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Jörg T. Epplen - One of the best experts on this subject based on the ideXlab platform.
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Generalized Progressive Retinal Atrophy in the Irish Glen of Imaal Terrier is associated with a deletion in the ADAM9 gene.
Molecular and cellular probes, 2010Co-Authors: Regina Kropatsch, Jörg T. Epplen, Elisabeth Petrasch-parwez, Denis A. Akkad, Wanda M. Gerding, Dominik Seelow, Annegrit Schlichting, Gabriele DekomienAbstract:Generalized Progressive Retinal Atrophy (gPRA) belongs to a group of inherited Retinal diseases which are associated with gradual vision loss in various dog breeds, including the Irish Glen of Imaal Terrier (GIT). By genome-wide homozygosity mapping using SNP arrays and fine mapping of candidate regions, we assigned the gPRA candidate locus in this breed to canine chromosome 16. The respective region is syntenic with human chromosome 8 comprising the ADAM metallopeptidase domain 9 (ADAM9) gene. ADAM9 represents a strong candidate gene for canine Retinal disease because mutations have previously been shown to cause autosomal recessively inherited human cone-rod dystrophy, a Retinal disorder affecting photoreceptor function. Sequence analysis of ADAM9 in affected and carrier GITs revealed a deletion of exons 15 and 16 which alters the reading frame leading to a premature stop codon. This mutation was absent from 34 other dog breeds. A variable and, at times, very late onset of gPRA was confirmed in GITs by a relatively mild Retinal degeneration at an advanced age. Hence, the identification of the genetic defect underlying gPRA in the GIT represents a suitable model for cone-rod dystrophy of humans, with superior potential to elucidate functional consequences of the recently described null mutations in the human ADAM9 gene.
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Progressive Retinal Atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene
neurogenetics, 2010Co-Authors: Gabriele Dekomien, Conni Vollrath, Elisabeth Petrasch-parwez, Michael H. Boevé, Denis A. Akkad, Wanda M. Gerding, Jörg T. EpplenAbstract:Canine generalized Progressive Retinal Atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and Progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 ( CCDC66 ) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease. The insertion is present in all affected dogs in the homozygous state as well as in all obligatory mutation carriers in the heterozygous state. The CCDC66 gene is evolutionarily conserved in different vertebrate species and exhibits a complex pattern of differential RNA splicing resulting in various isoforms in the retina. Immunohistochemically, CCDC66 protein is detected mainly in the inner segments of photoreceptors in mouse, dog, and man. The affected Schapendoes retina lacks CCDC66 protein. Thus this natural canine model for gPRA yields superior potential to understand functional implications of this newly identified protein including its physiology, and it opens new perspectives for analyzing different aspects of the general pathophysiology of gPRA.
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Haplotype-defined linkage region for gPRA in Schapendoes dogs.
Molecular vision, 2007Co-Authors: Tanja Lippmann, Jörg T. Epplen, Elisabeth Petrasch-parwez, Anna Jonkisz, Tadeusz Dobosz, Gabriele DekomienAbstract:Purpose In order to determine the molecular basis of canine generalized Progressive Retinal Atrophy (gPRA), we initiated whole-genome scanning for linkage in gPRA-informative pedigrees of the Schapendoes breed.
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Evaluation of the canine RPE65 gene in affected dogs with generalized Progressive Retinal Atrophy.
Molecular vision, 2003Co-Authors: Gabriele Dekomien, Jörg T. EpplenAbstract:Purpose: The RPE65 gene was screened in 26 breeds of dogs in order to identify potential disease-causing mutations in dogs with generalized Progressive Retinal Atrophy (gPRA). Methods: Intronic sequences were obtained from canine genomic DNA by intron-overlapping polymerase chain reactions (PCRs). Mutation analysis was performed by PCR and demonstration of single strand conformation polymorphisms (SSCP). Genomic variations were verified by sequencing. Results: A series of exonic and intronic single nucleotide polymorphisms (SNPs) were identified in the investigated breeds, but none of the dogs examined showed the typical RPE deletion for Retinal dystrophy in Briards nor any other disease-causing mutation. Conclusions: The informative SNPs provide evidence allowing indirect exclusion of mutations in the RPE65 gene as causing Retinal degeneration in 25 of the 26 dog breeds investigated with presumed autosomal recessively transmitted gPRA.
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Analysis of PDE6D and PDE6G genes for generalised Progressive Retinal Atrophy (gPRA) mutations in dogs
Genetics Selection Evolution, 2003Co-Authors: Gabriele Dekomien, Jörg T. EpplenAbstract:The δ and γ subunits of the cGMP-phosphodiesterase ( PDE6D , PDE6G ) genes were screened in order to identify mutations causing generalised Progressive Retinal Atrophy (gPRA) in dogs. In the PDE6D gene, single nucleotide polymorphisms (SNP) were observed in exon 4, in introns 2 and 3 and in the 3' untranslated region (UTR) of different dog breeds. In the coding region of the PDE6G gene, exclusively healthy Labrador Retrievers showed an A → G transition in exon 4 without amino acid exchange. SNP were also observed in introns 1 and 2 in different dog breeds. The different SNP were used as intragenic markers to investigate the involvement of both genes in gPRA. The informative substitutions allowed us to exclude mutations in the PDE6D and PDE6G genes as causing Retinal degeneration in 15 of the 22 dog breeds with presumed autosomal recessively transmitted (ar) gPRA.
Gustavo D. Aguirre - One of the best experts on this subject based on the ideXlab platform.
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Critical Decrease in the Level of Axon Guidance Receptor ROBO1 in Rod Synaptic Terminals Is Followed by Axon Retraction.
Investigative ophthalmology & visual science, 2020Co-Authors: Tatyana Appelbaum, Evelyn Santana, Gustavo D. AguirreAbstract:Purpose To define remodeling of photoreceptor synaptic terminals and second-order Retinal neurons in canine X-linked Progressive Retinal Atrophy 1 caused by a five-nucleotide deletion in the RPGR exon ORF15. Methods Retinas of normal and mutant dogs were used for gene expression, Western blot, and immunohistochemistry. Cell-specific markers were used to examine disease-dependent Retinal remodeling. Results In mutant retinas, a number of rod axon terminals retract into the outer nuclear layer. This neuritic Atrophy preceded significant loss of rods and was evident early in disease. Rod bipolar and horizontal cell processes were found to extend into the outer nuclear layer, where they seemed to form contacts with the spherules of rod photoreceptors. No ectopic rewiring was observed. Because cytoskeletal reorganization was previously shown to underlie photoreceptor axon retraction, we examined normal and mutant retinas for expression of axon guidance receptors ROBO1 and ROBO2, which are known to regulate actin cytoskeleton dynamics. We found that the overall expression of both ROBO1 and ROBO2 is retained at the same level in premature and fully developed normal retinas. However, analysis of predisease and early disease retinas identified markedly decreased levels of ROBO1 in rod spherules compared with controls. In contrast, no differences in ROBO1 signals were noted in cone pedicles in normal and mutant retinas, where ROBO1 levels remained similarly low. Conclusions Depletion of ROBO1 in rod synaptic terminals correlates with the remodeling of axonal and dendritic processes in the outer retina of dogs with X-linked Progressive Retinal Atrophy 1 and may play a role in the retraction of rod axons.
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The Briard Problem
2015Co-Authors: Ronald C Riis, Gustavo D. AguirreAbstract:The Briard breed has stimulated some ophthalmic interest in Canada, Europe, and the United States. Ophthalmoscopic changes similar to central Progressive Retinal Atrophy have been diagnosed. This report adds further insight into the type of Retinal degeneration and questions the associated physical findings as they may relate to the Retinal disease. Disciplines Eye Diseases | Medicine and Health Sciences | Ophthalmology | Veterinary Medicine This conference paper is available at ScholarlyCommons: http://repository.upenn.edu/vet_papers/108 THE BRIARD PROBLEM Ronald C. Riis, DVM, MS, DACVO 'Nw York State College of Veterinary Medicine Cornell University Ithaca, Nw York 14853 Gustavo D. Aquirre, DVM, DACVO School of Veterinary 1\hi cine University of Pennsylvania Philadelphia, Pennsylvania 19104 'I"re Briard breed has stimulated !Olle ophthalmic interest in Canada, Europe, and the United States. Ophthalmoscopic changes similar to central Progressive Retinal Atrophy have been diagnosed. This report adds further insight into the type of Retinal degeneration and questions the associated physical findings as they may relate to the Retinal disease. CASE REPORT Eight puppies (born June 7, 1982) were produced from a'mating of a male with questionable visual ability at night to a nonnal female. Three (2 males and l female) of the pups were sold and no record of ocular examinations were available. Too ( 1 female and 1 male) were evaluated to be normal ophthalmoscopically and functionally. Three (2 female and l male) were noted to be functionally night-blind by 6 months of age or before. The owners requested ocular evaluations of Dr. David Covitz who also diagnosed nystagmus in 2 of the 3 night-blind puppies. Dr. Covitz requested an ERG evaluation at Cornell University on March 4, 1983. The ocular evaluations were essentially similar with the exception of nystagmus absent from 1 female. All displayed an absent menace reflex. All pupils were dilated but responsive to bright light stimulation. 1he fundus evaluations found good vasculature and tapetal nontapetal character. A I I I I I I I I I I I I I I I I I I -
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Mapping of X-linked Progressive Retinal Atrophy (XLPRA), the canine homolog of retinitis pigmentosa 3 (RP3)
Human molecular genetics, 2000Co-Authors: Caroline J. Zeiss, Kunal Ray, Gregory M. Acland, Gustavo D. AguirreAbstract:X-linked Progressive Retinal Atrophy (XLPRA) in the Siberian husky dog is a naturally occurring X-linked retinopathy closely resembling X-linked retinitis pigmentosa (XLRP) in humans. In affected males, initial degeneration of rods is followed by cone degeneration and complete Retinal Atrophy; carrier females have random patches of rod degeneration consistent with random X chromosome inactivation. By typing the XLPRA pedigree with five intragenic markers [dystrophin, retinitis pigmentosa GTPase regulator (RPGR), tissue inhibitor of metalloproteinases 1, androgen receptor and factor IX], we established a linkage map of the canine X chromosome, and confirmed that the order of these five genes is identical to that on the human X. XLPRA was tightly linked to an intragenic RPGR polymorphism (LOD 11.7, zero recombination), thus confirming locus homology with RP3. We cloned the full-length canine RPGR cDNA and three additional splice variants. No disease-causing mutation was found in the RPGR-coding sequence of the four splice variants characterized, a finding similar to ~80% of human XLRP patients whose disease maps to the RP3 locus. In addition, there were no significant differences in the proportional expression of each splice variant in normal and pre-degenerate XLPRAaffected retina. Expression of all RPGR splice variants increased later in the disease, when retinas were undergoing active degeneration. The results provide further evidence of cross-species retention of a complex splicing pattern in the 3′ portion of RPGR ,t he functional significance of which is unknown. In addition, the possibility of another disease locus in the RP3 region is supported.
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Retinal Pathology of Canine X-linked Progressive Retinal Atrophy, the Locus Homologue of RP3
Investigative ophthalmology & visual science, 1999Co-Authors: Caroline J. Zeiss, Gregory M. Acland, Gustavo D. AguirreAbstract:Retinas from 55 dogs (44 males, 8 carrier females, 3 homozygous females) were obtainedby enucleation under general anesthesia. After fixation and dehydration, tissues were embedded inepoxy resin, sectioned at 1 mm for light microscopy and stained with azure II/methylene blue anda paraphenylenediamine counterstain. For electron microscopy, regions identified by light micros-copy were selected and cut at 60 nm. Sections were stained with uranyl acetate-lead citrate.Electroretinography from an additional group of normal males, affected males, and carrier femaleswas performed and the rod and cone responses evaluated.
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TIMP-1 Expression is Increased in X-linked Progressive Retinal Atrophy Despite its Exclusion as a Candidate Gene
Gene, 1998Co-Authors: Caroline J. Zeiss, Gustavo D. Aguirre, Gregory M. Acland, Kunal RayAbstract:Abstract X-linked Progressive Retinal Atrophy (XLPRA) is the only known natural animal model for X-linked retinitis pigmentosa (XLRP), a blinding disorder in man. The tissue inhibitor metalloproteinase 1 gene (TIMP-1), present in close proximity to one of the two XLRP loci, was tested as a candidate for XLPRA, by first characterizing the cDNA and gene from a normal dog. The cloned canine TIMP-1 cDNA is predicted to encode a protein of 207 amino acids with 66–83% identity in the deduced aa sequence with homologous mammalian genes. No sequence difference in the coding sequence of TIMP-1 was observed between normal and XLPRA-affected dogs. TIMP-1 was found to be expressed in all of the canine tissues examined by reverse transcription and polymerase chain reaction. The canine TIMP-1 spans 3.5 kb and is interrupted by five introns with sizes comparable to those observed in the human and mouse homologues of the gene. The proximal promoter region of canine TIMP-1 contains sequence motifs shown to have regulatory significance in transcription of human TIMP-1. Linkage analysis between XLPRA and TIMP-1 using a newly identified intragenic polymorphism identified recombinants, which conclusively excluded the gene as a candidate for the disease. TIMP-1 is overexpressed several months before Retinal degeneration is histologically evident in XLPRA dogs, implying that alterations in interphotoreceptor matrix composition precede Retinal degeneration by a significant time period.
Gabriele Dekomien - One of the best experts on this subject based on the ideXlab platform.
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Generalized Progressive Retinal Atrophy in the Irish Glen of Imaal Terrier is associated with a deletion in the ADAM9 gene.
Molecular and cellular probes, 2010Co-Authors: Regina Kropatsch, Jörg T. Epplen, Elisabeth Petrasch-parwez, Denis A. Akkad, Wanda M. Gerding, Dominik Seelow, Annegrit Schlichting, Gabriele DekomienAbstract:Generalized Progressive Retinal Atrophy (gPRA) belongs to a group of inherited Retinal diseases which are associated with gradual vision loss in various dog breeds, including the Irish Glen of Imaal Terrier (GIT). By genome-wide homozygosity mapping using SNP arrays and fine mapping of candidate regions, we assigned the gPRA candidate locus in this breed to canine chromosome 16. The respective region is syntenic with human chromosome 8 comprising the ADAM metallopeptidase domain 9 (ADAM9) gene. ADAM9 represents a strong candidate gene for canine Retinal disease because mutations have previously been shown to cause autosomal recessively inherited human cone-rod dystrophy, a Retinal disorder affecting photoreceptor function. Sequence analysis of ADAM9 in affected and carrier GITs revealed a deletion of exons 15 and 16 which alters the reading frame leading to a premature stop codon. This mutation was absent from 34 other dog breeds. A variable and, at times, very late onset of gPRA was confirmed in GITs by a relatively mild Retinal degeneration at an advanced age. Hence, the identification of the genetic defect underlying gPRA in the GIT represents a suitable model for cone-rod dystrophy of humans, with superior potential to elucidate functional consequences of the recently described null mutations in the human ADAM9 gene.
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Progressive Retinal Atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene
neurogenetics, 2010Co-Authors: Gabriele Dekomien, Conni Vollrath, Elisabeth Petrasch-parwez, Michael H. Boevé, Denis A. Akkad, Wanda M. Gerding, Jörg T. EpplenAbstract:Canine generalized Progressive Retinal Atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and Progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 ( CCDC66 ) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease. The insertion is present in all affected dogs in the homozygous state as well as in all obligatory mutation carriers in the heterozygous state. The CCDC66 gene is evolutionarily conserved in different vertebrate species and exhibits a complex pattern of differential RNA splicing resulting in various isoforms in the retina. Immunohistochemically, CCDC66 protein is detected mainly in the inner segments of photoreceptors in mouse, dog, and man. The affected Schapendoes retina lacks CCDC66 protein. Thus this natural canine model for gPRA yields superior potential to understand functional implications of this newly identified protein including its physiology, and it opens new perspectives for analyzing different aspects of the general pathophysiology of gPRA.
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Haplotype-defined linkage region for gPRA in Schapendoes dogs.
Molecular vision, 2007Co-Authors: Tanja Lippmann, Jörg T. Epplen, Elisabeth Petrasch-parwez, Anna Jonkisz, Tadeusz Dobosz, Gabriele DekomienAbstract:Purpose In order to determine the molecular basis of canine generalized Progressive Retinal Atrophy (gPRA), we initiated whole-genome scanning for linkage in gPRA-informative pedigrees of the Schapendoes breed.
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Indirect exclusion of four candidate genes for generalized Progressive Retinal Atrophy in several breeds of dogs
Journal of Negative Results in BioMedicine, 2006Co-Authors: Tanja Lippmann, Sandra M Pasternack, Britta Kraczyk, Sabine E Dudek, Gabriele DekomienAbstract:Background Generalized Progressive Retinal Atrophy (gPRA) is a hereditary ocular disorder with Progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina ( ABCA 4), connexin 36 ( CX 36), c-mer tyrosin kinase receptor ( MERTK ) and photoreceptor cell retinol dehydrogenase ( RDH 12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs. Results Mutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA 4, CX 36, MERTK and RDH 12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs. Conclusion Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA 4 (for 9 breeds), CX 36 (for 12 breeds), MERTK (for all 29 breeds) and RDH 12 (for 9 breeds).
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Evaluation of the canine RPE65 gene in affected dogs with generalized Progressive Retinal Atrophy.
Molecular vision, 2003Co-Authors: Gabriele Dekomien, Jörg T. EpplenAbstract:Purpose: The RPE65 gene was screened in 26 breeds of dogs in order to identify potential disease-causing mutations in dogs with generalized Progressive Retinal Atrophy (gPRA). Methods: Intronic sequences were obtained from canine genomic DNA by intron-overlapping polymerase chain reactions (PCRs). Mutation analysis was performed by PCR and demonstration of single strand conformation polymorphisms (SSCP). Genomic variations were verified by sequencing. Results: A series of exonic and intronic single nucleotide polymorphisms (SNPs) were identified in the investigated breeds, but none of the dogs examined showed the typical RPE deletion for Retinal dystrophy in Briards nor any other disease-causing mutation. Conclusions: The informative SNPs provide evidence allowing indirect exclusion of mutations in the RPE65 gene as causing Retinal degeneration in 25 of the 26 dog breeds investigated with presumed autosomal recessively transmitted gPRA.
Cathryn S. Mellersh - One of the best experts on this subject based on the ideXlab platform.
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A novel mutation in TTC8 is associated with Progressive Retinal Atrophy in the golden retriever
Canine Genetics and Epidemiology, 2014Co-Authors: Louise M. Downs, Berit Wallin-håkansson, Tomas Bergström, Cathryn S. MellershAbstract:Background Generalized Progressive Retinal Atrophy (PRA) is a group of inherited eye diseases characterised by Progressive Retinal degeneration that ultimately leads to blindness in dogs. To date, more than 20 different mutations causing canine-PRA have been described and several breeds including the Golden Retriever are affected by more than one form of PRA. Genetically distinct forms of PRA may have different clinical characteristics such as rate of progression and age of onset. However, in many instances the phenotype of different forms of PRA cannot be distinguished at the basic clinical level achieved during routine ophthalmoscopic examination. Mutations in two distinct genes have been reported to cause PRA in Golden Retrievers (prcd-PRA and GR_PRA1), but for approximately 39% of cases in this breed the causal mutation remains unknown. Results A genome-wide association study of 10 PRA cases and 16 controls identified an association on chromosome 8 not previously associated with PRA (p_raw = 1.30×10^-6 and corrected with 100,000 permutations, p_genome = 0.148). Using haplotype analysis we defined a 737 kb critical region containing 6 genes. Two of the genes ( TTC8 and SPATA7 ) have been associated with Retinitis Pigmentosa (RP) in humans. Using targeted next generation sequencing a single nucleotide deletion was identified in exon 8 of the TTC8 gene of affected Golden Retrievers. The frame shift mutation was predicted to cause a premature termination codon. In a larger cohort, this mutation, TTC8 _c.669delA, segregates correctly in 22 out of 29 cases tested (75.9%). Of the PRA controls none are homozygous for the mutation, only 3.5% carry the mutation and 96.5% are homozygous wildtype. Conclusions Our results show that PRA is genetically heterogeneous in one of the world’s numerically largest breeds, the Golden Retriever, and is caused by multiple, distinct mutations. Here we discuss the mutation that causes a form of PRA, that we have termed PRA2, that accounts for approximately 30% of PRA cases in the breed. The genetic explanation for approximately 9% of cases remains to be identified. PRA2 is a naturally occurring animal model for Retinitis Pigmentosa, and potentially Bardet-Biedl Syndrome.
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A novel mutation in TTC8 is associated with Progressive Retinal Atrophy in the golden retriever
Canine genetics and epidemiology, 2014Co-Authors: Louise M. Downs, Berit Wallin-håkansson, Tomas F. Bergström, Cathryn S. MellershAbstract:Generalized Progressive Retinal Atrophy (PRA) is a group of inherited eye diseases characterised by Progressive Retinal degeneration that ultimately leads to blindness in dogs. To date, more than 20 different mutations causing canine-PRA have been described and several breeds including the Golden Retriever are affected by more than one form of PRA. Genetically distinct forms of PRA may have different clinical characteristics such as rate of progression and age of onset. However, in many instances the phenotype of different forms of PRA cannot be distinguished at the basic clinical level achieved during routine ophthalmoscopic examination. Mutations in two distinct genes have been reported to cause PRA in Golden Retrievers (prcd-PRA and GR_PRA1), but for approximately 39% of cases in this breed the causal mutation remains unknown. A genome-wide association study of 10 PRA cases and 16 controls identified an association on chromosome 8 not previously associated with PRA (praw = 1.30×10-6 and corrected with 100,000 permutations, pgenome = 0.148). Using haplotype analysis we defined a 737 kb critical region containing 6 genes. Two of the genes (TTC8 and SPATA7) have been associated with Retinitis Pigmentosa (RP) in humans. Using targeted next generation sequencing a single nucleotide deletion was identified in exon 8 of the TTC8 gene of affected Golden Retrievers. The frame shift mutation was predicted to cause a premature termination codon. In a larger cohort, this mutation, TTC8 c.669delA, segregates correctly in 22 out of 29 cases tested (75.9%). Of the PRA controls none are homozygous for the mutation, only 3.5% carry the mutation and 96.5% are homozygous wildtype. Our results show that PRA is genetically heterogeneous in one of the world’s numerically largest breeds, the Golden Retriever, and is caused by multiple, distinct mutations. Here we discuss the mutation that causes a form of PRA, that we have termed PRA2, that accounts for approximately 30% of PRA cases in the breed. The genetic explanation for approximately 9% of cases remains to be identified. PRA2 is a naturally occurring animal model for Retinitis Pigmentosa, and potentially Bardet-Biedl Syndrome.
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An Intronic SINE insertion in FAM161A that causes exon-skipping is associated with Progressive Retinal Atrophy in Tibetan Spaniels and Tibetan Terriers.
PloS one, 2014Co-Authors: Louise M. Downs, Cathryn S. MellershAbstract:Progressive Retinal Atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 19 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome-wide association with 22 Tibetan Spaniel PRA cases and 10 controls, we identified a novel PRA locus, PRA3, on CFA10 (praw = 2.01×10−5, pgenome = 0.014), where a 3.8 Mb region was homozygous within 12 cases. Using targeted next generation sequencing, a short interspersed nuclear element insertion was identified near a splice acceptor site in an intron of a provocative gene, FAM161A. Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product. This mutation segregates with the disease in 22 out of 35 cases tested (63%). Of the PRA controls, none are homozygous for the mutation, 15% carry the mutation and 85% are homozygous wildtype. This mutation was also identified in Tibetan Terriers, although our results indicate that PRA is genetically heterogeneous in both Tibetan Spaniels and Tibetan Terriers.
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Genetic screening for PRA-associated mutations in multiple dog breeds shows that PRA is heterogeneous within and between breeds.
Veterinary ophthalmology, 2013Co-Authors: Louise M. Downs, Rebekkah J. Hitti, Silvia Pregnolato, Cathryn S. MellershAbstract:Objective To assess the extent of Progressive Retinal Atrophy (PRA) genetic heterogeneity within and between domestic dog breeds. Methods DNA from 231 dogs with PRA, representing 36 breeds, was screened for 17 mutations previously associated with PRA in at least one breed of dog. Screening methods included amplified fragment size discrimination using gel electrophoresis or detection of fluorescence, (TaqMan®; Life Technologies, Carlsbad, CA, USA) allelic discrimination, and Sanger sequencing. Results Of the 231 dogs screened, 129 were homozygous for a PRA-associated mutation, 29 dogs were carriers, and 73 were homozygous for the wild-type allele at all loci tested. In two of the 129 dogs, homozygous mutations were identified that had not previously been observed in the respective breeds: one Chinese Crested dog was homozygous for the RCD3-associated mutation usually found in the Cardigan Welsh Corgi, and one Standard Poodle was homozygous for the RCD4-associated mutation previously reported to segregate in Gordon and Irish Setters. In the majority of the breeds (15/21) in which a PRA-associated mutation is known to segregate, cases were identified that did not carry any of the known PRA-associated mutations. Conclusion Progressive Retinal Atrophy in the dog displays significant genetic heterogeneity within as well as between breeds. There are also several instances where PRA-associated mutations segregate among breeds with no known close ancestry.
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late onset Progressive Retinal Atrophy in the gordon and irish setter breeds is associated with a frameshift mutation in c2orf71
Animal Genetics, 2013Co-Authors: L. M. Downs, Jerold Bell, J. Freeman, Claudia Hartley, Louisa J. Hayward, Cathryn S. MellershAbstract:Summary Progressive Retinal Atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 14 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome-wide association with 16 Gordon Setter PRA cases and 22 controls, we identified a novel PRA locus, termed rod–cone degeneration 4 (rcd4), on CFA17 (Praw = 2.22 × 10−8, Pgenome = 2.00 × 10−5), where a 3.2-Mb region was homozygous within cases. A frameshift mutation was identified in C2orf71, a gene located within this region. This variant was homozygous in 19 of 21 PRA cases and was at a frequency of approximately 0.37 in the Gordon Setter population. Approximately 10% of cases in our study (2 of 21) are not associated with this C2orf71 mutation, indicating that PRA in this breed is genetically heterogeneous and caused by at least two mutations. This variant is also present in a number of Irish Setter dogs with PRA and has an estimated allele frequency of 0.26 in the breed. The function of C2orf71 remains unknown, but it is important for Retinal development and function and has previously been associated with autosomal recessive retinitis pigmentosa in humans.
Simon M. Petersen-jones - One of the best experts on this subject based on the ideXlab platform.
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A novel mutation in PDE6B in Spanish Water Dogs with early-onset Progressive Retinal Atrophy.
Veterinary ophthalmology, 2020Co-Authors: Paige A. Winkler, Harrison D. Ramsey, Simon M. Petersen-jonesAbstract:OBJECTIVE To identify the underlying mutation in a recently identified early-onset Progressive Retinal Atrophy (PRA) in the Spanish Water Dog (SWD) breed. ANIMAL STUDIED Eighteen SWDs were used in this study. Six SWDs diagnosed with PRA and 12 phenotypically normal SWDs. PROCEDURES An exclusion analysis using an established microsatellite panel to screen PRA candidate genes was combined with whole genome sequencing of two affected SWD siblings and two phenotypically normal SWDs (a sibling and the dam). RESULTS A 6-bp deletion was identified in exon 19 of PDE6B removing two highly conserved amino acids from the enzymatic domain of the PDE6B protein (c.2218-2223del; p.Phe740_Phe741del). This segregated with the disease status in the small study pedigree. CONCLUSIONS Identification of this novel PDE6B mutation adds to the already described PDE6B mutations responsible for PRA in the Irish Setter, Sloughi, and American Staffordshire Terrier dog breeds. A DNA-based test was designed to allow breeders to genotype their animals and make informed breeding decisions in the effort to eradicate PRA from the SWD breed.
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Characterization of a novel form of Progressive Retinal Atrophy in Whippet dogs: a clinical, electroretinographic, and breeding study.
Veterinary ophthalmology, 2016Co-Authors: André Tavares Somma, Simon M. Petersen-jones, Juan Carlos Duque Moreno, Mario Teruo Sato, Blanche Dreher Rodrigues, Marianna Bacellar-galdino, Laurence M. Occelli, Fabiano Montiani-ferreiraAbstract:Objective To describe a form of Progressive Retinal Atrophy (PRA) in Whippets including clinical, electroretinographic, optical coherence tomographic changes and pedigree analysis. Animals studied Client-owned Whippet dogs (n = 51) living in Brazil. Procedures All animals were submitted for routine ophthalmic screening for presumed inherited ocular disease, which included the following: visual tests, such as obstacle course tests, in scotopic and photopic conditions, cotton ball test, dazzle reflex, ocular fundus evaluation by indirect ophthalmoscopy followed by fundus photography. Additionally, electroretinography (ERG) and optical coherence tomography (OCT) were performed in 24 and four dogs, respectively. Results Sixteen dogs were diagnosed with PRA. Vision deficits in dim light were detected in dogs examined at a young age associated with nystagmus. Funduscopic changes included the development of multifocal Retinal bullae from 6 months of age. Retinal thinning became apparent later, at which time the bullae were no longer detected. OCT examination of selected young dogs revealed that the Retinal bullae were due to separation between photoreceptors and the Retinal pigment epithelium, and of dogs with more advanced disease confirmed the development of Retinal thinning. Electroretinography in young dogs revealed a negative ERG due to a lack of b-wave in both scotopic and photopic recordings. With progression, the ERG became unrecordable. Pedigree analysis suggested an autosomal recessive mode of inheritance. Conclusion The Retinal dystrophy reported here in Whippet dogs has a unique phenotype of an initial lack of ERG b-wave, development of Retinal bullae then a Progressive generalized Retinal degeneration.
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Progressive Retinal Atrophy in the Polski Owczarek Nizinny dog: a clinical and genetic study
Veterinary ophthalmology, 2015Co-Authors: Marika Svensson, Simon M. Petersen-jones, Paige A. Winkler, Tomas F. Bergström, Lena Olsén, Yacek Garncarz, Kristina NarfströmAbstract:Objective To describe ophthalmic, functional, structural, and genetical characteristics of Progressive Retinal Atrophy (PRA) in the polski owczarek nizinny (PON) breed of dog. Animals studied clinically Client-owned PON dogs (n = 82) from Sweden. Procedures Routine examination for presumed inherited eye disease was performed in all dogs. Bilateral full-field electroretinography (ERG) was performed in 11 affected and 4 control dogs. Eyes from one affected dog were studied with light microscopy. DNA samples from 34 Swedish and 30 PON dogs collected by Michigan State University (MSU) were tested for the mutations causing the rcd4 and prcd forms of PRA. Results Sixteen of the eighty-two Swedish dogs were diagnosed with PRA. Slight vascular attenuation, first seen at 4.5 years of age, preceded changes in tapetal reflectivity. The initial ERG changes in affected dogs showed markedly diminished rod responses, while cone responses were barely affected. Eventually, cone responses were also reduced. Retinal morphology showed approximately a 50% reduction of photoreceptor nuclei in the outer nuclear layer. Fourteen of fifteen PRA-affected Swedish dogs and eighteen of twenty of the MSU PRA-affected dogs tested genetically were positive for the rcd4 mutation. All tested dogs were negative for the mutation causing prcd-PRA. Conclusions PRA of PON dogs is a late-onset degenerative disease with slow progression. There is early loss of rod function, while the cone system deteriorates later. The rcd4 mutation in the C2ORF71 gene was associated with the majority of the PRA cases tested. The possibility of additional forms of PRA in the breed cannot be excluded.
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Advances in the molecular understanding of canine Retinal diseases.
The Journal of small animal practice, 2005Co-Authors: Simon M. Petersen-jonesAbstract:Retinal dystrophies are a common cause of blindness in purebred dogs. Progressive Retinal Atrophy, the canine equivalent of retinitis pigmentosa in humans, is the most common dystrophy. Molecular studies have led to the identification of the genetic defect underlying some forms of Progressive Retinal Atrophy and the mapping of the chromosomal location of others. Additionally, the gene mutation that causes a severe Retinal dystrophy in the briard, which is the equivalent of Leber congenital amaurosis in humans, has been identified. These advances have led to the development of DNA-based diagnostic tests for some Retinal dystrophies, thus facilitating their eradication. The study of these dystrophies in dogs has also provided useful information about the equivalent diseases in humans. Recently, gene therapy has been used to restore vision to dogs with a Retinal dystrophy due to a mutation in the RPE65 gene. Such studies are important in the quest to develop therapies for similar conditions in humans.
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An improved DNA-based test for detection of the codon 616 mutation in the alpha cyclic GMP phosphodiesterase gene that causes Progressive Retinal Atrophy in the Cardigan Welsh Corgi.
Veterinary ophthalmology, 2002Co-Authors: Simon M. Petersen-jones, David D. EntzAbstract:The aim of the study was to develop an improved test to detect the codon 616 gene mutation in the alpha cyclic GMP phosphodiesterase gene that causes Progressive Retinal Atrophy in the Cardigan Welsh Corgi. We studied 10 control dogs of known genotype at codon 616 of the alpha cyclic GMP phosphodiesterase gene and 80 Cardigan Welsh Corgis of unknown genotype. A polymerase chain reaction (PCR) utilizing a mismatched primer was designed so that it introduced a HinfI restriction enzyme digestion site into the PCR product only if the normal gene sequence was present, the restriction site was not introduced if the codon 616 mutation was present. An additional HinfI site present in the amplified section from both normal and mutant alleles acted as a positive control for restriction enzyme digestion. The PCR reliably amplified a portion of the alpha cyclic GMP phosphodiesterase gene spanning the codon 616 mutation site. Restriction enzyme digestion with HinfI and analysis on a suitable agarose gel reliably ascertained the genotype of the control dogs and was used to identify the genotype of a further 80 test dogs. An improved DNA-based test for detection of the codon 616 mutation in the alpha cyclic GMP phosphodiesterase gene that causes Progressive Retinal Atrophy in the Cardigan Welsh Corgi has been designed. This overcomes potential problems that could be associated with allele-specific PCR tests such as that used previously in a diagnostic test for this gene mutation.
