Test Detail
crd4-PRA / PRA-MAP9 (multi-breed)
Ocular · Dog
RPGRIP1-CRD retinal degeneration (historically cord1 and registered in OMIA as cone-rod dystrophy 4, crd4) is a progressive retinal atrophy with onset in the puppy caused by the 44 bp insertion in RPGRIP1. The ~22 kb deletion in MAP9 behaves as an oligogenic modifier: it accelerates and aggravates the degeneration of cones and rods when it coexists with the RPGRIP1 variant. Homozygosity for MAP9 alone is not associated with a clinically relevant phenotype. Penetrance and severity depend on the set of variants (RPGRIP1, MAP9 and other modifier loci).
Incidence
Donner and Mellersh (2024) genotyped both variants in at least 50 dogs from 132 breeds: each variant is frequent in subsets of breeds that barely overlap, and both exceed a frequency of 0.05 only in the Miniature Long-haired Dachshund. Prevalences must not be extrapolated between breeds: limited data.
Breeder management
- Test breeding animals before mating, without interpreting the MAP9 result in isolation.\n- Avoid mating two dogs carrying the RPGRIP1 variant; remember that MAP9 modifies severity.\n- A carrier can be mated with a clear dog; test the offspring intended for breeding.\n- Because of incomplete penetrance, do not discard animals based only on the MAP9 genotype.\n- Combine the genetic data with periodic ophthalmological examination.
Specialist notes
MAP9 is a modifier, not the single causal mutation of PRA: a dog homozygous positive for MAP9 is not equivalent to being blind, and an animal clear for MAP9 does not exclude other forms of PRA. Interpretation must integrate the RPGRIP1 genotype (cord1/crd4) and, if possible, the L3 modifiers, together with serial ophthalmology. In breeds with another known PRA, test for that variant as well.
References
1. Mellersh CS, Binns MM, Pettitt L, et al. Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics. 2006;88(3):293-301. PMID: 16806805.
2. Miyadera K, Kato K, Boursnell M, et al. Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mamm Genome. 2012;23(1-2):212-223. PMID: 22193413.
3. Forman OP, Hitti RJ, Pettitt L, et al. Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration. Mamm Genome. 2016;27(5-6):237-245. PMID: 27017229.
4. Das RG, Becker D, Jagannathan V, et al. Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology. Sci Rep. 2017;7(1):12823. PMID: 28993665.
5. Ripolles-Garcia A, Mellema MS, et al. Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci. Hum Mol Genet. 2023;32(15):2453-2465. PMID: 36951959.
6. Donner J, Mellersh C. Frequency of RPGRIP1 and MAP9 genetic modifiers of canine progressive retinal atrophy, in 132 breeds of dog. Anim Genet. 2024;55(4):559-568. PMID: 38752391.
7. OMIA:001432-9615. Retinal atrophy - Cone-rod dystrophy 4 in Canis lupus familiaris. https://omia.org/OMIA001432/9615/
2. Miyadera K, Kato K, Boursnell M, et al. Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mamm Genome. 2012;23(1-2):212-223. PMID: 22193413.
3. Forman OP, Hitti RJ, Pettitt L, et al. Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration. Mamm Genome. 2016;27(5-6):237-245. PMID: 27017229.
4. Das RG, Becker D, Jagannathan V, et al. Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology. Sci Rep. 2017;7(1):12823. PMID: 28993665.
5. Ripolles-Garcia A, Mellema MS, et al. Natural disease history of a canine model of oligogenic RPGRIP1-cone-rod dystrophy establishes variable effects of previously and newly mapped modifier loci. Hum Mol Genet. 2023;32(15):2453-2465. PMID: 36951959.
6. Donner J, Mellersh C. Frequency of RPGRIP1 and MAP9 genetic modifiers of canine progressive retinal atrophy, in 132 breeds of dog. Anim Genet. 2024;55(4):559-568. PMID: 38752391.
7. OMIA:001432-9615. Retinal atrophy - Cone-rod dystrophy 4 in Canis lupus familiaris. https://omia.org/OMIA001432/9615/