School of Veterinary Medicine
The School of Veterinary Medicine at the University of Pennsylvania was founded in 1884, and has a long-standing tradition as a global leader in veterinary medicine education, research, and clinical care, with a tradition of compassionate clinical expertise, intellectual rigor and the pursuit of innovative thinking.
Our mission at Penn Vet is to train the next generation of veterinary leaders to advance healthcare outcomes and access, ensure global health, bolster sustainable agriculture, support interdisciplinary career paths, and foster diversity, equity, and inclusion in the profession.
PublicationExonic SINE Insertion in STK38L Causes Canine Early Retinal Degeneration (erd)(2010-12-01) Goldstein, Orly; Aguirre, Gustavo D; Aguirre, Gustavo D; Kukekova, Anna V; Acland, Gregory MFine mapping followed by candidate gene analysis of erd — a canine hereditary retinal degeneration characterized by aberrant photoreceptor development — established that the disease cosegregates with a SINE insertion in exon 4 of the canine STK38L/NDR2 gene. The mutation removes exon 4 from STK38L transcripts and is predicted to remove much of the N terminus from the translated protein, including binding sites for S100B and Mob proteins, part of the protein kinase domain, and a Thr-75 residue critical for autophosphorylation. Although known to have roles in neuronal cell function, the STK38L pathway has not previously been implicated in normal or abnormal photoreceptor development. Loss of STK38L function in erd provides novel potential insights into the role of the STK38L pathway in neuronal and photoreceptor cell function, and suggests that genes in this pathway need to be considered as candidate genes for hereditary retinal degenerations. PublicationPosterior Lenticonus in the Dog(1973-07-01) Aguirre, Gustavo D; Bistner, Stephen IPosterior lenticonus is a congenital defect of the posterior lenticular surface. The posterior cortical and capsular regions of the lens have a circumscribed conelike or globular protrusion of variable size. Opacities may be present in the region of the conus. The defect has been reported in man, rabbits, calves and mice. This report documents 2 cases in unrelated dogs. The possible mechanism for the formation of this defect is discussed. PublicationIdentification of Genetic Variation and Haplotype Structure of the Canine ABCA4 Gene for Retinal Disease Association Studies(2010-10-01) Zangerl, Barbara; Aguirre, Gustavo D; Zangerl, Barbara; Aguirre, Gustavo D; Lindauer, Sarah J; Acland, Gregory MOver 200 mutations in the retina specific member of the ATP-binding cassette transporter superfamily (ABCA4) have been associated with a diverse group of human retinal diseases. The disease mechanisms, and genotype–phenotype associations, nonetheless, remain elusive in many cases. As orthologous genes are commonly mutated in canine models of human blinding disorders, canine ABCA4 appears to be an ideal candidate gene to identify and study sequence changes in dogs affected by various forms of inherited retinal degeneration. However, the size of the gene and lack of haplotype assignment significantly limit targeted association and/or linkage approaches. This study assessed the naturally observed sequence diversity of ABCA4 in the dog, identifying 80% of novel variations. While none of the observed polymorphisms have been associated with blinding disorders to date, breed and potentially disease specific haplotypes have been identified. Moreover, a tag SNP map of 17 (15) markers has been established that accurately predicts common ABCA4 haplotypes (frequency > 5%) explaining >85% (>80%) of the observed genetic diversity and will considerably advance future studies. Our sequence analysis of the complete canine ABCA4 coding region will clearly provide a baseline and tools for future association studies and comparative genomics to further delineate the role of ABCA4 in canine blinding disorders. PublicationCanine RD3 Mutation Establishes Rod-Cone Dysplasia Type 2 (rcd2) as Ortholog of Human and Murine rd3(2009-02-01) Kukekova, Anna V; Aguirre, Gustavo D; Aguirre, Gustavo D; Goldstein, Orly; Johnson, Jennifer L; Richardson, Malcolm A; Pearce-Kelling, Susan E; Swaroop, Anand; Friedman, James S; Acland, Gregory MRod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend the open reading frame. Thus, combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within-breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations. PublicationCloning of Canine Galactokinase (GALK1) and Evaluation as a Candidate Gene for Hereditary Cataracts in Labrador Retrievers(2005-06-01) Sidjanin, Duska J; Aguirre, Gustavo D; Aguirre, Gustavo D; McElwee, John L; Miller, BrianWe identified a pedigree of Labrador retrievers (LR) that develop hereditary cataracts between 6 and 18 months of age. In humans, galactokinase deficiency is an autosomal recessive disorder characterized by juvenile onset of cataracts.1 In order to evaluate GALK1 as a candidate gene, we cloned and sequenced the canine GALK1 gene and tested a single nucleotide polymorphism (SNP) in the gene for segregation with cataracts in the LR pedigree. PublicationAge-Dependent Disease Expression Determines Remodeling of the Retinal Mosaic in Carriers of RPGR Exon ORFn15 Mutations(2009-08-01) Beltran, William; Aguirre, Gustavo D; Beltran, William; Aguirre, Gustavo D; Acland, Gregory MPURPOSE. To characterize the retinal histopathology in carriers of X-linked progressive retinal atrophy (XLPRA1 and XLPRA2), two canine models of X-linked retinitis pigmentosa caused, respectively, by a stop and a frameshift mutation in RPGRORF15. METHODS. Retinas of XLPRA2 and XLPRA1 carriers of different ages were processed for morphologic evaluation, TUNEL assay, and immunohistochemistry. Cell-specific markers were used to examine retinal remodeling events. RESULTS. A mosaic pattern composed of patches of diseased and normal retina was first detected in XLPRA2 carriers at 4.9 weeks of age. A peak of photoreceptor cell death led to focal rod loss; however, in these patches an increased density of cones was found to persist over time. Patches of disease gradually disappeared so that by 39 weeks of age the overall retinal morphology, albeit thinner, had improved lamination. In older XLPRA2 carriers (≥8.8 years), extended regions of severe degeneration occurred in the peripheral/mid-peripheral retina. In XLPRA1 carriers, opsin mislocalization and rare events of rod death were detected by TUNEL assay at 20 weeks of age; however, only patchy degeneration was seen by 1.4 years and was still apparent at 7.8 years. CONCLUSIONS. The time of onset and the progression of the disease differed between the two models. In the early-onset form (XLPRA2) the morphologic appearance of the retinal mosaic changed as a function of age, suggesting that structural plasticity persists in the early postnatal canine retina as mutant photoreceptors die. In the late-onset form (XLPRA1), patches of disease persisted until later ages. PublicationGenetic and Phenotypic Variations of Inherited Retinal Diseases in Dogs: The Power of Within- and Across-Breed Studies(2012-02-01) Aguirre, Gustavo D; Aguirre, Gustavo D; Acland, Gregory MConsiderable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision. PublicationMelanoma of the Choroid in a Dog(1984-05-01) Aguirre, Gustavo D; Aguirre, Gustavo D; Brown, Gary; Shields, Jerry A; Dubielzig, Richard RIntraocular tumors are rare in the dog. Of the reported neoplasms, melanomas are the most common. These tumors characteristically arise in the anterior uvea and secondarily infiltrate posteriorly into the choroid and/or anteriorly into the corneoscleral region. Advanced tumors may extend extraocularly. In the dog, isolated choroidal melanomas are extremely uncommon; to the authors' knowledge, only two cases have been previously reported. This report describes a pigmented choroidal tumor in a dog with clinical and histopathologic features resembling a benign melanoma. PublicationDécollement Rétinien Associé à une Cataracte Unilatérale [Retinal Detachments Associated with Unilateral Cataracts](2001-06-01) Beltran, William; Beltran, William; Jégou, Jean-PierreLe décollement de rétine rend la chirurgie de la cataracte inutile : il doit donc être recherché lors de l'examen préopératoire. La technique de choix dans le diagnostic de cette affection est l'échographie oculaire. L'étude de huit cas révèle l'intérêt de cet examen dans le diagnostic des décollements de rétine associés à la cataracte chez le chien à travers la variété des images échographiques obtenues. PublicationPrimary Adenocarcinoma of the Gland of the Nictitating Membrane in a Cat(1997-07-01) Komáromy, András M; Komáromy, András M; Ramsey, David T; Render, James A; Clark, PhillipAn 11-year-old, neutered, male domestic shorthair was presented with a five-month history of recurrent, unilateral, seromucoid discharge from the right eye. A verrucous mass extended from the posterior aspect of the nictitating membrane. Adenocarcinoma of the gland of the nictitating membrand (GNM) was diagnosed upon biopsy. The cat subsequently developed metastases to the lungs, pleura, mediastinum, liver, and kidneys and died six months after clinical signs first were observed. Little is known about the biological behavior of adenocarcinoma of the GNM in cats. This is the first report that describes the natural progression of this disease.