OMIA 001521-9615 : Progressive retinal atrophy, CCDC66 related in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2010

Cross-species summary: This disorder was named 'Generalized PRA' in the review by Miyadera et al. (2012)

Species-specific name: Generalized PRA (gPRA), early‑onset progressive retinal atrophy

Species-specific symbol: (gPRA^SPD), gPRA, EOPRA

History: Lippman et al. (2007) mapped generalized progressive retinal atrophy (gPRA) in the Schapendoes dogs to chromosome 20 and Dekomien et al. (2010) identified a 1-bp insertion in exon 6 leading to a stop codon as the likely cause of disease in this breed.

Murgiano et al. (2020) investigated early‑onset progressive retinal atrophy (EOPRA) in Portugese water dogs, mapped EOPRA to chromosome 20 and identified a different 1 bp insertion in the CCDC66 gene associated with EOPRA.

Mapping: Lippman et al. (2007) and Dekomien et al. (2010) mapped generalized progressive retinal atrophy on in the Schapendoes breed to canine chromosome 20 via linkage analysis.

Murgiano et al. (2020): "GWAS, linkage analysis and homozygosity mapping defined a 26‑Mb candidate region in canine chromosome 20" for EOPRA in Portugese water dogs.

Molecular basis: Dekomien et al. (2010): "Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease" for generalized progressive retinal atrophy on in the Schapendoes breed.

Murgiano et al. (2020): "Whole‑genome sequencing in one affected [Portugese water] dog and its obligatory carrier parents identified a 1 bp insertion (CFA20:g.33,717,704_33,717,705insT (CanFam3.1); c.2262_c.2263insA) in CCDC66 predicted to cause a frameshift and truncation (p.Val747SerfsTer8). Screening of an extended PWD population confirmed perfect co‑segregation of this genetic variant with the disease. Western blot analysis of COS‑1 cells transfected with recombinant mutant CCDC66 expression constructs showed the mutant transcript translated into a truncated protein."

Clinical features: Lippman et al. (2007): "gPRA in Schapendoes is characterized by late onset and slow progression ... . Affected Schapendoes dogs appear normal when young, but develop gPRA at an age of onset between 2-5 years. Early in the disease, affected dogs are night-blind, lacking the ability to adjust their vision to dim light; later, their daytime vision also fails. This process of complete photoreceptor degeneration takes up to 2 years."

Murgiano et al. (2020) describe the clinical signs in Portugese water dogs: "...visual deficits, including difficulty following moving objects and walking into still objects, which were reportedly worse under dim light, consistent with nyctalopia. These signs became progressively worse, compromising the animals’ vision under both dim and well-lit conditions. The age of onset was determined by the time point at which the visual deficits became noticeable to the owners or when ophthalmoscopic abnormalities were first noted. The male proband and the two affected females had decreased vision per the owner at initial presentation and were diagnosed ophthalmoscopically as EOPRA with an age of onset at 2 years. A second male dog had no obvious visual deficit per the owner at initial presentation at age 2 years and had unremarkable fundus when examined ophthalmoscopically. However, peripapillar changes suggestive of PRA developed by 3 years of age at which time electroretinography (ERG) was recommended but declined. This dog was re-examined at 6 years of age when visual impairment was evident, ERGs were undetectable ..., and ophthalmoscopic changes were consistent with mid-stage disease. The ophthalmoscopic changes observed were common in all affected dogs, characterized by generalized tapetal hyper-reflectivity, diffuse vascular attenuation, optic disc pallor, and multifocal depigmenta-tion of the non-tapetal fundus. .... A feature that was unique to this disease in all affected dogs was a distinct peripapillary ring of hyper-reflectivity or peripapillary conus ..., which progressed into a broader zone of hyper-reflectivity around the optic disc in advanced disease ... ."

Pathology: Lippman et al. (2007): "Compared to a normal retina ..., the gPRA-affected eyes of a five year old Schapendoes displayed typical degeneration signs in peripheral and central areas ... . The outer retina with the photoreceptor layer and the outer nuclear layer was missing in all retinal parts investigated. The inner retina showed reduced inner nuclear and inner plexiform layers, whereas the ganglion cell layer appeared comparatively preserved."

Breeds: Portugese water dog, Schapendoes.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CCDC66 coiled-coil domain containing 66 Canis lupus familiaris 20 NC_051824.1 (34030861..33985924) CCDC66 Homologene, Ensembl, NCBI gene

Variants

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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.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
1274 Portugese water dog Progressive retinal atrophy, early onset CCDC66 EOPRA insertion, small (<=20) Naturally occurring variant CanFam3.1 20 g.33717704_33717705insT c.2262_c.2263insA p.(V747Sfs*8) 2020 33273526
574 Schapendoes Generalized PRA CCDC66 insertion, small (<=20) Naturally occurring variant CanFam3.1 20 g.33745452_33745453insT c.521_522insA p.(N174Kfs*2) NM_001168012.1; NP_001161484.1; genomic coordinates in accordance with HGVS 3'-rule 2010 19777273 Genomic coordinates in CanFam3.1 provided by Zoe Shmidt and Robert Kuhn.

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.
2020 Murgiano, L., Becker, D., Spector, C., Carlin, K., Santana, E., Niggel, J.K., Jagannathan, V., Leeb, T., Pearce-Kelling, S., Aguirre, G.D., Miyadera, K. :
CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs. Sci Rep 10:21162, 2020. Pubmed reference: 33273526. DOI: 10.1038/s41598-020-77980-5.
2012 Miyadera, K., Acland, G.M., Aguirre, G.D. :
Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61, 2012. Pubmed reference: 22065099. DOI: 10.1007/s00335-011-9361-3.
2010 Dekomien, G., Vollrath, C., Petrasch-Parwez, E., Boevé, M.H., Akkad, D.A., Gerding, W.M., Epplen, J.T. :
Progressive retinal atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene. Neurogenetics 11:163-74, 2010. Pubmed reference: 19777273. DOI: 10.1007/s10048-009-0223-z.
2007 Lippmann, T., Jonkisz, A., Dobosz, T., Petrasch-Parwez, E., Epplen, JT., Dekomien, G. :
Haplotype-defined linkage region for gPRA in Schapendoes dogs. Mol Vis 13:174-80, 2007. Pubmed reference: 17327822.

Edit History


  • Created by Frank Nicholas on 02 Nov 2010
  • Changed by Frank Nicholas on 28 Sep 2011
  • Changed by Frank Nicholas on 02 Dec 2011
  • Changed by Frank Nicholas on 07 Dec 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Imke Tammen2 on 11 Dec 2020