Cone-rod dystrophy 4 | cord1 (crd4-PRA Dachshund)
Cone-rod dystrophy 4 (crd4) was first published as cord1-PRA; however, after a change in nomenclature was designated as crd4-PRA which resulted in the double name for the disease.
Current research indicates that crd4-PRA is a genetic form of PRA (progressive retinal atrophy) in which multiple genes work together in a complex process. The mutation in the RPGRIP1 gene is considered to be the major gene effect. The only other currently identified factor is a mutation in the MAP9 gene but more are believed to exist. Onset and severity of PRA vary depending on the presence/absence of these factors.
Only the mutation in the RPGRIP1 gene is currently testable by standard DNA analysis.
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According to current research, there are two main disease progression forms:
a) Early-onset form:
Some changes to the cone cells of the retina may be visible at 6 months of age. Cell degeneration progresses to the whole retina and usually leads to full blindness. The trigger is the inherited mutation in RPGRIP1 in combination with other genetic mutations. MAP9 has been identified as a contributing mutation, but it is not available as a routine test.
b) Subclinical form:
The subclinical form is characterized by a slow, gradual degeneration of the cone cells of the retina. These are "only" required for color and sharp vision; because the animal can compensate for these changes, they may remain functionally asymptomatic.The mutation in RPGRIP1 is involved but may not be solely responsible. The MAP9 gene mutation may be involved, alternative transcripts from the RPGRIP1 gene, and other, not yet identified factors.
In long-haired miniature dachshunds, the mutation in RPGRIP1 has been described as a risk factor for the occurrence of PRA in all ages. In other breeds, the occurrence of the mutation has not yet been found to have any clinical significance and is regarded as an incidental finding.
According to the current state of research, the test for the RPGRIP1 mutation does not yet predict if the dog will develop cord1/crd4-PRA.
It is undisputed that the examined mutation [RPGRIP1:c.142_143insA(29)GGAAGCAACAGGATG] can lead to cord1/crd4-PRA when other genetic factors are present (MAP9 and others not yet identified). The RPGRIP1 mutation is NOT the sole triggering cause in all cases, but matings that can result in offspring homozygous for the RPGRIP1 mutation should be avoided.
Genotype and Lab Report
Symptoms of the disease differ based on the combination of mutations (known and unknown). Dogs that have only one allele of the RPGRIP mutation are clinically healthy carriers.
N/N = genetically normal
The dog has no increased risk of developing crd4-PRA and cannot pass the variant on to its offspring.
N/rpgrip1 = carrier = heterozygous for the mutation
The dog is a clinically normal carrier and has no increased risk of developing crd4-PRA. It will pass the variant on to each offspring with a probability of 50%.
rpgrip1/rpgrip1 = homozygous for the mutation
This dog has the mutation in RPGRIP1 which is a prerequisite for developing crd4-PRA. Disease development and severity depends on the presence or absence of modifying gene mutations.
Several factors are required for the occurrence of crd4-PRA; currently only mutations in RPGRIP1 and MAP9 have been identified. A DNA test is only available for the RPGRIP1 mutation, so the results from this test has limited usage in breeding selection.
Studies to date suggest that the RPGRIP1 mutation in homozygosity (rpgrip1/rpgrip1) is necessary, but not sufficient, to cause severe symptoms of PRA.
The test for the mutation can be used to prevent matings that can produce offspring homozygous for the RPGRIP1 mutation.
Mellersh, CS., Boursnell, ME., Pettitt, L., Ryder, EJ., Holmes, NG., Grafham, D., Forman, OP., Sampson, J., Barnett, KC., Blanton, S., Binns, MM., Vaudin, M.: Canine RPGRIP1 mutation establishes cone-rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics 88:293-301, 2006. Pubmed reference: 16806805. DOI: 10.1016/j.ygeno.2006.05.004.
Miyadera, K., Kato, K., Boursnell, M., Mellersh, C.S., Sargan, D.R.: Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mamm Genome 23:212-23, 2012. Pubmed reference: 22193413. DOI: 10.1007/s00335-011-9384-9.
Further information is available at: Online Mendelian Inheritance in Animals.