Aguirre, Gustavo D
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ORCID
Disciplines
Medical Genetics
Ophthalmology
Veterinary Medicine
Ophthalmology
Veterinary Medicine
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Position
Professor of Medical Genetics and Ophthalmology
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Description of research
Research Interests
Molecular bases of inherited blindness
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Publication Window Into Retinal Studies(2010-10-01) Aguirre, Gustavo DProfessor Gustavo Aguirre discusses the context of his research studies at the University of Pennsylvania, which are currently concentrating on the degenerative disease, retinitis pigmentosa.Publication Age-Dependent Disease Expression Determines Remodeling of the Retinal Mosaic in Carriers of RPGR Exon ORFn15 Mutations(2009-08-01) 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.Publication Radiation Hybrid Mapping of Cataract Genes in the Dog(2006-05-24) Hunter, Linda S; Aguirre, Gustavo D; Sidjanin, Duska J; Johnson, Jennifer L; Zangerl, Barbara; Galibert, Francis; Andre, Catherine; Kirkness, Ewen; Talamas, Elijah; Acland, Gregory MPurpose: To facilitate the molecular characterization of naturally occurring cataracts in dogs by providing the radiation hybrid location of 21 cataract-associated genes along with their closely associated polymorphic markers. These can be used for segregation testing of the candidate genes in canine cataract pedigrees. Methods: Twenty-one genes with known mutations causing hereditary cataracts in man and/or mouse were selected and mapped to canine chromosomes using a canine:hamster radiation hybrid RH5000 panel. Each cataract gene ortholog was mapped in relation to over 3,000 markers including microsatellites, ESTs, genes, and BAC clones. The resulting independently determined RH-map locations were compared with the corresponding gene locations from the draft sequence of the canine genome. Results: Twenty-one cataract orthologs were mapped to canine chromosomes. The genetic locations and nearest polymorphic markers were determined for 20 of these orthologs. In addition, the resulting cataract gene locations, as determined experimentally by this study, were compared with those determined by the canine genome project. All genes mapped within or near chromosomal locations with previously established homology to the corresponding human gene locations based on canine:human chromosomal synteny. Conclusions: The location of selected cataract gene orthologs in the dog, along with their nearest polymorphic markers, serves as a resource for association and linkage testing in canine pedigrees segregating inherited cataracts. The recent development of canine genomic resources make canine models a practical and valuable resource for the study of human hereditary cataracts. Canine models can serve as large animal models intermediate between mouse and man for both gene discovery and the development of novel cataract therapies.Publication Variabilities in Retinal Function and Structure in a Canine Model of Cone-Rod Dystrophy Associated With RPGRIP1 Support Multigenic Etiology(2017-01-01) Das, Rueben G; Aguirre, Gustavo D; Marinho, Felipe P; Iwabe, Simone; Santana, Evelyn; McDaid, Kendra S; Miyadera, KeikoDefects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and cone-rod dystrophy in humans. A form of canine cone-rod dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1ins/ins) as the primary disease locus while a homozygous deletion in MAP9(MAP9del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, cone ERGabsentRPGRIP1ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and cone ERGabsentRPGRIP1ins/ins littermates. Cone morphology of the dogs lacking cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, cone ERGabsentRPGRIP1ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-cones, and lack GC1 in all cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects.Publication Cloning 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; 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.Publication Exonic SINE Insertion in STK38L Causes Canine Early Retinal Degeneration (erd)(2010-12-01) Goldstein, Orly; 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.Publication Identification of Genetic Variation and Haplotype Structure of the Canine ABCA4 Gene for Retinal Disease Association Studies(2010-10-01) 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.Publication Melanoma of the Choroid in a Dog(1984-05-01) 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.Publication Long-Term Restoration of Rod and Cone Vision by Single Dose rAAV-Mediated Gene Transfer to the Retina in a Canine Model of Childhood Blindness(2005-12-01) Aguirre, Gustavo D; Acland, Gregory M; Cideciyan, Artur V; Bennett, Jean; Bennicelli, Jeannette; Dejneka, Nadine S; Pearce-Kelling, Susan E; Jacobson, Samuel G; Maguire, Albert M; Palczewski, Krzysztof; Hauswirth, William WThe short- and long-term effects of gene therapy using AAV-mediated RPE65 transfer to canine retinal pigment epithelium were investigated in dogs affected with disease caused by RPE65 deficiency. Results with AAV 2/2, 2/1, and 2/5 vector pseudotypes, human or canine RPE65 cDNA, and constitutive or tissue-specific promoters were similar. Subretinally administered vectors restored retinal function in 23 of 26 eyes, but intravitreal injections consistently did not. Photoreceptoral and postreceptoral function in both rod and cone systems improved with therapy. In dogs followed electroretinographically for 3 years, responses remained stable. Biochemical analysis of retinal retinoids indicates that mutant dogs have no detectable 11-cis-retinal, but markedly elevated retinyl esters. Subretinal AAV-RPE65 treatment resulted in detectable 11-cis-retinal expression, limited to treated areas. RPE65 protein expression was limited to retinal pigment epithelium of treated areas. Subretinal AAV-RPE65 vector is well tolerated and does not elicit high antibody levels to the vector or the protein in ocular fluids or serum. In long-term studies, wild-type cDNA is expressed only in target cells. Successful, stable restoration of rod and cone photoreceptor function in these dogs has important implications for treatment of human patients affected with Leber congenital amaurosis caused by RPE65 mutations.Publication Exploring Human/Animal Intersections: Converging Lines of Evidence in Comparative Models of Aging(2008-01-01) Trojanowski, John Q; Aguirre, Gustavo D; Jedrziewski, Kathryn; Johnson, F. Brad; Hess, Rebecka S; Cancro, Michael P; Sleeper, Margaret M; Pignolo, Robert; Lee, Virginia Man-Yee; Hendricks, Joan C; Pack, Allan I; Davies, Peter F; Michel, Kathryn E; Teff, Karen L; Lawler, Dennis FAt a symposium convened on March 8, 2007 by the Institute on Aging at the University of Pennsylvania, researchers from the University’s Schools of Medicine and Veterinary Medicine explored the convergence of aging research emerging from the two schools. Studies in human patients, animal models, and companion animals have revealed different but complementary aspects of the aging process, ranging from fundamental biologic aspects of aging to the treatment of age-related diseases, both experimentally and in clinical practice. Participants concluded that neither animal nor human research alone will provide answers to most questions about the aging process. Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research.