OMIA:002723-9615 : Retinal atrophy, progressive, CNGB1-related in Canis lupus familiaris (dog)
Categories: Vision / eye phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2013
Species-specific name: Information presented here was initially listed under 'OMIA:000830-9615 : Retinal atrophy, progressive'. The CNGB1-related entry was created to distinguish this retinal atrophy from other variants for which the underlying genetic cause is unknown [16/06/2023]
Inheritance: Winkler et al. (2013) reported pedigree analysis results consistent with autosomal recessive inheritance in the Papillon breed.
Molecular basis: 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.
Have human generated variants been created, e.g. through genetic engineering and gene editing
Clinical features: As reported by Ahonen et al. (2013) "Papillon breed is affected with an autosomal recessive late onset PRA with a mean onset at 5.6 years of age [Hakanson and Narfstrom, 1995]. ... affected dogs have a primary loss of the rod photoreceptor cells, followed by loss of cone cell function [Narfstrom and Ekesten, 1998], [Narfstrom and Wrigstad,1999]. The first clinical signs are seen as difficulties in the dim light. The disease progress very slowly and the affected dogs seem to be visually normal throughout their life, as the cone function is fairly well preserved [Narfstrom and Ekesten, 1998], [Narfstrom and Wrigstad,1999]. The ophthalmoscopical signs include increased tapetal reflectivity and retinal vascular attenuation followed by pigment migration in the non-tapetal fundus [Hakanson and Narfstrom, 1995]."
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."
Control: Petersen-Jones et al. (2019) reported "that gene therapy to introduce a normal copy of canine Cngb1a into the rod photoreceptors results in robust, sustained restoration of rod function and retinal structural preservation in Cngb1–/– dogs and represents what we believe to be an important preclinical step toward gene augmentation therapy for human RP45".
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|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|
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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|
|918||Papillon Phalène||Progressive retinal atrophy||CNGB1||delins, small (<=20)||Naturally occurring variant||CanFam3.1||2||g.58622673_58622675delinsCTAGCTAC||c.2387_2389delinsCTAGCTAC||p.(Y796Sfs*7)||NM_001284462.1; NP_001271391.1; published as c.2685delA2687_2688insTAGCTA and p.(Y889Sfs*5); coordinates in the table have been updated to a recent reference genome and / or transcript and updated to HGVS recommendations||rs1152388403||2013||24015210|
Cite this entry
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.
|2023||Occelli, L.M., Zobel, L., Stoddard, J., Wagner, J., Pasmanter, N., Querubin, J., Renner, L.M., Reynaga, R., Winkler, P.A., Sun, K., Felipe Lp Marinho, L., O'Riordan, C.R., Frederick, A., Lauer, A., Tsang, S.H., Hauswirth, W.W., McGill, T.J., Neuringer, M., Michalakis, S., Petersen-Jones, S.M. :|
|Development of a translatable gene augmentation therapy for CNGB1-Retinitis Pigmentosa. Mol Ther , 2023. Pubmed reference: 37056049. DOI: 10.1016/j.ymthe.2023.04.005.|
|2018||Petersen-Jones, S.M., Occelli, L.M., Winkler, P.A., Lee, W., Sparrow, J.R., Tsukikawa, M., Boye, S.L., Chiodo, V., Capasso, J.E., Becirovic, E., Schön, C., Seeliger, M.W., Levin, A.V., Michalakis, S., Hauswirth, W.W., Tsang, S.H. :|
|Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach. J Clin Invest 128:190-206, 2018. Pubmed reference: 29202463. DOI: 10.1172/JCI95161.|
|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.|
|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.|
|1995||Håkanson, N., Narfström, K. :|
|Progressive retinal atrophy in papillon dogs in Sweden: A clinical survey. Vet Comp Ophthalmol 5:83-87, 1995.|
- Created by Imke Tammen2 on 16 Jun 2023