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.

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Author: Acland, Gregory M ×

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  • Publication
    Exonic SINE Insertion in STK38L Causes Canine Early Retinal Degeneration (erd)
    (2010-12-01) Goldstein, Orly; Aguirre, Gustavo D; Acland, Gregory M
    Fine 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
    Radiation Hybrid Mapping of Cataract Genes in the Dog
    (2006-05-24) Hunter, Linda S; Aguirre, Gustavo D; Johnson, Jennifer L; Zangerl, Barbara; Galibert, Francis; Andre, Catherine; Kirkness, Ewen; Talamas, Elijah; Acland, Gregory M
    Purpose: 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
    A Non-Stop S-Antigen Gene Mutation Is Associated With Late Onset Hereditary Retinal Degeneration in Dogs
    (2013-08-01) Goldstein, Orly; Aguirre, Gustavo D; Acland, Gregory M
    Purpose: To identify the causative mutation of canine progressive retinal atrophy (PRA) segregating as an adult onset autosomal recessive disorder in the Basenji breed of dog. Methods: Basenji dogs were ascertained for the PRA phenotype by clinical ophthalmoscopic examination. Blood samples from six affected cases and three nonaffected controls were collected, and DNA extraction was used for a genome-wide association study using the canine HD Illumina single nucleotide polymorphism (SNP) array and PLINK. Positional candidate genes identified within the peak association signal region were evaluated. Results: The highest -Log10(P) value of 4.65 was obtained for 12 single nucleotide polymorphisms on three chromosomes. Homozygosity and linkage disequilibrium analyses favored one chromosome, CFA25, and screening of the S-antigen (SAG) gene identified a non-stop mutation (c.1216T>C), which would result in the addition of 25 amino acids (p.*405Rext*25). Conclusions: Identification of this non-stop SAG mutation in dogs affected with retinal degeneration establishes this canine disease as orthologous to Oguchi disease and SAG-associated retinitis pigmentosa in humans, and offers opportunities for genetic therapeutic intervention.
  • Publication
    Congenital Stationary Night Blindness in the Dog: Common Mutation in the RPE65 Gene Indicates Founder Effect
    (1998-10-30) Baldwin, Victoria; Aguirre, Gustavo D; Pearce-Kelling, Sue; Narfström, Kristina; Ray, Kunal; Acland, Gregory M
    Purpose: To clone and characterize the canine RPE65 cDNA from normal dog, examine for mutations, and establish if the mutation identified in Swedish briard dogs with retinal dystrophy is present in dogs of the same breed that originated from the United States and other countries, and are affected with congenital stationary night blindness. Methods: Fifteen briard dogs were studied, of which 10 were affected with csnb, and five were clinically normal. In addition, we tested samples from four Swedish dogs, and samples from a briard affected with progressive retinal atrophy. RPE65 cDNA was cloned a from retinal cDNA library by PCR, and from canine retina by RT-PCR. ERG and morphology were used to characterize csnb. Results: The normal RPE65 cDNA spans 1724 nucleotides (GenBank accession number AF084537), and includes 1602 nucleotides of coding sequence; the deduced amino acid sequence shares 98%, 97%, and 93% identity with homologous human, bovine, and rat sequences, respectively. A homozygous four nucleotide (AAGA) deletion, representing nucleotides 487-490 of wildtype RPE65 sequence, was found only in csnb and retinal dystrophy affected dogs; heterozygous animals had normal and mutant alleles. The mutation produces a frameshift, causing a deduced mistranslation with a premature stop codon. The mutation causes retinal dysfunction and RPE accumulation of lipid vacuoles. Conclusions: Identification of the same mutation in csnb and retinal dystrophy confirms the molecular identity of the two disorders. A common mutation in dogs derived from different countries suggests a founder effect causing the propagation of a common mutant allele in the population at risk.
  • 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; Acland, Gregory M
    Over 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
    Canine 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; Johnson, Jennifer L; Richardson, Malcolm A; Pearce-Kelling, Susan E; Swaroop, Anand; Friedman, James S; Acland, Gregory M
    Rod-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.
  • 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
    PURPOSE. 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
    Cloning and Characterization of the Canine Photoreceptor Specific Cone-Rod Homeobox (CRX) Gene and Evaluation as a Candidate for Early Onset Photoreceptor Diseases in the Dog
    (2002-03-22) Akhmedov, Novrouz B; Aguirre, Gustavo D; Zangerl, Barbara; Kijas, James K; Hunter, Linda S; Minoofar, Katayoun D; Mellersh, Cathryn; Ostrander, Elaine A; Acland, Gregory M; Farber, Debora B
    PURPOSE: The cone-rod homeobox protein (CRX) is a member of the homeodomain-containing protein family expressed in the retinal photoreceptors and pinealocytes; it is involved in the regulation of the coordinate expression of multiple photoreceptor specific genes during retinal development. Mutations in the CRX gene are causally associated with retinal degeneration phenotypes in man. To clone the full length cDNA, characterize the genomic organization of canine CRX, map the gene in a radiation hybrid (RH) panel, and evaluate it as a candidate for canine inherited retinal degenerations. METHODS: cDNA representational difference analysis (RDA) was done using normal and cone degeneration (cd) affected retinas. Exonic primers designed from consensus sequences of mammalian CRX cDNA were used to amplify and sequence dog genomic DNA. Canine specific primers were used for RH mapping of CRX on the RH3000 cell line. Linkage, sequencing and/or mapping the disease locus was used to evaluate CRX as a disease associated candidate gene. RESULTS: The gene comprises three exons and two introns and codes for a transcript with a 900 bp open reading frame (ORF). In agreement with human map data, RH mapping placed canine CRX on the proximal end of CFA1, in a region of synteny with HSA19q13-q13.3. Based on RH mapping, meiotic linkage or sequencing data, we excluded CRX as the cause of canine early onset photoreceptor degenerations affecting Alaskan malamutes (cd), collies (rod-cone dysplasia 2, rcd2), American Staffordshire terriers, and Tibetan terriers. CONCLUSIONS: Canine CRX has a high level of nucleotide and amino acid sequence identity with orthologous sequences reported for other species. The gene is excluded from causal association with 4 early onset photoreceptor diseases affecting cones (cd) or rods and cones (rcd2, PRA in American Staffordshire terriers, and Tibetan terriers).
  • Publication
    Breed Relationships Facilitate Fine-Mapping Studies: A 7.8-kb Deletion Cosegregates With Collie Eye Anomaly Across Multiple Dog Breeds
    (2007-10-01) Parker, Heidi G; Aguirre, Gustavo D; Akey, Danya T; Goldstein, Orly; Kirkness, Ewen F; Baysac, Kathleen C; Mosher, Dana S; Acland, Gregory M; Ostrander, Elaine A
    The features of modern dog breeds that increase the ease of mapping common diseases, such as reduced heterogeneity and extensive linkage disequilibrium, may also increase the difficulty associated with fine mapping and identifying causative mutations. One way to address this problem is by combining data from multiple breeds segregating the same trait after initial linkage has been determined. The multibreed approach increases the number of potentially informative recombination events and reduces the size of the critical haplotype by taking advantage of shortened linkage disequilibrium distances found across breeds. In order to identify breeds that likely share a trait inherited from the same ancestral source, we have used cluster analysis to divide 132 breeds of dog into five primary breed groups. We then use the multibreed approach to fine-map Collie eye anomaly (cea), a complex disorder of ocular development that was initially mapped to a 3.9-cM region on canine chromosome 37. Combined genotypes from affected individuals from four breeds of a single breed group significantly narrowed the candidate gene region to a 103-kb interval spanning only four genes. Sequence analysis revealed that all affected dogs share a homozygous deletion of 7.8 kb in the NHEJ1 gene. This intronic deletion spans a highly conserved binding domain to which several developmentally important proteins bind. This work both establishes that the primary cea mutation arose as a single disease allele in a common ancestor of herding breeds as well as highlights the value of comparative population analysis for refining regions of linkage.
  • Publication
    Genetic and Phenotypic Variations of Inherited Retinal Diseases in Dogs: The Power of Within- and Across-Breed Studies
    (2012-02-01) Miyadera, Keiko; Aguirre, Gustavo D
    Considerable 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.