OMIA 000830-9615 : Progressive retinal atrophy in Canis lupus familiaris

In other species: domestic cat , sheep

Possibly relevant human trait(s) and/or gene(s) (MIM number): 613767

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Progressive, non-inflammatory degeneration or dysplasia of rods and cones or just of rods, leading to firstly night blindness, and later to blindness during the day.

Inheritance: Winkler et al. (2013) reported pedigree analysis results consistent with autosomal recessive inheritance in the Papillon breed.

Molecular basis: Extensive molecular investigations have excluded the opsin gene as a candidate locus for this disorder in Miniature Poodles, English Cocker Spaniels or Labrador Retrievers (Gould et al., 1995).

In a GWAS on 9 affected, 4 obligate carriers and 10 control Papillon dogs, each genotyped with the Illumina Canine HD BeadChip (yielding 116,235 informative SNPs), Winkler et al. (2013) found no significant associations. They then tried homozygosity mapping, which yielded 13 candidate regions, four of which contained likely candidate genes. Subsequent haplotype analysis and comparative clinical phenotyping (in humans and mice) pointed to the region containing the CNGB1 gene. Sequencing of this gene revealed the causal mutation to be "a complex mutation consisting of the combination of a one basepair deletion and a 6 basepair insertion was identified in exon 26 (c.2387delA;2389_2390insAGCTAC) leading to a frameshift and premature stop codon".

A week later, Ahonen et al. (2013) reported a GWAS on 6 affecteds (4 Papillons, 2 Phalènes) and 14 normals (3 Papillons, 11 Phalènes), each genotyped with the same Illumina CanineHD BeadChip (yielding 109,022 informative SNPs), which implicated the same region on chromosome CFA2 as identified by Winkler et al. (2013). Sequencing then identified the same causal indel mutation, which they numbered slightly differently and placed in exon 25, namely c.2685delA2687_2688insTAGCTA, which creates a frameshift, leading to "a premature stop-codon p.Tyr889Serfs*5 in an evolutionary conserved region" of CNGB1.

Prevalence: As reported by Winkler et al. (2013), "A population study did not identify the CNGB1 mutation in PRA-affected dogs in other breeds and documented that the CNGB1 mutation accounts for ~70% of cases of Papillon PRA in our PRA-affected canine DNA bank". Thus, there are other causal mutations (some most likely in other genes) awaiting discovery in this breed and in other breeds.

As reported by Ahonen et al. (2013) "a larger cohort of 145 Papillons and Phalènes [had] a carrier frequency of 17.2 %. This breed specific mutation was not present in 334 healthy dogs from 10 other breeds or 121 PRA affected dogs from 44 other breeds."

Breed: Papillon.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CNGB1 cyclic nucleotide gated channel beta 1 Canis lupus familiaris 2 NC_006584.2 (61454518..61519006) CNGB1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Papillon Phalène Progressive retinal atrophy CNGB1 indel, small (<=20) 2 c.2685delA2687_2688insTAGCTA p.Tyr889Serfs*5 2013 24015210

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2015 Reddy, B., Kelawala, D.N., Shah, T., Patel, A.B., Patil, D.B., Parikh, P.V., Patel, N., Parmar, N., Mohapatra, A.B., Singh, K.M., Menon, R., Pandya, D., Jakhesara, S.J., Koringa, P.G., Rao, M.V., Joshi, C.G. :
Identification of putative SNPs in progressive retinal atrophy affected Canis lupus familiaris using exome sequencing. Mamm Genome 26:638-49, 2015. Pubmed reference: 26515695. DOI: 10.1007/s00335-015-9607-6.
2013 Ahonen, S.J., Arumilli, M., Lohi, H. :
A CNGB1 Frameshift Mutation in Papillon and Phalène Dogs with Progressive Retinal Atrophy. PLoS One 8:e72122, 2013. Pubmed reference: 24015210. DOI: 10.1371/journal.pone.0072122.
Winkler, P.A., Ekenstedt, K.J., Occelli, L.M., Frattaroli, A.V., Bartoe, J.T., Venta, P.J., Petersen-Jones, S.M. :
A Large Animal Model for CNGB1 Autosomal Recessive Retinitis Pigmentosa. PLoS One 8:e72229, 2013. Pubmed reference: 23977260. DOI: 10.1371/journal.pone.0072229.
2010 Hertil, E., Bergström, T., Kell, U., Karlstam, L., Ekman, S., Ekesten, B. :
Retinal degeneration in nine Swedish Jämthund dogs. Vet Ophthalmol 13:110-6, 2010. Pubmed reference: 20447030. DOI: 10.1111/j.1463-5224.2010.00761.x.
2008 Jeong, M.B., Han, C.H., Narfström, K., Awano, T., Johnson, G.S., Min, M.S., Seong, J.K., Seo, K.M. :
A phosducin (PDC ) gene mutation does not cause progressive retinal atrophy in Korean miniature schnauzers. Anim Genet 39:455-6, 2008. Pubmed reference: 18724412.
2007 Aguirre-Hernández, J., Wickström, K., Sargan, D.R. :
The Finnish lapphund retinal atrophy locus maps to the centromeric region of CFA9. BMC Vet Res 3:14, 2007. Pubmed reference: 17623091. DOI: 10.1186/1746-6148-3-14.
2005 Bedford, PG. :
Progressive retinal atrophy in dogs. Vet Rec 156:124, 2005. Pubmed reference: 15704559.
Moody, JA., Famula, TR., Sampson, RC., Murphy, KE. :
Identification of microsatellite markers linked to progressive retinal atrophy in American Eskimo Dogs. Am J Vet Res 66:1900-2, 2005. Pubmed reference: 16334947.
Turba, ME., Binns, M., Mellersh, C., Godoy, JR. :
Canine microsatellites associated with genes known to cause progressive retinal atrophy in dogs or retinitis pigmentosa in humans. Anim Genet 36:259-61, 2005. Pubmed reference: 15932411. DOI: 10.1111/j.1365-2052.2005.01271.x.
2004 Ketteritzsch, K., Hamann, H., Brahm, R., Grussendorf, H., Rosenhagen, C.U., Distl, O. :
Genetic analysis of presumed inherited eye diseases in Tibetan Terriers. Vet J 168:151-9, 2004. Pubmed reference: 15301763. DOI: 10.1016/j.tvjl.2003.08.005.
2003 Dekomien, G., Epplen, J.T. :
Analysis of PDE6D and PDE6G genes for generalised progressive retinal atrophy (gPRA) mutations in dogs Genetics Selection Evolution 35:445-56, 2003.
Dekomien, G., Epplen, JT. :
Evaluation of the canine RPE65 gene in affected dogs with generalized progressive retinal atrophy. Mol Vis 9:601-5, 2003. Pubmed reference: 14627956.
2002 Augusteyn, R.C. :
Genetic testing for progressive retinal atrophy in Irish Setters, an update Australian Veterinary Journal 80:503, 2002. Pubmed reference: 12224622.
Dekomien, G., Epplen, J. :
The canine Phosducin gene: characterization of the exon-intron structure and exclusion as a candidate gene for generalized progressive retinal atrophy in 11 dog breeds Molecular Vision 8:138-142, 2002. Pubmed reference: 12091798.
Dekomien, G., Epplen, J.T. :
Screening of the arrestin gene in dogs afflicted with generalized progressive retinal atrophy BMC Genetics 3:12, 2002. Pubmed reference: 12123530.
Dekomien, G., Epplen, J.T. :
The canine Recoverin (RCV1) gene: a candidate gene for generalized progressive retinal atrophy Molecular Vision 8:436-441, 2002. Pubmed reference: 12447165.
2000 Dekomien, G., Epplen, J.T. :
Exclusion of the PDE6A gene for generalised progressive retinal atrophy in 11 breeds of dog Animal Genetics 31:135-139, 2000. Pubmed reference: 10782214.
Maroudas, P., Jobling, A.I., Augusteyn, R.C. :
Genetic screening for progressive retinal atrophy in the Australian population of Irish Setters Australian Veterinary Journal 78:773-774, 2000. Pubmed reference: 11194724.
Runte, M., Dekomien, G., Epplen, J.T. :
Evaluation of RDS/Peripherin and ROM1 as candidate genes in generalised progressive retinal atrophy and exclusion of digenic inheritance Animal Genetics 31:223-227, 2000. Pubmed reference: 10895316.
1999 Holmes, N.G., Wood, J.L.N., Binns, M.M. :
DNA markers for generalised PRA in labrador retrievers Veterinary Record 144:160, 1999.
Narfström, K., Wrigstad, A. :
Clinical, electrophysiological and morphological changes in a case of hereditary retinal degeneration in the Papillon dog. Vet Ophthalmol 2:67-74, 1999. Pubmed reference: 11397244.
Ray, K., Wang, W., Czarnecki, J., Zhang, Q., Acland, G.M., Aguirre, G.D. :
Strategies for identification of mutations causing hereditary retinal diseases in dogs: Evaluation of opsin as a candidate gene Journal of Heredity 90:133-137, 1999. Pubmed reference: 9987920.
1998 Anon. :
Researchers discover likely link between human, canine gene and blindness American Journal of Veterinary Research 59:525-526, 1998.
Anon. :
Genetic test to detect inherited blindness disorder in the Cardigan Welsh corgi Journal of Small Animal Practice 39:311, 1998.
Dekomien, G., Klein, W., Epplen, J.T. :
Polymorphisms in the canine rod transducin gene and exclusion as cause for generalised progressive retinal atrophy (gPRA) Journal of Experimental Animal Science 39:86-90, 1998.
Klein, W., Dekomien, G., Holmes, N., Epplen, J.T. :
Evaluation of ROM1 as a candidate gene in generalised progressive retinal atrophy in dogs Animal Genetics 29:316-318, 1998. Pubmed reference: 9745671.
Narfstrom, K., Ekesten, B. :
Electroretinographic evaluation of papillons with and without hereditary retinal degeneration American Journal of Veterinary Research 59:221-226, 1998. Pubmed reference: 9492941.
Petersenjones, S.M. :
A review of research to elucidate the causes of the generalized progressive retinal atrophies [Review] Veterinary Journal 155:5-18, 1998.
1997 Akhmedov, N.B., Piriev, N.I., Ray, K., Acland, G.M., Aguirre, G.D., Farber, D.B. :
Structure and analysis of the transducin BETA-3-SUBUNIT gene, a candidate for inherited cone degeneration (cd) in the dog Gene 194:47-56, 1997. Pubmed reference: 9266671.
Kylma, T., Paulin, L., Hurwitz, M.Y., Hurwitz, R.L., Kommonen, B. :
Cloning and analysis of the cdna encoding the rod g-protein transducin alpha, BETA-1 and GAMMA-1 subunits from the canine retina Gene 193:1-4, 1997. Pubmed reference: 9249060.
Ray, K., Baldwin, V.J., Zeiss, C., Acland, G.M., Aguirre, G.D. :
Canine rod transducin ALPHA-1 - cloning of the cdna and evaluation of the gene as a candidate for progressive retinal atrophy Current Eye Research 16:71-77, 1997. Pubmed reference: 9043826.
Zhang, Q., Pearcekelling, S., Acland, G.M., Aguirre, G.D., Ray, K. :
Canine rod photoreceptor cgmp-gated channel protein alpha-subunit - studies on the expression of the gene and characterization of the cdna Experimental Eye Research 65:301-309, 1997. Pubmed reference: 9268598. DOI: 10.1006/exer.1997.0342.
1996 Clements, P.J.M., Sargan, D.R., Gould, D.J., Petersen-Jones, S.M. :
Recent advances in understanding the spectrum of canine generalised progressive retinal atrophy [Review] Journal of Small Animal Practice 37:155-162, 1996. Pubmed reference: 8731401.
1995 Gould, D.J., Petersen-Jones, S.M., Sohal, A., Barnett, K.C., Sargan, D.R. :
Investigation of the role of opsin gene polymorphism in generalized progressive retinal atrophies in dogs Animal Genetics 26:261-267, 1995. Pubmed reference: 7661398.
Hilsenroth, R. :
Progressive retinal atrophy Canine Practice 20:1, 1995.
Håkanson, N., Narfström, K. :
Progressive retinal atrophy in papillon dogs in Sweden: A clinical survey. Vet Comp Ophthalmol 5:83-87, 1995.
1994 Granitz, U. :
Decreased vision and blindness in dogs - A retrospective study Berliner und Munchener Tierarztliche Wochenschrift 107:295-299, 1994. Pubmed reference: 7980378.
Spiess, B.M. :
[Inherited Ocular Diseases in the Entlebucher Mountain Dog] Schweizer Archiv Fur Tierheilkunde 136:105-110, 1994. Pubmed reference: 8171308.
1992 Christmas, R.E. :
Common Ocular Problems of Shih-Tzu Dogs Canadian Veterinary Journal - Revue Veterinaire Canadienne 33:390-393, 1992.
1991 Walde, I., Neumann, W. :
International Eye Examination Certificate for Inherited Eye Diseases in Dogs Wiener Tierarztliche Monatsschrift 78:284, 1991.
1990 Bjerkas, E. :
Generalised Progressive Retinal Atrophy in the English Setter in Norway Veterinary Record 126:217, 1990. Pubmed reference: 2316162.
1989 Bedford, P.G.C. :
Control of inherited retinal degeneration in dogs and cats in the United Kingdom Journal of Small Animal Practice 30:172-177, 1989.
1986 Garmer, L. :
[Progressive retinal atrophy (PRA) in Labrador Retrievers] Svensk Veterinartidning 38:120-123, 1986.
Hedhammar, A. :
[Current situation regarding the eradication of genetically conditioned eye disorders in Sweden] Svensk Veterinartidning 38:152-160, 1986.
1980 Walde, I. :
Visual defects in dogs as the result of breed specific fundus diseases (progressive retinal atrophy and collie eye anomaly) Wiener Tierarztliche Monatsschrift 67:20-24, 1980.
1977 Anon. :
Hereditary eye abnormalities in the dog. II. Central progressive retinal atrophy Animal Health Trust and Small Animal Centre :?, 1977.
1976 Aguirre, G. :
Inherited retinal degenerations in the dog Transactions of the American Academy of Ophthalmology and Otology 81:667-676, 1976.
1975 Peiffer, R.L., Gelatt, K.N. :
Progressive retinal atrophy in two atypical breeds of dogs Veterinary Medicine and Small Animal Clinician 70:1476-1478, 1975. Pubmed reference: 1043555.
1969 Barnett, K.C., Dunn, W.L. :
The international sheep dog society and progressive retinal atrophy Journal of Small Animal Practice 10:301-307, 1969. Pubmed reference: 5816740.
1967 Roberts, S.R. :
Three inherited ocular defects in the dog Modern Veterinary Practice 48:30-34, 1967.
1965 Anon. :
Progressive retinal atrophy certification scheme Veterinary Record 77:1592-1593, 1965.
Barnett, K.C. :
Canine retinopathies. III. The other breeds Journal of Small Animal Practice 6:185-196, 1965.
Barnett, K.C. :
Canine retinopathies. II. The Miniature and Toy Poodle Journal of Small Animal Practice 6:93-109, 1965.
Barnett, K.C. :
Canine retinopathies. IV. Causes of retinal atrophy Journal of Small Animal Practice 6:229-242, 1965.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
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  • Changed by Frank Nicholas on 28 Aug 2013
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  • Changed by Frank Nicholas on 08 Jun 2017