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CURRENT RESEARCH IN PROGRESSIVE RETINAL ATROPHY

22-06-2014

PRA TODAY:
CURRENT RESEARCH IN PROGRESSIVE RETINAL ATROPHY

 

By
Gregory Acland
Senior Research Associate
and
Gustavo Aguirre
Caspary Professor of Ophthalmology
Center for Canine Genetics & Reproduction
James A. Baker Institute for Animal Health
Cornell University

CLASSIFICATION OF DIFFERENT FORMS OF PRA

Early Onset
Forms of PRA
Breed Disease name gene
symbol
  I.

Autosomal

Recessive
Irish Setter Rod Cone Dysplasia 1 rcd1
  Collie
(Rough & Smooth)
Rod Cone Dysplasia 2 rcd2
  Norwegian Elkhound Rod Dysplasia rd
  Norwegian Elkhound Early Retinal Degeneration erd
  Miniature Schnauzer Photoreceptor Degeneration pd
Late Onset
Forms of PRA
Breed Disease name gene
symbol
  I.

Autosomal

Recessive
Miniature Poodle Progressive Rod Cone Degeneration prcd
  English Cocker Spaniel Progressive Rod Cone Degeneration prcd
  American Cocker Spaniel Progressive Rod Cone Degeneration prcd
  Labrador Retriever Progressive Rod Cone Degeneration prcd
  Tibetan Terrier Progressive Retinal Atrophy PRA
  II.
X-Linked
Siberian Husky X-Linked
Progressive Retinal Atrophy
XLPRA
  III.

Undefined
    Australian Cattle Dog
      Belgian Malinois
      Dachshund (MLH)
      English Setter
      Novia Scotia Duck Tolling Retriever
      Portuguese Water Dog
      Rottweiler
      Tibetan Spaniel
  and numerous other breeds

 

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A BRIEF AND PARTIAL TIMELINE OF RESEARCH IN PRA

1911 First description of PRA, in Gordon Setters (Magnusson)
1938-55 PRA recognized in Irish Setters (UK: Rasbridge, Hodgman, Parry, Lucas)
1962-65 PRA in Miniature Poodles (UK: Barnett)
1975 First definition of the rod & cone disease in different forms of PRA (Aguirre, 1976)
1975- Characterization of breed-specific single gene diseases:
  Irish Setter Rod-Cone Dysplasia 1 (Aguirre et al, 1975; 1978; 1982)
  Collie Rod-Cone Dysplasia 2 (Wolf et al, 1978)
  Norwegian Elkhound Rod Dysplasia (Aguirre et al, 1971; Aguirre, 1978)
  Miniature Poodle Progressive Rod Cone Degeneration (Aguirre et al, 1975; 1982)
  Norwegian Elkhound Early Retinal Degeneration (Acland & Aguirre, 1983)
  Tibetan Terrier PRA (Millichamp et al, 1988)
  Miniature Schnauzer Photoreceptor Dysplasia (Parshall et al, 1991)
  Siberian Husky X-Linked PRA (Acland et al, 1994)
1978 Definition of biochemical defect in rcd1 (Aguirre et al)
1982 Definition of biochemical defect in rcd2 (Woodford et al)
1986 Recognition by Siberian Husky Breeders & Dolly Trauner of CERF that only male Huskys get PRA
1987 Recognition of nonallelism of rcd1, rcd2 & erd (Acland & Aguirre)
1988 Discovery that prcd in Miniature Poodles, English and American Cocker Spaniels and Labrador retrievers represents mutations at the same locus (Aguirre & Acland)
1991 Recognition of PDEB mRNA defect in rcd1 (Farber et al)
1993 Gene mutation in rcd1 reported (Suber et al)
1993-94 DNA tests for rcd1 (UK: Clements et al; USA: Ray et al)
1994 Publication of first study of XLPRA, establishing that Husky PRA is X-linked
1995 Exclusion of Opsin, PDEB and rds/peripherin as candidate genes for prcd and erd.

 

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PRA: CLINICAL SIGNS AND AGE OF ONSET

  Early Onset Forms Late Onset Forms
Vision Problems
  Night Blindness from birth 1 to 5 years
  Total Blindness 1 to 5 years 3 to > 5 years
Electroretinogram
  Rod Dysfunction from birth < 6 months to > 3 years
  Cone Dysfunction from birth to 2 years from < 6 months to > 5 years
Fundus (Eye Exam)
  Early Disease from 8 weeks to 12 months from 1 to > 3 years
  Mid-Stage PRA from 6 months to 2 years from 2 to > 5 years
  Late-Stage PRA from 1 to > 2 years from 3 to > 5 years

 

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PRA: OPHTHALMOSCOPY VS. ERG DIAGNOSIS

    AGE OF DIAGNOSIS
BREED DISEASE GENE OPHTHALMOSCOPY ERG
Irish setter rcd 1 16 wks 6 wks
Collie rcd 2 16 wks 6 wks
Norwegian elkhound erd 6-8 ms 35 days
Dachshund-Mlh __ 6-12 ms 9 ms
Tibetan terrier __ 1-1.5 yrs 10 ms
Akita __ 1.5-2 yrs 1.5-2 yrs
Norwegian elkhound rd 1-1.5 yrs 6 wks
Miniature schnauzer pd >1.5 yrs 6 wks
Siberian husky XLPRA 1.5-2 yrs 1 yr
Poodle-Toy,Min,Std prcd 3-5 yrs 9 ms
Am Cocker spaniel prcd 3-5 yrs 9 ms
Portuguese water dog prcd 3-6 yrs 1.5 yrs
Labrador retriever prcd 4-6 yrs 1.5 yrs
Eng cocker spaniel prcd 4-8 yrs 2-2.5 yrs

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BIBLIOGRAPHY

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Acland, G.M., Ray, K., Aguirre, G.D.: Exclusion of the cyclic GMP-PDE beta subunit gene as a candidate in the prcd-dog. ARVO Abstracts. Invest Ophthalmol Vis Sci. 1995; 36: 4090.

Acland, G. Fletcher, R.T., Gentleman, S., Chader, G. and Aguirre, G.: Non-allelism of Three Genes (rcd 1, rcd 2 and erd) for Early-Onset Hereditary Retinal Degeneration. Exp. Eye Res.49 : 983, 1989.

Acland, G., Blanton, S.H., Hershfield, B. and Aguirre, G.: XLPRA: A canine retinal degeneration inherited as an X-linked trait. Am J. Med. Gen. 52:27, 1994.

Acland, G., Halloran-Blanton, S., Boughman, J. and Aguirre, G.: Segregation Distortion in Inheritance of Progressive Rod-Cone Degeneration (prcd) in Miniature Poodle Dogs. Am. J. Med. Gen. 35 : 354, 1990.

Acland, G.M. and Aguirre, G.D.: Retinal Degenerations in the Dog: IV. Early Retinal Degeneration (erd) in Norwegian Elkhounds. Exp. Eye Res. 44: 491, 1987.

Aguirre, G.D. and Acland, G.M.: Variation in Retinal Degeneration Phenotype Inherited at the prcd Locus. Exp. Eye Res. 46: 663, 1988.

Aguirre, G. and Acland, G.: Inherited Retinal Degeneration in the Labrador Retriever Dog. A New Animal Model of RP? Invest. Ophthalmol. Vis Sci.(Supp). 32(4), 1991.

Aguirre, G., Farber, D., Lolley, R., Fletcher, R. and Chader, G.J. (1978) Rod-cone dysplasia in Irish setters: a defect in cyclic GMP in visual cells. Science. 201, 1133-1134.

Aguirre, G., Farber, D., Lolley, R., O'Brien, P., Alligood, J., Fletcher, R.T. and Chader, G. (1982) Retinal degeneration in the dog. III. Abnormal cyclic nucleotide metabolism in rod-cone dysplasia. Exp Eye Res. 35, 625-642.

Aguirre, G., Alligood, J., O'Brien, P., Buyukmihci, N.: Pathogenesis of Progressive Rod-Cone Degeneration in Miniature Poodles. Inv. Ophth. Vis. Sci. 23: 610, 1982.

Aguirre, G.D. and Rubin, L.F. (1975) Rod-Cone Dysplasia (Progressive Retinal Atrophy) in the Irish Setter. J Amer Vet Med Assoc. 166, 157-164.

Aguirre, G.D. and Rubin, L.F.: Progressive Retinal Atrophy (Rod Dysplasia) in the Norwegian Elkhound. JAVMA 158: 208, 1971.

Aguirre, G.D.: Retinal Degenerations in the Dog. I. Rod Dysplasia. Exp. Eye Res. 26: 233, 1978.

Aguirre, G.D.: Inherited Retinal Degenerations in the Dog Trans. Amer. Acad. Ophth. and Otol. 81: 667, 1976.

Barnett, K.C.: Canine retinopathies-II. The Miniature and Toy Poodle. J Small Anim Pract 6: 93-109, 1965a

Barnett, K.C.: Canine retinopathies-III. The other breeds. J Small Anim Pract 6: 185-196, 1965b

Clements, P.J.M., Gregory, C.Y., Peterson-Jones, S.M., Sargan, D.R., Bhattacharya, S.S.: Confirmation of the rod cGMP phosphodiesterase ' subunit (PDEB) nonsense mutation in affected rcd-1 Irish setters in the UK and development of a diagnostic test. Curr Eye Res. 1993; 12, 861-866.

Farber, D.B., Danciger, J.S., Aguirre, G.: The ' subunit of cyclic GMP phosphodiesterase mRNA is deficient in canine rod-cone dysplasia 1. Neuron. 1992; 9, 349-356.

Hodgman, S.E.J., Parry, H.B., Rasbridge, W.J. and Steel, J.D. (1949) Progressive Retinal Atrophy in Dogs 1. The Disease in Irish Setters (Red). Vet Rec. 61, 185-190.

Lucas, D.R. (1954) Retinal Dystrophy in the Irish Setter. I. Histology. Journal of Experimental Zoology. 126, 537-551.

Magnusson, H.: Uber Retinitis Pigmentosa und Konsanquinitat Beim Hunde. Arch Vergl. Ophthalmol 2: 147, 1911.

Nilsson, S.E., Wrigstad, A., Narfstrom, K.: Changes in the DC electroretinogram in Briard dogs with hereditary congenital night blindness and partial day blindness. Exp Eye Res 1992 Feb;54(2):291-6.

Parry, H.B.: Degenerations of the dog retina, II. Generalized progressive atrophy of hereditary origin. Brit J Ophthalmol 37: 487-502, 1953.

Parshall, C., Wyman, M., Nitroy, S., Acland, G. and Aguirre, G.: Photoreceptor Dysplasia: An Inherited Progressive Retinal Atrophy of Miniature Schnauzer Dogs. Prog. Vet. Comp. Ophth. 1:187, 1991.

Rasbridge, W.J.: Our Dogs. 1959; cited by Barnett, K.C. (1965) Canine Retinopathies III. The Other Breeds. J Small Anim Prac. 6, 185-196.

Ray, K., Baldwin, V., Acland, G., Blanton, S., Aguirre, G.: Co-segregation of codon 807 mutation of the rod cGMP phosphodiesterase ' gene (PDEB) in rcd1. Inv Ophth Vis Sci . 1994; 35: 4291-4299.

Ray, K., Baldwin, V., Acland, G. and Aguirre, G.: Molecular diagnostic tests for ascertainment of genotype at the rod cone dysplasia 1 (rcd1) locus in Irish setters. Curr. Eye Res.14:243, 1995.

Ray, K., Baldwin, V., Acland, G., Blanton, S. and Aguirre, G.: Co-segregation of codon 807 mutation of the rod cGMP phosphodiesterase ' gene (PDEB) in rcd1. Inv Ophth Vis Sci 35: 4291, 1994.

Santos-Anderson, R.M., Tso, M.O.M., Wolf, E.D.: An inherited retinopathy in collies. A light and electron microscopic study. Invest Ophthalmol Vis Sci 19(11): 1282-1294, 1980.

Suber, M.L., Pittler, S.J., Qin, N., Wright, G.C., Holcombe, V., Lee, R.H., Craft, C.M., Lolley, R.N., Baehr, W.B., Hurwitz, R.L.: Irish setter dogs affected with rod/cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta subunit gene. Proc Natl Acad Sci USA. 1993; 90: 3968-3972.

Wang, W., Acland, G.M., Aguirre, G.D., Ray, K.: Exclusion of rhodopsin, and probable exclusion of rds/peripherin, as candidates for canine progressive rod cone degeneration (prcd). ARVO Abstracts. Invest Ophthalmol Vis Sci. 1995; 36: 3570.

Wolf, E.D., Vainisi, S., Santos-Anderson, R.: Inherited rod-cone dysplasia in the collie. J Amer Vet Med Assoc 173: 1331-1333, 1978.

Woodford, B.J., Liu, Y., Fletcher, R.T., Chader, G.J., Farber, D.B., Santos-Anderson, R., Tso, M.O.M. (1982) Cyclic nucleotide metabolism in inherited retinopathy in collies: A biochemical and histochemical study. Exp Eye Res 34:703-714.

Woolridge, W.R. and Roberts, J.A.F.: Eradication of Night Blindness in Red Setters. Report to the Kennel Club. 1947; cited by Barnett, K.C. (1965) Canine Retinopathies III. The Other Breeds. J Small Anim Prac. 6, 185-196.

Wrigstad, A., Nilsson, S.E., Narfstrom, K.: Ultrastructural changes of the retina and the retinal pigment epithelium in Briard dogs with hereditary congenital night blindness and partial day blindness. Exp Eye Res 1992 Dec;55(6):805-18.

 

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