In other species: domestic cat , sheep

Categories: Vision / eye phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 613767 (trait) , 600724 (gene)

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

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.

Species-specific description: Many different forms of progressive retinal atrophy (PRA) exist and more than 10 different genes have been identified so far in dogs to have likely causal variants for PRA. Please review OMIA for other variants.

This OMIA entry will focus on PRA due the variants in the CNGB1 gene but also lists references to other forms of PRA.

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.

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: Papillon, Phalène.

Associated gene: