim red light, the test differentiated between unaffected dogs and dogs affected with either mutation with a high degree of certainty. The white-light intensity series showed a significantly different performance between the unaffected and affected dogs. A significant difference in performance was detected between the dogs with each mutation. CONCLUSIONS. The results indicate that this novel canine visiontesting method is an accurate and sensitive means of distinguishing between unaffected dogs and dogs affected with two different forms of inherited retinal disease and should be useful as a means of assessing response to therapy in future studies.
BMC Veterinary Research
Background A number of etiologies for different canine chorioretinal lesions have been proved or ... more Background A number of etiologies for different canine chorioretinal lesions have been proved or suggested but some fundic lesions remain unclear in terms of an etiologic diagnosis, treatment options and prognosis. The purpose of this case series is to describe atypical chorioretinal lesions observed in dogs with primary angle-closure glaucoma (PACG). Case presentation Two spayed-female Siberian Huskies (3- and 4-year-old) and one Siberian Husky/Australian Shepherd mixed breed dog (11-month-old) that had multifocal depigmented retinal lesions and PACG were included. Procedures: Ophthalmic examination, gross, and histopathologic examination findings are described. One of the dogs underwent further clinical diagnostics. Advanced clinical diagnostics on the fellow, presumed to be non-glaucomatous eye of a dog revealed: pectinate ligament dysplasia by gonioscopy, retinal thinning in the depigmented area and wedge shaped retinal thinning with delayed choroidal vascular perfusion by optic...
Investigative Ophthalmology & Visual Science, 2015
BMC Veterinary Research, 2021
Background Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports... more Background Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited. Results Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2–3 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550 days (453–1160 days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced H...
Investigative Ophthalmology & Visual Science, 2011
Gene Therapy, 2015
Delivery of therapeutic transgenes to retinal photoreceptors using adeno-associated virus (AAV) v... more Delivery of therapeutic transgenes to retinal photoreceptors using adeno-associated virus (AAV) vectors has traditionally required subretinal injection. Recently, photoreceptor transduction efficiency following intravitreal injection (IVT) has improved in rodent models through use of capsid-mutant AAV vectors; but remains limited in large animal models. Thickness of the inner limiting membrane (ILM) in large animals is thought to impair retinal penetration by AAV. Our study compared two newly developed AAV vectors containing multiple capsid amino acid substitutions following IVT in dogs. The ability of two promoter constructs to restrict reporter transgene expression to photoreceptors was also evaluated. AAV vectors containing the interphotoreceptor-binding protein (IRBP) promoter drove expression exclusively in rod and cone photoreceptors, with transduction efficiencies of ~ 4% of cones and 2% of rods. Notably, in the central region containing the cone-rich visual streak, 15.6% of cones were transduced. Significant regional variation existed, with lower transduction efficiencies in the temporal regions of all eyes. This variation did not correlate with ILM thickness. Vectors carrying a cone-specific promoter failed to transduce a quantifiable percentage of cone photoreceptors. The newly developed AAV vectors containing the IRBP promoter were capable of producing photoreceptor-specific transgene expression following IVT in the dog.
PurposeTo compare the transduction efficiency or a self-complimentary AAV (scAAV) vector with a s... more PurposeTo compare the transduction efficiency or a self-complimentary AAV (scAAV) vector with a single-stranded AAV (ssAAV) vector at transducing retinal cells of the dog when delivered by subretinal injection. MethodsScAAV 2/5 and ssAAV 2/5 both delivering the green fluorescent protein driven by the chicken beta actin promoter were prepared. Two normal dogs were used. In each dog one eye was given a subretinal injection in the dorsal tapetal fundus of 250 {micro}l of 0.5x1012 vgp/ml of scAAV and the other eye given a subretinal injection of 250 {micro}l of 0.5x1012 vgp/ml of ssAAV. The eyes were monitored for GFP expression using a RetCam II fundus camera equipped for fluorescein angiography. One dog was euthanized 6 months after injection and the eyes processed for immunohistochemistry. ResultsThe results of fundus examinations from both dogs were very similar. In the scAAV injected eye very faint GFP expression could be seen on fundus examination at 6 days post-injection, this wa...
Molecular vision, Jan 4, 2007
The purpose of the study was to characterize the electroretinographic features of the autosomal r... more The purpose of the study was to characterize the electroretinographic features of the autosomal recessive retinopathy, globe enlarged (rge) phenotype, in chickens (Gallus gallus). Dark-adapted, light-adapted intensity series and light-adapted 30 Hz flicker responses were recorded from rge and age matched normal control chicks from one to 270 days of age. Retinal sections from rge and control retinas were examined in 7 and 270-day-old chicks. Electroretinogram (ERG) thresholds of rge birds were raised, the intensity response plots were shifted toward brighter intensities, and retinal sensitivity was reduced. The leading slope of the dark- and light-adapted a-waves was more shallow than normal, suggesting altered photoreceptor responses. The inner retinal components to the ERG were also abnormal; there was a marked lack of oscillatory potentials and an abnormally smooth and broad shape to the b-wave. Additionally, the b-wave was supernormal in response to brighter stimuli in the earli...
Veterinary Ophthalmology, 2014
To establish a method for isolation and culture of canine uveal melanocytes. Uveal explants from ... more To establish a method for isolation and culture of canine uveal melanocytes. Uveal explants from five mixed-breed dogs. Donor globes were dissected, and the anterior uvea removed. The uveal explants were placed in trypsin solution for enzymatic digestion. Extracted cells were cultured in modified F12 media. Immunocytochemistry was performed to confirm the identity of the extracted cells. Melanocytes were successfully isolated from uveal explants. Contaminating cell types were not observed. Repeated passaging of the melanocytes resulted in a gradual decrease in intracellular pigment. Melanocyte cell lines could be cryopreserved, thawed, and cultures successfully reestablished. This extraction technique allows for generation of large populations of canine uveal melanocytes in a relatively short period of time. This technique could be a useful tool for future studies investigating both normal cellular characteristics and alterations found in melanocytes from dogs with ocular melanocytic disorders.
Advances in experimental medicine and biology, 2012
... of Human Clinical Trials Simon M. Petersen-Jones , Matthew J. Annear , Joshua T. Bartoe ,Frey... more ... of Human Clinical Trials Simon M. Petersen-Jones , Matthew J. Annear , Joshua T. Bartoe ,Freya M. Mowat , Susie E. Barker , Alexander J. Smith , James W. Bainbridge , and Robin R. Ali MM LaVail et al. ... 1997, 1998, 2000; Wang et al. 2007) . ...
Veterinary Ophthalmology, 2007
Objective To describe the clinical features of ocular melanosis in Cairn Terriers. Animal studied... more Objective To describe the clinical features of ocular melanosis in Cairn Terriers. Animal studied One hundred and fourteen Cairn Terriers diagnosed with ocular melanosis. Procedure(s) A complete eye examination was performed on each dog. Four dogs (and two unaffected control dogs) underwent a high frequency ultrasound examination of the anterior segment. The pedigrees of affected dogs were analyzed. Results Forty-four (38.6%) dogs were male and 67 (58.7%) female; the sex of three dogs (2.6%) was not provided. A four-stage grading system of the ocular changes was developed. There was a variable age of onset, and the earliest change was a dark-colored thickening of the iris root. This was followed by the development of episcleral/scleral pigment plaques, release of pigment into the aqueous and deposition in the drainage apparatus, particularly ventrally. Secondary glaucoma developed in the most severely affected dogs. A slow progression of pigmentation in the tapetal fundus was observed and in some dogs pigment on the surface of the optic nerve head was seen. Three dogs developed uveal melanocytic neoplasms. Pedigree analysis suggested a possible autosomal dominant mode of inheritance. Conclusions Ocular melanosis is an inherited, probably autosomal-dominant condition with a variable age of onset and rate of progression. It results in a thickening and pigmentation of the iris, release of pigmented material into the aqueous, pigment deposition in the sclera/episclera, and to a lesser extent posterior segment pigment deposition. Following extensive pigment deposition in the aqueous drainage pathways it can result in secondary glaucoma.
PLoS ONE, 2014
The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. T... more The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA) and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1) produce a detailed description of the ocular phenotype of WDPs, (2) objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3) determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs); cutaneous tumors were noted in 12/20 WDP (,5 years of age: 4/12; .5 years of age: 8/8) and 1/20 SDPs (p,0.00001). Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4:77,062,968-77,067,051). This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model.
Neuroscience, 2010
Guanine nucleotide-binding protein β3 (GNB3) is an isoform of the β subunit of the heterotrimeric... more Guanine nucleotide-binding protein β3 (GNB3) is an isoform of the β subunit of the heterotrimeric G protein second messenger complex that is commonly associated with transmembrane receptors. The presence of GNB3 in photoreceptors, and possibly bipolar cells, has been confirmed in murine, bovine and primate retinas (Lee et al., 1992, Peng et al., 1992, Huang et al., 2003). Studies have indicated that a mutation in the GNB3 gene causes progressive retinopathy and globe enlargement (RGE) in chickens. The goals of this study were to 1) examine the expression pattern of GNB3 in wild-type and RGE mutant chickens, 2) characterize the types of bipolar cells that express GNB3 and 3) examine whether the expression of GNB3 in the retina is conserved across vertebrate species. We find that chickens homozygous for the RGE allele completely lack GNB3 protein. We find that the pattern of expression of GNB3 in the retina is highly conserved across vertebrate species, including teleost fish (Carassius auratus), frogs (Xenopus laevis), chickens (Gallus domesticus), mice (Mus musculata), guinea pigs (Cavia porcellus), dogs (Canis familiaris) and non-human primates (Macaca fasicularis). Regardless of the species, we find that GNB3 is expressed by Islet1-positive cone ON-bipolar cells and by cone photoreceptors. In some vertebrates, GNB3-immunoreactivity was observed in both rod and cone photoreceptors. A protein-protein alignment of GNB3 across different vertebrates, from fish to humans, indicates a high degree (>92%) of sequence conservation. Given that analogous types of retinal neurons express GNB3 in different species, we propose that the functions and the mechanisms that regulate the expression of GNB3 are highly conserved.
Journal of Negative Results in BioMedicine, 2013
Background: Ocular melanosis of Cairn terrier dogs is an inherited defect characterized by progre... more Background: Ocular melanosis of Cairn terrier dogs is an inherited defect characterized by progressive pigmentation of both eyes which can result in glaucoma and blindness. Pedigree analysis suggests the trait has an autosomal dominant mode of inheritance. We selected 11 potential candidate genes and used an exclusion analysis approach to investigate the likelihood that one of the candidate gene loci contained the Cairn terrier-ocular melanosis locus. Results: Two polymorphic loci were identified within or close to each candidate gene. Genotyping of at least 10 ocular melanosis Cairn terriers for each marker showed that there was no single shared allele for either of the two polymorphic markers identified in ASIP, COMT, GPNMB, GSK3B, LYST, MC1R, MITF, SILV, TYR, TYRP1,and TYRP2. This is strong evidence to exclude each locus as the site of the ocular melanosis mutation (probability of a false exclusion calculated for each gene ranged from 1.59 × 10-4 to 1 × 10-9). Conclusions: None of the 11 potential candidate genes selected are likely to be the gene locus for ocular melanosis in Cairn terriers.
Documenta Ophthalmologica, 2013
The full-field, flash electroretinogram (ERG) is now a widely used test of canine retinal functio... more The full-field, flash electroretinogram (ERG) is now a widely used test of canine retinal function for the clinical diagnosis of hereditary retinal dystrophies and other causes of retinal degeneration, assessment of retinal function in patients with opaque media, ruling out of generalized retinal diseases in patients with sudden loss of vision and in ophthalmological research, as well as in pharmaceutical and toxicological screening for deleterious side effects of drugs and other chemical compounds. In 2002, the first guidelines for clinical ERGs in this species adopted by the European College of Veterinary Ophthalmologists were published. This work provides an update of these guidelines.
American Journal of Veterinary Research, 2005
Objective—To investigate the duration of dark-adaptation time required for recovery of electroret... more Objective—To investigate the duration of dark-adaptation time required for recovery of electroretinographic responses after fundus photography or indirect ophthalmoscopy in dogs. Animals—6 dogs. Procedure—Initially, scotopic-intensity series of electroretinograms (ERGs) were recorded after 20 minutes of dark adaptation. The fundus of the left eye of each dog was photographed (n = 10) or examined via indirect ophthalmoscopy for 5 minutes with moderate- (117 candela [cd]/m2) or bright-intensity (1,693 cd/m2) light; ERGs were repeated after a further 20 or 60 minutes of dark adaptation (6 procedures/dog). Results—Following 20 minutes of dark adaptation after fundus photography, the b- and a-wave amplitudes were reduced in response to brighter stimuli, compared with pretest ERGs; after 60 minutes of dark adaptation, ERG amplitudes had recovered. Following 20 minutes of dark adaptation after indirect ophthalmoscopy (moderate-intensity light), significantly lower b-wave amplitudes were re...
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Papers by Simon M Petersen-Jones