138 results on '"Narfström K"'
Search Results
2. A phosducin (PDC) gene mutation does not cause progressive retinal atrophy in Korean miniature schnauzers
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Jeong, M. B., Han, C. H., Narfström, K., Awano, T., Johnson, G. S., Min, M. S., Seong, J. K., and Seo, K. M.
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- 2008
3. Hereditary and congenital ocular disease in the cat
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Narfström, K.
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- 1999
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4. Accumulation of taurine in the nasal mucosa and the olfactory bulb
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Lindquist, N. G., Lydén, A., Narfström, K., and Samaan, H.
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- 1983
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5. Ocular blood flow and retinal metabolism in abyssinian cats with hereditary retinal degeneration
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Nilsson, S F E, Mäepea, O, Alm, A, Narfström, K, Nilsson, S F E, Mäepea, O, Alm, A, and Narfström, K
- Abstract
Purpose. To investigate if retinal blood flow decreases with progression of the disease in Abyssinian cats with progressive retinal atrophy (PRA), to examine if the choroidal blood flow was affected by the disease, and to determine the uptake of glucose and formation of lactate in the outer retina. Methods. Local blood flow in different parts of the eye was determined with radioactive microspheres, in 9 normal cats and in 10 cats at different stages of PRA. Three blood flow determinations were made in each animal, during control conditions, after IV administration of indomethacin and after subsequent administration of Nw-nitro-L-arginine (L-NA). Blood samples from a choroidal vein and a femoral artery were collected to determine the retinal formation of lactate and uptake of glucose. Results. In Abyssinian cats with PRA (n = 10), the retinal blood flow was significantly (P = 0.01) lower than in normal cats (n = 9) during control conditions, 6.4 ▒ 1.7 compared with 14.1 ▒ 1.9 g min-1 (100 g)-1. The vascular resistance in the iris and ciliary body was significantly higher in the cats at a late stage of PRA, both compared with normal cats and to cats at an early stage of the disease, whereas the choroidal vascular resistance was not significantly affected. Indomethacin had no effect on ocular blood flows in normal cats, but in cats with PRA, iridal blood flow was more than doubled after indomethacin. The retinal formation of lactate was significantly (P = 0.001) lower in cats with PRA than in normal cats, 0.111 ▒ 0.035 (n = 8) compared with 0.318 ▒ 0.024 (n = 8) ╡mol rain-1. The uptake of glucose was not significantly different in cats with PRA. Conclusions. Retinal blood flow is severely decreased in Abyssinian cats at a late stage of retinal degeneration, whereas the choroidal microcirculation is not significantly affected by the disease. At a late stage of retinal degeneration, vascular resistance in the iris is significantly increased, which at least in part could
- Published
- 2001
6. Neuronal ceroid lipofuscinosis: clinical and morphologic findings in nine affected Polish Owczarek Nizinny (PON) dogs
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Narfström, K., primary, Wrigstad, A., additional, Ekesten, B., additional, and Berg, A.-L., additional
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- 2007
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7. Retinal dystrophy of swedish Briard/Briard-Beagle dogs is due to a 4-bp deletion in RPE65.
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Veske, A., Nilsson, Sven Erik, Narfström, K, Gal, A., Veske, A., Nilsson, Sven Erik, Narfström, K, and Gal, A.
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- 1999
8. Clinical, electrophysiological and morphological changes in a case of hereditary retinal degeneration in the Papillon dog.
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Narfström, K, Wrigstad, Anders, Narfström, K, and Wrigstad, Anders
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- 1999
9. Clinical, electrophysiological, and morphological findings in a case of neuronal ceroid lipofuscinosis in The Polish Owczarek Nizinny (PON) dog
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Narfström, K., primary and Wrigstad, A., additional
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- 1995
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10. An early decrease in IRBP gene expression in Abyssinian cats homozygous for progressive retinal atrophy
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Wiggert, B., primary, Lee, L., additional, Kutty, G., additional, Nickerson, J., additional, Si, J-S., additional, Chader, G.J., additional, and Narfström, K., additional
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- 1992
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11. Photoreceptor degeneration and loss of immunoreactive GABA in the Abyssinian cat retina
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Ehinger, B., primary, Narfström, K., additional, Nilsson, S.E., additional, and van Veen, T., additional
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- 1991
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12. The Briard dog: a new animal model of congenital stationary night blindness.
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Narfström, K, Wrigstad, A, and Nilsson, S E
- Abstract
Congenital stationary night blindness (CSNB), apparently inherited in an autosomal recessive manner, was observed in a litter of Briard dogs in Sweden. Of nine litter mates five had nyctalopia. The results of different clinical tests, including electroretinography (ERG), were compared with the results found in four human cases of CSNB, three of which were most probably associated with autosomal recessive inheritance and one with X-linked inheritance. The congenital and stationary nature of the disease, ophthalmoscopically normal appearing fundi, and recordable but reduced photopic flicker responses were some of the similarities found between canine and human cases. The single-flash ERG response was abnormal in the humans as well as in the affected Briards. However, the human cases showed a "negative' ERG, whereas in the Briards both the a and b waves were extremely reduced and present only at a photopic level. Cases similar to these Briards have been described also in man, where rhodopsin concentration and regeneration were found to be normal, suggesting a disturbed transduction mechanism. It thus appears that the Briard dog may become a valuable model of human CSNB. [ABSTRACT FROM PUBLISHER]
- Published
- 1989
13. Retinal sensitivity in hereditary retinal degeneration in Abyssinian cats: electrophysiological similarities between man and cat.
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Narfström, K, Arden, G B, and Nilsson, S E
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The functional and electrophysiological similarities in the changes in the electroretinogram (ERG) of man and cat affected by hereditary retinal degenerative disease were studied. The results of a series of log intensity-amplitude studies in a group of young affected Abyssinian cats were fitted to the Naka-Rushton relationship by means of a mathematical package on the University of London mainframe. The analysis showed that the amplitude of the maximum dark-adapted b-wave was significantly reduced by the end of the period studied but that the value of k, a variable inversely equivalent to retinal sensitivity, was only slightly reduced by the retinal degenerative process. The electrophysiological findings thus are similar to those found in cases of human diffuse dominantly inherited retinitis pigmentosa. [ABSTRACT FROM PUBLISHER]
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- 1989
14. Progressive retinal atrophy in the Abyssinian cat: studies of the DC-recorded electroretinogram and the standing potential of the eye.
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Narfström, K L, Nilsson, S E, and Andersson, B E
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DC-recorded electroretinography (ERG) and direct recordings of the standing potential (SP) were performed on a group of normal cats and Abyssinian cats affected by a hereditary retinal degenerative disease with similarities to human retinitis pigmentosa. A significant reduction of a- and b-wave amplitudes was found at an early stage of disease at a time when there were no major alterations in the c-wave and SP. At later stages both the c-wave and the SP oscillations were significantly reduced or absent. These findings indicate a primary photo-receptor disorder. Threshold studies for the scotopic b-wave showed a loss of retinal sensitivity early in the disease at a time when 30 Hz flicker responses were normal, which could indicate an earlier involvement of the rods than of the cones. There were no major alterations in the timing of the ERG in the affected animals tested. [ABSTRACT FROM PUBLISHER]
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- 1985
15. Cataract in the West Highland White Terrier.
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NARFSTRÖM, K.
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- 1981
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16. Hereditary progressive retinal atrophy in the Abyssinian cat.
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Narfström, K
- Abstract
Progressive retinal atrophy (PRA), a hereditary eye disease leading to blindness, was found in the Abyssinian breed of cat. Sixty-eight cases of a bilateral generalized retinopathy, at different stages of the disease process, were seen in the breed during ophthalmoscopic examinations of cats throughout Sweden during a 2-year period. Forty-five percent of cats aged 2 years or older were affected in the examined group. The earliest case was diagnosed in a 16-month-old cat. At the age of 3-4 years a bilateral retinal atrophy was usually present in affected cats. Genetic analysis indicates that PRA in the Abyssinian cat is caused by an autosomal recessive gene.
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- 1983
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17. Assessing the efficacy of gene therapy in Rpe65-/- mice using photoentrainment of circadian rhythm
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Stoddart, C. W., Yu, M. J. T., Martin-Iverson, M. T., Daniels, D. M., Lai, C. -M, Barnett, N. L., T. Michael Redmond, Narfström, K., and Rakoczy, P. E.
18. Electroretinographic evaluation of Papillons with and without hereditary retinal degeneration
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Narfström, K. and Björn Ekesten
19. T3-T4 disc herniation in a German shepherd dog.
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Jäderlund, K. H., Hansson, K., Lindberg, R., and Narfström, K.
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- 2002
20. Correspondence.
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Aguirre, G. and Narfström, K.
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RETINAL degeneration , *BRIARD - Abstract
Comments on retinal dystrophy versus congenital stationary night blindness based on the presumed progression that occurs in Briard breed disorder. Substantiation of the progression of the disease; Documentation of the changes; Observation of typically progressive retinal disorders.
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- 2000
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21. An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease.
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Mäkeläinen S, Gòdia M, Hellsand M, Viluma A, Hahn D, Makdoumi K, Zeiss CJ, Mellersh C, Ricketts SL, Narfström K, Hallböök F, Ekesten B, Andersson G, and Bergström TF
- Subjects
- ATP Binding Cassette Transporter, Subfamily A, Member 4 chemistry, ATP Binding Cassette Transporter, Subfamily A, Member 4 metabolism, ATP-Binding Cassette Transporters genetics, Amino Acid Sequence, Animals, Base Sequence, Codon, Nonsense, Disease Models, Animal, Dog Diseases metabolism, Dog Diseases pathology, Dogs, Female, Genes, Recessive, Homozygote, Humans, Lipofuscin metabolism, Macular Degeneration genetics, Macular Degeneration metabolism, Macular Degeneration veterinary, Male, Microscopy, Fluorescence, Models, Molecular, Mutagenesis, Insertional, Pedigree, Protein Conformation, Retina metabolism, Retina pathology, Stargardt Disease, Whole Genome Sequencing, ATP Binding Cassette Transporter, Subfamily A, Member 4 genetics, Dog Diseases genetics, Macular Degeneration congenital, Mutation
- Abstract
Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: A patent application (US No. 62/662,362) has been filed by the following authors and inventors, TB, GA, BE and SM. CM and SR are affiliated with a diagnostic lab marketing genetic tests for dogs. TB, GA and SM are affiliated with a university department that provides genetic testing for animals.
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- 2019
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22. Hereditary cataracts in Russian Blue cats.
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Nygren K, Jalomäki S, Karlstam L, and Narfström K
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- Animals, Breeding, Cat Diseases diagnosis, Cataract genetics, Cats, Diagnostic Techniques, Ophthalmological veterinary, Female, Male, Prevalence, Retinal Diseases veterinary, Sweden, Cat Diseases genetics, Cataract veterinary, Pedigree
- Abstract
Objectives: The purpose of this study was to investigate the prevalence of cataracts in the Russian Blue breed of cats in Sweden, and to describe the clinical appearance of this presumed inherited form of cataract., Methods: A total of 66 Russian Blue cats were examined in Sweden, between March and October 2014, using standard examination techniques. The examined cats were between 3 months and 14 years of age. Pedigrees were collected from all examined cats for genetic studies., Results: Mild-to-severe forms of mainly bilateral cataracts were observed in 22/66 examined Russian Blue cats of both sexes. Two affected cats were <1 year of age. The most frequently observed appearance of a cataract was a small triangular, Y-shaped or circular opacity at the border of the posterior nucleus and the anterior part of the posterior cortex, which caused no observable visual impairment. More extended forms were observed in 6/22 cats, with involvement of both the nucleus and either the entire cortex or parts of the posterior and/or anterior cortex. Visual impairment or blindness was observed in the latter six cases. Pedigree analyses indicated a simple autosomal recessive mode of inheritance for the defect, although a dominant mode with incomplete penetrance could not be excluded., Conclusions and Relevance: This study indicates that the Russian Blue breed of cat is affected by hereditary cataracts. The high prevalence in young cats and the characteristic location of the most frequently observed defect in the study suggest an early onset type of cataract. The breeders should be aware of this defect and have their cats examined by a veterinary ophthalmologist before breeding of an individual Russian Blue cat is considered.
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- 2018
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23. Central retinal preservation in rdAc cats.
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Minella AL, Occelli LM, Narfström K, and Petersen-Jones SM
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- Animals, Cat Diseases pathology, Cats, Female, Humans, Male, Optic Atrophies, Hereditary genetics, Optic Atrophies, Hereditary pathology, Retina pathology, Retinal Degeneration genetics, Retinal Degeneration pathology, Cat Diseases genetics, Mutation, Optic Atrophies, Hereditary veterinary, Retinal Degeneration veterinary, Tomography, Optical Coherence veterinary
- Abstract
Objective: Children with Leber congenital amaurosis (LCA) due to CEP290 mutations show characteristic macular preservation. Spectral domain-optical coherence tomography (SD-OCT) is a noninvasive technique to investigate retinal structural changes. Loss of integrity of the ellipsoid zone (EZ) on OCT in people with retinal disease has been associated with loss of visual function and is a useful measure of retinal disease progression. We hypothesized that rdAc felines with Cep290 mutation would have a similar pattern of degeneration, with relative central retinal preservation associated with maintenance of the EZ., Procedures: Fundus imaging, confocal scanning laser ophthalmoscopy, and SD-OCT cross-sectional imaging was performed on 11 rdAc cats ranging from 6 months to 10 years of age. Images were collected from the area centralis, visual streak, and the mid-superior and mid-inferior retina. Receptor plus (REC+, encompassing the entire length of photoreceptors) thicknesses were measured. Regional rates of degeneration were determined by regression analysis and compared using unpaired t-tests. The EZ was evaluated for the presence, absence, or loss of definition., Results: RdAc cats showed REC+ thinning over time in all regions. The area centralis and visual streak had a slower rate of thinning than the mid-peripheral retina. There was loss of integrity of the EZ initially in the more peripheral regions, while its integrity was maintained in the area centralis and visual streak at all ages studied., Conclusions: rdAc cats show preservation of the central retina with maintenance of EZ integrity, which recapitulates findings in human patients., (© 2017 American College of Veterinary Ophthalmologists.)
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- 2018
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24. Cataracts in the Norwegian Buhund-current prevalence and characteristics.
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Kristiansen E, Revold T, Lingaas F, Narfström K, Pedersen PB, Kielland C, Dahl S, and Ropstad EO
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- Animals, Cataract epidemiology, Denmark epidemiology, Dogs, Female, Male, Norway epidemiology, Prevalence, Species Specificity, Sweden epidemiology, Cataract veterinary, Dog Diseases epidemiology
- Abstract
Objective: To evaluate prevalence and characteristics of cataracts in the Norwegian Buhund breed 20 years after high reported prevalence of especially pulverulent nuclear cataracts (PNCs)., Animals Studied: Two hundred and fifty Norwegian Buhund dogs in Norway, Sweden, and Denmark (117 males and 133 females) with previously unknown eye health status were included. Forty-five dogs had multiple examinations (two to six times over a 6-year period). Median age was 4.4 years [0.2-15.2] at first examination and 5.3 years [0.2-15.2] at last examination., Procedures: All dogs underwent regular screening for inherited eye diseases., Results: At the last observation of each dog, 52.4% were affected by PNC, categorized as minimal (33 of 250 dogs; 13.2%), mild (31 dogs; 12.4%), moderate (38 dogs; 15.2%), or pronounced (29 dogs; 11.6%). Moderate or pronounced changes were only seen in older dogs, and progressive changes were identified in some of the re-examined dogs. Some dogs, free of lenticular changes at early examinations, were affected by PNC at re-examinations. The odds for finding PNC increased with dog's age up to approximately 8 years. Presumably inherited cataracts other than PNC were found in 53 dogs (21.2%) with cortical (17.6%) and posterior polar (6.4%) locations as the most common ones., Conclusions: The high prevalence of PNC in the breed reported 20 years ago persists. PNCs are not always visible in young dogs, and the rate of progression varies. The prevalence of other types of cataract is also high, but cataracts rarely cause loss of vision in this breed., (© 2017 American College of Veterinary Ophthalmologists.)
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- 2017
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25. CrxRdy Cat: A Large Animal Model for CRX-Associated Leber Congenital Amaurosis.
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Occelli LM, Tran NM, Narfström K, Chen S, and Petersen-Jones SM
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- Animals, Cats, Dark Adaptation physiology, Disease Models, Animal, Leber Congenital Amaurosis pathology, Leber Congenital Amaurosis physiopathology, Phenotype, Retina metabolism, Retina pathology, Retina physiopathology, Retinal Cone Photoreceptor Cells metabolism, Retinal Cone Photoreceptor Cells pathology, Retinal Cone Photoreceptor Cells physiology, Sensory Thresholds physiology, Transcription, Genetic, Frameshift Mutation genetics, Homeodomain Proteins genetics, Leber Congenital Amaurosis genetics, Trans-Activators genetics
- Abstract
Purpose: Mutations in the retinal transcription factor cone-rod homeobox (CRX) gene result in severe dominant retinopathies. A large animal model, the Rdy cat, carrying a spontaneous frameshift mutation in Crx, was reported previously. The present study aimed to further understand pathogenesis in this model by thoroughly characterizing the Rdy retina., Methods: Structural and functional changes were found in a comparison between the retinas of CrxRdy/+ kittens and those of wild-type littermates and were determined at various ages by fundus examination, electroretinography (ERG), optical coherence tomography, and histologic analyses. RNA and protein expression changes of Crx and key target genes were analyzed using quantitative reverse-transcribed PCR, Western blot analysis, and immunohistochemistry. Transcription activity of the mutant Crx was measured by a dual-luciferase transactivation assay., Results: CrxRdy/+ kittens had no recordable cone ERGs. Rod responses were delayed in development and markedly reduced at young ages and lost by 20 weeks. Photoreceptor outer segment development was incomplete and was followed by progressive outer retinal thinning starting in the cone-rich area centralis. Expression of cone and rod Crx target genes was significantly down-regulated. The mutant Crx allele was overexpressed, leading to high levels of the mutant protein lacking transactivation activity., Conclusions: The CrxRdy mutation exerts a dominant negative effect on wild-type Crx by overexpressing mutant protein. These findings, consistent with those of studies in a mouse model, support a conserved pathogenic mechanism for CRX frameshift mutations. The similarities between the feline eye and the human eye with the presence of a central region of high cone density makes the CrxRdy/+ cat a valuable model for preclinical testing of therapies for dominant CRX diseases.
- Published
- 2016
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26. Antioxidant supplementation increases retinal responses and decreases refractive error changes in dogs.
- Author
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Wang W, Hernandez J, Moore C, Jackson J, and Narfström K
- Abstract
The objective of the study was to examine whether a nutritional antioxidant supplementation could improve visual function in healthy dogs as measured by electroretinography (ERG) and autorefraction. A total of twelve Beagles, 6 to 8 years of age, with normal eyes upon indirect ophthalmoscopy and slit lamp biomicroscopy, were age and sex matched and randomly assigned to receive a feeding regimen for 6 months with or without a daily antioxidant supplementation. Portable, mini-Ganzfeld ERG and a Welch Allyn hand-held autorefractor were used to test retinal response and refractive error in the dogs at baseline and at the end of the supplementation period. All ERG a-wave amplitudes obtained were increased in the treatment group compared with those of dogs in the control group, with significant improvements in the scotopic high and photopic single flash cone ERG responses (P < 0·05 for both). For the b-wave amplitudes, all responses were similarly increased, with significant improvements in responses for the scotopic high light intensity stimulation (P < 0·05), and for photopic single flash cone and 30 Hz flicker (P < 0·01 for both) recordings. Change in refractive error was significantly less in the treatment group compared with that of the control group during the 6-month study (P < 0·05). Compared with the control group, the antioxidant-supplemented group showed improvement to varying degrees for retinal function and significantly less decline in refractive error. Dogs, like humans, experience retinal and lens functional decline with age. Antioxidant supplementation as demonstrated may be beneficial and effective in the long-term preservation and improvement of various functions of the canine eye.
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- 2016
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27. Progressive retinal atrophy in the Polski Owczarek Nizinny dog: a clinical and genetic study.
- Author
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Svensson M, Olsén L, Winkler PA, Petersen-Jones SM, Bergström T, Garncarz Y, and Narfström K
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- Animals, Dog Diseases diagnostic imaging, Dogs, Electroretinography veterinary, Female, Male, Mutation, Retinal Diseases diagnostic imaging, Retinal Diseases genetics, Species Specificity, Dog Diseases genetics, Retinal Diseases veterinary
- Abstract
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., (© 2015 American College of Veterinary Ophthalmologists.)
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- 2016
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28. Gene therapy for eye as regenerative medicine? Lessons from RPE65 gene therapy for Leber's Congenital Amaurosis.
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Rakoczy EP and Narfström K
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- Animals, Clinical Trials as Topic, Dependovirus genetics, Genetic Therapy trends, Genetic Vectors genetics, Humans, Recombination, Genetic, Regenerative Medicine trends, Time Factors, Treatment Outcome, Vision, Ocular, cis-trans-Isomerases metabolism, Genetic Therapy methods, Leber Congenital Amaurosis genetics, Leber Congenital Amaurosis therapy, Mutation, Regenerative Medicine methods, cis-trans-Isomerases genetics
- Abstract
Recombinant virus mediated gene therapy of Leber's Congenital Amaurosis has provided a wide range of data on the utility of gene replacement therapy for recessive diseases. Studies to date demonstrate that gene therapy in the eye is safe and can result in long-term recovery of visual function, but they also highlight that further research is required to identify optimum intervention time-points, target populations and the compatibility of associate therapies. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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29. Annotated features of domestic cat - Felis catus genome.
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Tamazian G, Simonov S, Dobrynin P, Makunin A, Logachev A, Komissarov A, Shevchenko A, Brukhin V, Cherkasov N, Svitin A, Koepfli KP, Pontius J, Driscoll CA, Blackistone K, Barr C, Goldman D, Antunes A, Quilez J, Lorente-Galdos B, Alkan C, Marques-Bonet T, Menotti-Raymond M, David VA, Narfström K, and O'Brien SJ
- Abstract
Background: Domestic cats enjoy an extensive veterinary medical surveillance which has described nearly 250 genetic diseases analogous to human disorders. Feline infectious agents offer powerful natural models of deadly human diseases, which include feline immunodeficiency virus, feline sarcoma virus and feline leukemia virus. A rich veterinary literature of feline disease pathogenesis and the demonstration of a highly conserved ancestral mammal genome organization make the cat genome annotation a highly informative resource that facilitates multifaceted research endeavors., Findings: Here we report a preliminary annotation of the whole genome sequence of Cinnamon, a domestic cat living in Columbia (MO, USA), bisulfite sequencing of Boris, a male cat from St. Petersburg (Russia), and light 30× sequencing of Sylvester, a European wildcat progenitor of cat domestication. The annotation includes 21,865 protein-coding genes identified by a comparative approach, 217 loci of endogenous retrovirus-like elements, repetitive elements which comprise about 55.7% of the whole genome, 99,494 new SNVs, 8,355 new indels, 743,326 evolutionary constrained elements, and 3,182 microRNA homologues. The methylation sites study shows that 10.5% of cat genome cytosines are methylated. An assisted assembly of a European wildcat, Felis silvestris silvestris, was performed; variants between F. silvestris and F. catus genomes were derived and compared to F. catus., Conclusions: The presented genome annotation extends beyond earlier ones by closing gaps of sequence that were unavoidable with previous low-coverage shotgun genome sequencing. The assembly and its annotation offer an important resource for connecting the rich veterinary and natural history of cats to genome discovery.
- Published
- 2014
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30. Enzyme replacement therapy delays pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.
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Whiting RE, Narfström K, Yao G, Pearce JW, Coates JR, Castaner LJ, Jensen CA, Dougherty BN, Vuillemenot BR, Kennedy D, O'Neill CA, and Katz ML
- Subjects
- Aminopeptidases deficiency, Analysis of Variance, Animals, Axons, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases deficiency, Disease Models, Animal, Disease Progression, Dogs, Electroretinography drug effects, Neuronal Ceroid-Lipofuscinoses physiopathology, Optic Nerve cytology, Recombinant Proteins therapeutic use, Serine Proteases deficiency, Tripeptidyl-Peptidase 1, Aminopeptidases therapeutic use, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases therapeutic use, Enzyme Replacement Therapy, Neuronal Ceroid-Lipofuscinoses drug therapy, Reflex, Pupillary drug effects, Serine Proteases therapeutic use
- Abstract
Late-infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. This fatal pediatric disease is caused by mutations in the CLN2 gene which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Utilizing a TPP1-/- Dachshund model of CLN2 disease, studies were conducted to assess the effects of TPP1 enzyme replacement administered directly to the CNS on disease progression. Recombinant human TPP1 (rhTPP1) or artificial cerebrospinal fluid vehicle was administered to CLN2-affected dogs via infusion into the CSF. Untreated and vehicle treated affected dogs exhibited progressive declines in pupillary light reflexes (PLRs) and electroretinographic (ERG) responses to light stimuli. Studies were undertaken to determine whether CSF administration of rhTPP1 alters progression of the PLR and ERG deficits in the canine model. rhTPP1 administration did not inhibit the decline in ERG responses, as rhTPP1 treated, vehicle treated, and untreated dogs all exhibited similar progressive and profound declines in ERG amplitudes. However, in some of the dogs treated with rhTPP1 there were substantial delays in the appearance and progression of PLR deficits compared with untreated or vehicle treated affected dogs. These findings indicate that CSF administration of TPP1 can attenuate functional impairment of neural pathways involved in mediating the PLR but does not prevent loss of retinal responses detectable with ERG., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2014
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31. Pupillary light reflex deficits in a canine model of late infantile neuronal ceroid lipofuscinosis.
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Whiting RE, Narfström K, Yao G, Pearce JW, Coates JR, Castaner LJ, and Katz ML
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- Animals, Disease Models, Animal, Dogs, Photic Stimulation methods, Electroretinography, Light, Neuronal Ceroid-Lipofuscinoses physiopathology, Reflex, Pupillary radiation effects, Retina physiopathology
- Abstract
Late-infantile neuronal ceroid lipofuscinosis (CLN2) is a hereditary neurological disorder characterized by progressive retinal degeneration and vision loss, cognitive and motor decline, seizures, and pronounced brain atrophy. The progressive loss of neurological functions eventually leads to death, usually by the early teenage years. Utilizing a canine model of CLN2, therapeutic studies to inhibit the brain and retinal degenerations are currently under way. Using this dog model, studies were undertaken to compare quantitative assessments of the pupillary light reflex (PLR) and electroretinography (ERG) as tools for evaluating the effects of the disease on retinal function. The PLR and ERG were recorded in normal and CLN2-affected Dachshunds at 2 month intervals between the ages of 4 and 10 months. Using custom instrumentation for quantitative PLR assessments, a series of white light stimuli of varying intensity was used to elicit pupil constriction, and pupil images were recorded using continuous infrared illumination and an infrared-sensitive camera. Electroretinography was used to evaluate retinal function in the same dogs. As the disease progressed, affected dogs exhibited progressive and profound declines in ERG amplitudes under both scotopic and photopic conditions. With low intensity light stimuli, CLN2 was also accompanied by progressive deficits in the PLR. Changes in the PLR to dim light stimuli included significant deficits in latency, constriction velocity, constriction amplitude, and redilation velocity. However, despite the almost complete loss of detectable ERG responses by disease end stage, the PLR to bright stimuli was well preserved throughout the disease progression. These findings demonstrate that the PLR is much more sensitive than the ERG in detecting residual retinal function in animal models of retinal degenerative disease. The preservation of the PLR in dogs with profoundly depressed ERGs correlates with a preservation of visually-mediated behavior even late in the disease progression. Quantitative analysis of the PLR has potential as a biomarker in animal models of retinal degenerative diseases and in evaluating the efficacy of therapeutic interventions in preserving retinal function., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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32. Guidelines for clinical electroretinography in the dog: 2012 update.
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Ekesten B, Komáromy AM, Ofri R, Petersen-Jones SM, and Narfström K
- Subjects
- Animals, Dark Adaptation physiology, Dog Diseases diagnosis, Photic Stimulation, Retinal Dystrophies diagnosis, Retinal Dystrophies veterinary, Dogs physiology, Electroretinography veterinary, Ophthalmology standards, Photoreceptor Cells, Vertebrate physiology, Veterinary Medicine standards
- Abstract
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.
- Published
- 2013
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33. Clinical and electroretinographic findings of progressive retinal atrophy in miniature schnauzer dogs of South Korea.
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Jeong MB, Park SA, Kim SE, Park YW, Narfström K, and Seo K
- Subjects
- Animals, Dog Diseases genetics, Dogs, Electroretinography veterinary, Female, Male, Republic of Korea, Retinal Degeneration genetics, Retinal Degeneration pathology, Dog Diseases pathology, Genetic Predisposition to Disease genetics, Retinal Degeneration veterinary
- Abstract
The purpose of the study was to describe the clinical and electroretinographic features of clinical cases of progressive retinal atrophy (PRA) in miniature schnauzer (MS) of South Korea. Sixty-six MS (14 normal and 52 affected) were included. All animals underwent routine ocular examinations. Electroretinogram (ERG) was recorded in the 14 normal and 15 affected dogs. For normal dogs, the mean age ± SD was 4.1 ± 2.4 years (1 to 9 years), and there were no ocular abnormalities on the basis of ocular examinations and ERG results. For the PRA-affected dogs, it was shown that the mean age ± SD was 4.3 ± 1.1 years (2 to 7 years), and 44 dogs (84.6%) were 3 to 5 years old. Most of the PRA-affected dogs had abnormal menace responses (98.1%) and pupillary light reflexes (PLRs, 88.5%); some dogs showed normal menace response (1.9%) and PLRs (11.5%). Ophthalmoscopic abnormalities in the affected group included one or more of the following changes: hyperreflectivity and discoloration of the tapetal area, attenuation of retinal vessels, depigmentation in non-tapetal area and optic disc atrophy. ERG in the affected dogs showed non-recordable responses in all cases tested with clinical signs of PRA. The present study showed that PRA in MS was mainly observed between the age of 3 to 5 years. ERG revealed abnormal rod and cone responses in affected dogs at the ages studied.
- Published
- 2013
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34. Quantitative assessment of the canine pupillary light reflex.
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Whiting RE, Yao G, Narfström K, Pearce JW, Coates JR, Dodam JR, Castaner LJ, and Katz ML
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- Animals, Dogs, Electroretinography, Eye Movements physiology, Photic Stimulation, Rod Opsins metabolism, Pupil physiology, Reflex, Pupillary physiology
- Abstract
Purpose: To develop instrumentation and methods for thorough quantitative assessment of the pupillary light reflex (PLR) in dogs under varying stimulus conditions., Methods: The PLR was recorded in normal Dachshunds using a custom system allowing full user control over stimulus intensity, color, and duration. Chemical restraint protocols were compared to determine which protocol provided for optimal baseline stability of pupil size and appropriate eye positioning. A series of white light stimuli of increasing intensity was used to elicit pupil constriction. Pupil images were concurrently recorded using continuous infrared illumination and an infrared-sensitive camera. The PLR was also recorded in response to blue and red stimuli., Results: With injectable chemical restraint alone, spontaneous fluctuations in pupil size occurred independent of light stimulation, and spontaneous eye movements made it difficult to fully visualize the pupil. Combined injectable chemical and inhalation restraint provided a steady baseline pupil size throughout PLR assessment and allowed for stable positioning of the eye using a conjunctival stay suture. Robust PLRs were elicited with all light colors. PLR constriction amplitude increased with increasing flash intensity and ranged from 5% to 70%., Conclusions: A recording system and protocol have been developed to reliably quantify the canine PLR. The techniques and instrumentation will be useful for objective quantitative assessment of the PLR in dogs and other species in research applications and may be useful in clinical veterinary ophthalmology and neurology if PLR abnormalities detected with these procedures can be associated with specific diseases.
- Published
- 2013
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35. Cats: a gold mine for ophthalmology.
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Narfström K, Deckman KH, and Menotti-Raymond M
- Subjects
- Animals, Cat Diseases genetics, Cats, Eye Diseases pathology, Eye Diseases, Hereditary pathology, Eye Diseases, Hereditary veterinary, Genetic Predisposition to Disease, Humans, Cat Diseases pathology, Eye anatomy & histology, Eye Diseases veterinary, Ocular Physiological Phenomena
- Abstract
Over 200 hereditary diseases have been identified and reported in the cat, several of which affect the eye, with homology to human hereditary disease. Compared with traditional murine models, the cat demonstrates more features in common with humans, including many anatomic and physiologic similarities, longer life span, increased size, and a genetically more heterogeneous background. The development of genomic resources in the cat has facilitated mapping and further characterization of feline models. During recent years, the wealth of knowledge in feline ophthalmology and neurophysiology has been extended to include new diseases of significant interest for comparative ophthalmology. This makes the cat an extremely valuable animal species to utilize for further research into disease processes affecting both cats and humans. This is especially true in the advancement and study of new treatment regimens and for extended therapeutic trials. Groups of feline eye diseases reviewed in the following are lysosomal storage disorders, congenital glaucoma, and neuroretinal degenerations. Each has important implications for human ophthalmic research.
- Published
- 2013
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36. Retinal capillary morphology in the Abyssinian cat with hereditary retinal degeneration.
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May CA and Narfström K
- Subjects
- Animals, Capillaries ultrastructure, Cat Diseases genetics, Cats, Disease Models, Animal, Endothelium, Vascular ultrastructure, Eye Diseases, Hereditary genetics, Eye Diseases, Hereditary pathology, Muscle, Smooth, Vascular ultrastructure, Mutation, Pericytes ultrastructure, Retinal Degeneration genetics, Retinal Degeneration pathology, Cat Diseases pathology, Eye Diseases, Hereditary veterinary, Photoreceptor Cells, Vertebrate ultrastructure, Retinal Degeneration veterinary, Retinal Vessels ultrastructure
- Published
- 2012
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37. Assessment of hereditary retinal degeneration in the English springer spaniel dog and disease relationship to an RPGRIP1 mutation.
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Narfström K, Jeong M, Hyman J, Madsen RW, and Bergström TF
- Abstract
Intensive breeding and selection on desired traits have produced high rates of inherited diseases in dogs. Hereditary retinal degeneration, often called progressive retinal atrophy (PRA), is prevalent in dogs with disease entities comparable to human retinitis pigmentosa (RP) and Leber's congenital amaurosis (LCA). Recent molecular studies in the English Springer Spaniel (ESS) dog have shown that PRA cases are often homozygous for a mutation in the RPGRIP1 gene, the defect also causing human RP, LCA, and cone rod dystrophies. The present study characterizes the disease in a group of affected ESS in USA, using clinical, functional, and morphological studies. An objective evaluation of retinal function using electroretinography (ERG) is further performed in a masked fashion in a group of American ESS dogs, with the examiner masked to the genetic status of the dogs. Only 4 of 6 homozygous animals showed clinical signs of disease, emphasizing the need and importance for more precise studies on the clinical expression of molecular defects before utilizing animal models for translational research, such as when using stem cells for therapeutic intervention.
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- 2012
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38. Characterization of feline hereditary retinal dystrophies using clinical, functional, structural and molecular genetic studies.
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Narfström K, Menotti Raymond M, and Seeliger M
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- Animals, Cat Diseases pathology, Cat Diseases physiopathology, Cats, Electroretinography, Genetic Predisposition to Disease genetics, Retina pathology, Retina physiopathology, Retinal Dystrophies genetics, Retinal Dystrophies pathology, Retinal Dystrophies physiopathology, Cat Diseases genetics, Retinal Dystrophies veterinary
- Abstract
Only in recent years have specific mutations been elucidated for feline hereditary retinal dystrophies. Molecular genetic characterization of feline diseases has so far been a slow process but with a full genome sequence for the cat recently completed and the development of a feline single nucleotide polymorphism chip, the characterization of feline monogenic disorders will be significantly simplified. This review summarizes current knowledge with regard to specific hereditary retinal dystrophies in cats and gives an overview of how cats can be used as models in translational research., (© 2011 American College of Veterinary Ophthalmologists.)
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- 2011
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39. Inactivation of Pmel alters melanosome shape but has only a subtle effect on visible pigmentation.
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Hellström AR, Watt B, Fard SS, Tenza D, Mannström P, Narfström K, Ekesten B, Ito S, Wakamatsu K, Larsson J, Ulfendahl M, Kullander K, Raposo G, Kerje S, Hallböök F, Marks MS, and Andersson L
- Subjects
- Alleles, Animals, Cells, Cultured, Epidermal Cells, Epidermis metabolism, Hair Color genetics, HeLa Cells, Humans, Melanins genetics, Melanosomes ultrastructure, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Mutation, Oxidoreductases metabolism, Phenotype, Skin metabolism, Melanins biosynthesis, Melanosomes metabolism, Pigmentation genetics, gp100 Melanoma Antigen genetics, gp100 Melanoma Antigen metabolism
- Abstract
PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel⁻/⁻). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel⁻/⁻ melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2011
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40. The domestic cat as a large animal model for characterization of disease and therapeutic intervention in hereditary retinal blindness.
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Narfström K, Holland Deckman K, and Menotti-Raymond M
- Abstract
Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well-characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research.
- Published
- 2011
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41. Electroretinography in the western gray kangaroo (Macropus fuliginosus).
- Author
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Labelle AL, Hamor RE, Narfström K, and Breaux CB
- Subjects
- Animals, Animals, Zoo, Female, Male, Electroretinography veterinary, Macropodidae anatomy & histology, Retina physiology
- Abstract
Objective: To perform electroretinography on normal anesthetized western gray kangaroos (Macropus fuliginosus). Animals studied Six captive western gray kangaroos., Procedures: The kangaroos were anesthetized using a combination of ketamine and medetomidine via a remote drug delivery system, then were maintained on isoflurane after endotracheal intubation and reversal of the medetomidine with atipamazole. After a minimum of 20 min of dark adaptation, electroretinograms were obtained using a handheld electroretinography (ERG) machine using a single flash protocol at three light intensities: 10 mcd.s/m(2), 3000 mcd.s/m(2), 10 000 mcd.s/m(2)., Results: At 10 mcd.s/m(2) the mean b-wave amplitude and implicit time was 102.0 μV (SD ± 41.3 and 95% CI 68.9-135.1) and 78.4 ms (SD ± 8.3 and 95% CI 71.8-85.0). At 3000 mcd.s/m(2) the mean a-wave amplitude and implicit time was 69.9 μV (SD ± 20.5 and 95% CI 53.5-86.3) and 17.6 ms (SD ± 1.5 and 95% CI 16.4-18.8) and the mean b-wave amplitude and implicit time was 175.4 μV (SD ± 35.9 and 95% CI 146.7-204.1) and 74.1 ms (SD ± 3.5 and 95% CI 71.2-76.9). At 10 000 mcd.s/m(2) the mean a-wave amplitude and implicit time was 89.1 μV (SD ± 27.1 and 95% CI 67.5-110.8) and 16.8 ms (SD ± 1.0 and 95% CI 16.0-17.0) and the mean b-wave amplitude and implicit time was 203.7 μV (SD ± 41.4 and 95% CI 170.6-236.8) and 75.4 ms (SD ± 3.3 and 95% CI 72.8-78.1)., Conclusion: Electroretinography outside of the typical clinical setting is feasible using a portable ERG system and allows for quick analysis of retinal function in exotic species.
- Published
- 2010
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42. Mutation discovered in a feline model of human congenital retinal blinding disease.
- Author
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Menotti-Raymond M, Deckman KH, David V, Myrkalo J, O'Brien SJ, and Narfström K
- Subjects
- Amino Acid Sequence, Animals, Base Sequence, Cat Diseases pathology, Cats, Chromosome Mapping, DNA Mutational Analysis veterinary, Dark Adaptation, Electroretinography veterinary, Exons genetics, Female, Male, Molecular Sequence Data, Pedigree, Phenotype, Retinal Dysplasia genetics, Retinal Dysplasia pathology, Sequence Homology, Amino Acid, Cat Diseases genetics, Codon, Nonsense, Disease Models, Animal, Homeodomain Proteins genetics, Photoreceptor Cells, Vertebrate pathology, Retinal Dysplasia veterinary, Trans-Activators genetics
- Abstract
Purpose: To elucidate the gene defect in a pedigree of cats segregating for autosomal dominant rod-cone dysplasia (Rdy), a retinopathy characterized extensively from a clinical perspective. Disease expression in Rdy cats is comparable to that in young patients with congenital blindness (Leber congenital amaurosis [LCA] or retinitis pigmentosa [RP])., Methods: A pedigree segregating for Rdy was generated and phenotyped by clinical ophthalmic examination methods including ophthalmoscopy and full-field flash electroretinography. Short tandem repeat loci tightly linked to candidate genes for autosomal dominant retinitis pigmentosa in humans were genotyped in the pedigree., Results: Significant linkage was established to the candidate gene CRX (LOD = 5.56, = 0) on cat chromosome E2. A single base pair deletion was identified in exon 4 (n.546delC) in affected individuals but not in unaffected littermates. This mutation generates a frame shift in the transcript, introducing a premature stop codon truncating the putative CRX peptide, which would eliminate the critical transcriptional activation region. Clinical observations corroborate previously reported clinical reports about Rdy. Results show that the cone photoreceptor system was more severely affected than the rods in the early disease process., Conclusions: A putative mutation causative of the Rdy phenotype has been described as a single base pair deletion in exon 4 of the CRX gene, thus identifying the first animal model for CRX-linked disease that closely resembles the human disease. As such, it will provide valuable insights into the mechanisms underlying these diseases and their variable presentation, as well as providing a suitable model for testing therapies for these diseases.
- Published
- 2010
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43. Effects of hereditary retinal degeneration due to a CEP290 mutation on the feline pupillary light reflex.
- Author
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Thompson S, Whiting RE, Kardon RH, Stone EM, and Narfström K
- Subjects
- Animals, Cat Diseases physiopathology, Cats, Genetic Testing, Mutation, Reflex, Pupillary physiology, Retinal Degeneration genetics, Retinal Degeneration physiopathology, Cat Diseases genetics, Reflex, Pupillary genetics, Retinal Degeneration veterinary
- Abstract
Objective: To understand how progressive rod cone degeneration due to a mutation in CEP290 affects the pupillary light reflex (PLR) in domestic cats., Animals Studied: Domestic cats identified as either normal wildtype (WT; n = 6), or homozygous for the rdAc mutation in CEP290 and having early stage retinal degeneration (stage 2, S2; n = 4), or advanced retinal degeneration (S4; n = 6)., Methods: The effect of light on pupil size was measured over a series of 10-s pulses of white and chromatic light in cats lightly sedated with medetomidine., Results: In WT cats, the PLR was characterized by a pronounced initial constriction that rapidly re-dilated during the stimulus (pupil escape), to a stable or sustained constriction. There was then a marked constriction at stimulus offset. Each component of the PLR was retained in affected cats, but with progressively reduced irradiance sensitivity from early to advanced retinal disease., Conclusions: The PLR of cats had multiple phases, with a remarkably high-amplitude 'paradoxical' off-constriction even in the absence of retinal disease. In rdAc cats, reduced irradiance sensitivity was consistent with progressive loss of rod and cone function. Based on previously characterized retinal pathology, this suggests the visual streak of the retina has a proportionally large contribution to PLR input. These findings support the hypothesis that the efficacy of planned therapeutic trials can be determined by careful evaluation of the PLR in cats.
- Published
- 2010
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44. Defining and mapping mammalian coat pattern genes: multiple genomic regions implicated in domestic cat stripes and spots.
- Author
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Eizirik E, David VA, Buckley-Beason V, Roelke ME, Schäffer AA, Hannah SS, Narfström K, O'Brien SJ, and Menotti-Raymond M
- Subjects
- Animals, Dogs, Epistasis, Genetic, Female, Genes, Dominant, Genetic Loci genetics, Genomics, Genotype, Humans, Male, Pedigree, Phenotype, Cats anatomy & histology, Cats genetics, Chromosome Mapping, Genome genetics, Hair, Pigmentation genetics
- Abstract
Mammalian coat patterns (e.g., spots, stripes) are hypothesized to play important roles in camouflage and other relevant processes, yet the genetic and developmental bases for these phenotypes are completely unknown. The domestic cat, with its diversity of coat patterns, is an excellent model organism to investigate these phenomena. We have established three independent pedigrees to map the four recognized pattern variants classically considered to be specified by a single locus, Tabby; in order of dominance, these are the unpatterned agouti form called "Abyssinian" or "ticked" (T(a)), followed by Spotted (T(s)), Mackerel (T(M)), and Blotched (t(b)). We demonstrate that at least three different loci control the coat markings of the domestic cat. One locus, responsible for the Abyssinian form (herein termed the Ticked locus), maps to an approximately 3.8-Mb region on cat chromosome B1. A second locus controls the Tabby alleles T(M) and t(b), and maps to an approximately 5-Mb genomic region on cat chromosome A1. One or more additional loci act as modifiers and create a spotted coat by altering mackerel stripes. On the basis of our results and associated observations, we hypothesize that mammalian patterned coats are formed by two distinct processes: a spatially oriented developmental mechanism that lays down a species-specific pattern of skin cell differentiation and a pigmentation-oriented mechanism that uses information from the preestablished pattern to regulate the synthesis of melanin profiles.
- Published
- 2010
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45. Comparison of the effects of three different combinations of general anesthetics on the electroretinogram of dogs.
- Author
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Jeong MB, Narfström K, Park SA, Chae JM, and Seo KM
- Subjects
- Animals, Dark Adaptation, Dogs, Female, Isoflurane pharmacology, Ketamine pharmacology, Light, Male, Medetomidine pharmacology, Thiopental pharmacology, Xylazine pharmacology, Anesthetics, Combined pharmacology, Anesthetics, General pharmacology, Electroretinography drug effects
- Abstract
The objective of this study is to compare the effects of three different anesthetic combinations on the electroretinogram in the same animals under similar laboratory conditions. Thiopental-isoflurane (TI), medetomidine-ketamine (MK), and xylazine-ketamine (XK) were used on each of 12 healthy miniature schnauzer dogs (MS) with a period of at least 3 weeks in between subsequent anesthesia protocols, using the Dog Standard Protocol. The scotopic ERGs consisted of scotopic low stimulus strength (S) responses designated S1, S2, S3, S4, and S5, at 1, 5, 10, 15, and 20 min after dark adaptation, respectively, and scotopic standard stimulus strength (S-ST) responses. The photopic ERGs consisted of a photopic single flash (P) response and 31 Hz flicker (P-FL) responses. For S-ST (2.5 cd s/m(2)), the amplitude of the a-wave using TI was significantly lower than that using MK (adjusted P = 0.05) and XK (adjusted P = 0.03), and the implicit time of the a-wave was significantly shorter than that using MK (adjusted P = 0.04). For P (2.5 cd s/m(2)), the amplitude of the b-wave using XK was significantly higher than that using MK (adjusted P = 0.01). The implicit times of the b-wave using TI was significantly longer and shorter than that of MK for S1, S2 and P-FL and for S4 and S-ST, respectively, and than that of XK for S2 and P-FL and for S5 and S-ST, respectively. The results of the present study showed that TI affected both the amplitude and the implicit time of the a-wave for S-ST and the implicit time of the b-wave relatively more so than was the case when using XK or MK. Therefore, it appears that either XK or MK could be advantageous to use rather than TI for clinical studies.
- Published
- 2009
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46. Retinal degeneration in the Abyssinian and Somali cat (rdAc): correlation between genotype and phenotype and rdAc allele frequency in two continents.
- Author
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Narfström K, David V, Jarret O, Beatty J, Barrs V, Wilkie D, O'Brien S, and Menotti-Raymond M
- Subjects
- Animals, Australia, Cats, Europe, Gene Frequency genetics, Genotype, Phenotype, Retinal Degeneration genetics, Cat Diseases genetics, Retinal Degeneration veterinary
- Abstract
Objective: To characterize hereditary retinal degeneration in the Abyssinian cat (rdAc) in a recently established closed colony segregating for the rdAc mutation, and evaluate possible differences in the age of onset and progression of disease phenotype since the initial description of rdAc 25 years ago. The sample size of an earlier study was increased in order to determine the allele frequency in Abyssinian and Somali cats on a worldwide basis., Animals Studied: Twenty rdAc affected cats from the closed animal facility, 87 Abyssinian and Somali cats for study of genotype-phenotype concordance, and DNA from 131 Abyssinian and Somali cats from Scandinavia, the UK and Australia for evaluation of the rdAc allele frequency., Procedures: DNA was extracted from blood and buccal swabs using commercially available kits, followed by genotyping. Ophthalmic examinations were performed in the USA and Sweden by two board-certified veterinary ophthalmologists., Results: A greater variation in the age of onset and progression of the disease was observed compared to that previously described. An excellent correlation between genotype and phenotype was observed. A population genetic survey revealed that the rdAc allele is in moderate abundance in the Abyssinian breed in Europe and Australia. Surprisingly, homozygosity for the mutant allele was observed in a Siamese cat with ophthalmoscopic findings similar to those originally described for affected rdAc individuals., Conclusions: Alertness to the potential of rdAc is needed on the part of the veterinary ophthalmology community, not only in Abyssinian and Somali cats but possibly also in other related cat breeds.
- Published
- 2009
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47. The effects of medetomidine hydrochloride on the electroretinogram of normal dogs.
- Author
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Norman JC, Narfström K, and Barrett PM
- Subjects
- Animals, Dog Diseases diagnosis, Dog Diseases drug therapy, Electroretinography drug effects, Female, Male, Photic Stimulation methods, Retina drug effects, Retinal Diseases diagnosis, Retinal Diseases drug therapy, Retinal Diseases veterinary, Dogs physiology, Electroretinography veterinary, Hypnotics and Sedatives pharmacology, Medetomidine pharmacology, Retina physiology
- Abstract
Purpose: To determine the effects of a standardized intravenous dose of an alpha-2 agonist (Domitor, Orion Pharma, distributed by Pfizer Animal Health, Exton, PA) on the electroretinogram (ERG) response in normal dogs., Methods: Twenty-five normal dogs were used to collect ERG responses including a- and b-wave implicit times (IT) and amplitudes (AMP) before and after administration of medetomidine. Dogs were dark adapted for 20 min and ERGs were obtained using the HMsERG (RetVetCorp Inc., Columbia, MO). The QuickRetCheck protocol (Narfström) was employed to provide the following flash intensities: 10 mcd s/m(2), 3 cd s/m(2), and 10 cd s/m(2). ERGs were repeated after 375 microg/m(2) of medetomidine intravenously. Statistical analysis of the difference between the responses before and after medetomidine at all flash intensities was performed using a mixed effects model for anova., Results: The P value for the effect of medetomidine on each of the ERG responses was < 0.01. The estimates of the effect of medetomidine were (+)1.35 ms, (-)23 microV, (+)3.16 ms, and (-)47 microV for the a-wave IT, a-wave AMP, b-wave IT, and the b-wave AMP, respectively., Conclusions: Medetomidine significantly prolongs the implicit time and lowers the amplitude response of both the a- and b-waves in normal dogs at all flash intensities examined. Clinically, however, medetomidine only minimally affects the retinal responses and is a viable choice for use in dog ERGs.
- Published
- 2008
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48. Amax to scotopic Imax diagnoses feline hereditary rod cone degeneration more efficiently than any other combination of long protocol electroretinogram parameters.
- Author
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Vaegan and Narfström K
- Subjects
- Animals, Cat Diseases genetics, Cats, Discriminant Analysis, Genes, Recessive, Retinal Degeneration diagnosis, Retinal Degeneration genetics, Cat Diseases diagnosis, Electroretinography veterinary, Photoreceptor Cells, Vertebrate pathology, Retinal Degeneration veterinary
- Abstract
Aim: To evaluate two recent methods for detecting feline hereditary rod cone degeneration with maximum efficiency from a long full-field flash ERG protocol. One combines 12 of these measures in an equation that is derived from iterative principal components factor analysis. The other uses the amplitude of the a-wave to the brightest available flash alone., Methods: We tested the original 12-parameter equation, by applying it to 50 new ERG series in 23 backcrossed cats. They were necessarily either heterozygous or homozygous for hereditary rod cone degeneration. A masked observer compared the ERG score and fundus examinations. We reanalyzed the old, new and combined data sets. Data sets with only one session per animal were analysed to avoid problems from non-random sampling. A two factor linear model of the a-wave was evaluated., Results: The prior equation, applied to the new data, discriminated the groups as well as it had initially. In the reanalysis, group separation continued to increase with even fewer measures compared to the previously reported study. Eventually, one measure, the amplitude of the a-wave (amax) to the brightest scotopic flash (Imax) discriminated the groups better than any other measure or combination of measures in all analyses, including data sets using only one session for each animal and in a two factor linear model of the a-wave., Conclusion: Amax to Imax alone proved to be the best diagnostic criterion in all analyses. No linear model is likely to discriminate affected from unaffected animals more effectively because additional variables increased variance more rapidly than they increased discrimination. Amax to Imax may detect other rod and rod/cone dystrophies equally efficiently.
- Published
- 2008
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49. Retinal pathology in a canine model of late infantile neuronal ceroid lipofuscinosis.
- Author
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Katz ML, Coates JR, Cooper JJ, O'Brien DP, Jeong M, and Narfström K
- Subjects
- Aminopeptidases, Animals, Ceroid metabolism, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Disease Models, Animal, Dog Diseases genetics, Dogs, Electroretinography veterinary, Endopeptidases genetics, Endopeptidases metabolism, Female, Frameshift Mutation, Lipofuscin metabolism, Male, Neuronal Ceroid-Lipofuscinoses genetics, Neuronal Ceroid-Lipofuscinoses pathology, Retina metabolism, Retina pathology, Retinal Diseases genetics, Retinal Diseases pathology, Serine Proteases, Tripeptidyl-Peptidase 1, Dog Diseases pathology, Neuronal Ceroid-Lipofuscinoses veterinary, Retinal Diseases veterinary
- Abstract
Purpose: Late infantile neuronal ceroid lipofuscinosis (NCL) is an inherited disorder characterized by progressive vision loss. The disease results from mutations in the TPP1 (CLN2) gene. Studies were undertaken to characterize the effects of a TPP1 frameshift mutation on the retina in Dachshunds., Methods: A litter of four puppies consisting of one homozygous affected dog, two heterozygotes, and one homozygous normal dog were monitored for neurologic and retinal changes through 10 months of age. The affected and homozygous normal dogs, as well as one of the heterozygotes, were then euthanatized, and the retinas were examined morphologically., Results: The affected dog exhibited normal visual behavior and retinal function at 3 months of age, but vision was clearly impaired by 7 months, with markedly reduced ERG b-wave amplitudes. Beyond 7 months of age, the affected dog was functionally blind, and pupillary light reflexes and ERG response amplitudes continued to decline through 10 months of age. Both rod and cone system functions were severely impaired. The retina exhibited accumulation of autofluorescent storage bodies with distinctive curvilinear contents. Substantial cell loss occurred in the inner nuclear layer, with a smaller reduction in photoreceptor cell density., Conclusions: The canine TPP1 mutation results in progressive vision loss and retinal degeneration similar to that which occurs in human late infantile NCL. With the canine model, the natural history of disease progression in the retina provides a better understanding of the pathologic course of the disease and provides objective markers that can be used to assess the efficacy of therapeutic interventions.
- Published
- 2008
- Full Text
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50. Functional and structural changes in the retina of wire-haired dachshunds with early-onset cone-rod dystrophy.
- Author
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Ropstad EO, Narfström K, Lingaas F, Wiik C, Bruun A, and Bjerkås E
- Subjects
- Animals, Disease Models, Animal, Dog Diseases metabolism, Dogs, Female, Fluorescent Antibody Technique, Indirect, Glial Fibrillary Acidic Protein metabolism, Male, Microscopy, Electron, Pedigree, Phenotype, Protein Kinase C metabolism, Retina metabolism, Retinal Degeneration metabolism, Retinal Degeneration physiopathology, Rhodopsin metabolism, Rod Opsins metabolism, Synaptophysin metabolism, Dog Diseases physiopathology, Electroretinography veterinary, Photoreceptor Cells, Vertebrate physiology, Photoreceptor Cells, Vertebrate ultrastructure, Retina physiopathology, Retina ultrastructure, Retinal Degeneration veterinary
- Abstract
Purpose: To describe and classify the morphologic changes in a naturally occurring dog model of early-onset cone-rod dystrophy (CRD) and to correlate these with earlier described clinical characteristics of the disease in dogs., Methods: Purpose-bred Standard Wire-Haired Dachshunds (SWHDs) derived from a large pedigree of dogs with early-onset CRD were euthanatized at defined ages to characterize morphologic changes in the disease process. Specimens were examined by light microscopy, including morphometric studies, electron microscopy, and immunohistochemistry. Peanut agglutinin (PNA), protein kinase C (PKC), synaptophysin (Syn), rhodopsin (Rho)-63, glial fibrillary acidic protein (GFAP), and short-wavelength cone opsin (OS) were used for immunohistochemical characterization., Results: The photopic cone-system-derived ERG amplitudes were already significantly reduced or nonrecordable in CRD-affected dogs at 5 weeks, the earliest age studied. The outer retina was morphologically most severely affected initially, with a subsequent degeneration of the inner retina. Cone degeneration was more pronounced than rod degeneration in young CRD-affected dogs. There was a marked phenotypic variation based on morphologic findings in the affected dogs. At the earliest time point studied (5-8 weeks) cone photoreceptor and glial cell abnormalities were observed, in accordance with earlier studies based on electrophysiological and clinical findings in which day blindness and abnormal cone ERGs were observed in young affected SWHD puppies. Preliminary genetic studies have indicated an autosomal recessive mode of inheritance for the defect., Conclusions: Through functional and structural characterization, early-onset cone abnormalities were found, consistent with a cone dysplasia at an age when rod structure was normal. Further studies are in progress to identify the gene(s) involved in this retinal disease process. The presently described natural animal model of primary cone dysplasia followed by rod degeneration may provide further insight into the human counterpart. Further studies are needed to ascertain an autosomal recessive mode of inheritance for CRD in the SWHD.
- Published
- 2008
- Full Text
- View/download PDF
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